Oral contraceptives and stroke: Foes or friends.

Incidents of strokes are increased in young women relative to young men, suggesting that oral contraceptive (OC) use is one of the causes of stroke among young women. Long-term exposures to the varying combinations of estrogen and progestogen found in OCs affect blood clotting, lipid and lipoprotein metabolism, endothelial function, and de novo synthesis of neurosteroids, especially brain-derived 17ß-estradiol. The latter is essential for neuroprotection, memory, sexual differentiation, synaptic transmission, and behavior. Deleterious effects of OCs may be exacerbated due to comorbidities like polycystic ovary syndrome, sickle cell anemia, COVID-19, exposures to endocrine disrupting chemicals, and conventional or electronic cigarette smoking. The goal of the current review is to revisit the available literature regarding the impact of OC use on stroke, to explain possible underlying mechanisms, and to identify gaps in our understanding to promote future research to reduce and cure stroke in OC users.

Xenoestrogens impact brain estrogen receptor signaling during the female lifespan: A precursor to neurological disease?

Xenoestrogens, foreign synthetic chemicals mimicking estrogens, are lurking in our surroundings. Climate change may alter their toxicity and bioavailability. Since xenoestrogens have extremely high lipid solubility and are structurally similar to natural endogenous estrogens, they can bind to estrogen receptors (ERs) -alpha (ER-α) and -beta (ER-ß). Scientific evidence accumulated over the past decades have suggested that natural 17ß-estradiol (E2; a potent estrogen), via activation of its receptors, plays a pivotal role in regulation of brain development, differentiation, metabolism, synaptic plasticity, neuroprotection, cognition, anxiety, body temperature, feeding and sexual behavior. In the brain, ER-ß is predominantly expressed in the various regions, including cerebral cortex and hippocampus, that have been shown to play a key role in cognition. Therefore, disturbances in function of ER-ß mediated E2 signaling by xenoestrogens can lead to deleterious effects that potentiate a variety of neurological diseases starting from prenatal to post-menopause in women. The goal of this review is to identify the possible neurological effects of xenoestrogens that can alter estrogen receptor-mediated signaling in the brain during different stages of the female lifespan.

Neuroleptic malignant syndrome as a presenting feature of subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a slowly progressive degenerative disorder caused by measles virus. It is characterised by typical clinical and electrophysiological features in the form of slow myoclonic jerks, with progressive cognitive impairment, visual symptoms, and periodic complexes on EEG, with raised titres of anti-measles antibodies in CSF and serum. Atypical presentations of SSPE have been reported including brainstem involvement, ADEM-like presentation, acute encephalitis, and cerebellar ataxia. Presentation with predominant extrapyramidal features is uncommon. We describe a case of SSPE presenting with extensive rigidity with highly elevated CPK values, mimicking neuroleptic malignant syndrome (NMS) which was most probably due to central dopaminergic blockade induced by the disease process. To our knowledge, this is the first case of SSPE presenting with a NMS-like syndrome.

Impact of technological advances in treatment planning, image guidance, and treatment delivery on target margin design for prostate cancer radiotherapy: an updated review.

Recent innovations in image guidance, treatment delivery, and adaptive radiotherapy (RT) have created a new paradigm for planning target volume (PTV) margin design for patients with prostate cancer. We performed a review of the recent literature on PTV margin selection and design for intact prostate RT, excluding post-operative RT, brachytherapy, and proton therapy. Our review describes the increased focus on prostate and seminal vesicles as heterogenous deforming structures with further emergence of intra-prostatic GTV boost and concurrent pelvic lymph node treatment. To capture recent innovations, we highlight the evolution in cone beam CT guidance, and increasing use of MRI for improved target delineation and image registration and supporting online adaptive RT. Moreover, we summarize new and evolving image-guidance treatment platforms as well as recent reports of novel immobilization strategies and motion tracking. Our report also captures recent implementations of artificial intelligence to support image guidance and adaptive RT. To characterize the clinical impact of PTV margin changes via model-based risk estimates and clinical trials, we highlight recent high impact reports. Our report focusses on topics in the context of PTV margins but also showcase studies attempting to move beyond the PTV margin recipes with robust optimization and probabilistic planning approaches. Although guidelines exist for target margins conventional using CT-based image guidance, further validation is required to understand the optimal margins for online adaptation either alone or combined with real-time motion compensation to minimize systematic and random uncertainties in the treatment of patients with prostate cancer.

Impact of anti-CD25 monoclonal antibody on dendritic cell-tumor fusion vaccine efficacy in a murine melanoma model.

BACKGROUND: A promising cancer vaccine involves the fusion of tumor cells with dendritic cells (DCs). As such, a broad spectrum of both known and unidentified tumor antigens is presented to the immune system in the context of the potent immunostimulatory capacity of DCs. Murine studies have demonstrated the efficacy of fusion immunotherapy. However the clinical impact of DC/tumor fusion vaccines has been limited, suggesting that the immunosuppresive milieu found in patients with malignancies may blunt the efficacy of cancer vaccination. Thus, novel strategies to enhance fusion vaccine efficacy are needed. Regulatory T cells (Tregs) are known to suppress anti-tumor immunity, and depletion or functional inactivation of these cells improves immunotherapy in both animal models and clinical trials. In this study, we sought to investigate whether functional inactivation of CD4+CD25+FoxP3+ Treg with anti-CD25 monoclonal antibody (mAb) PC61 prior to DC/tumor vaccination would significantly improve immunotherapy in the murine B16 melanoma model. METHODS: Treg blockade was achieved with systemic PC61 administration. This blockage was done in conjunction with DC/tumor fusion vaccine administration to treat established melanoma pulmonary metastases. Enumeration of these metastases was performed and compared between experimental groups using Wilcoxon Rank Sum Test. IFN-gamma ELISPOT assay was performed on splenocytes from treated mice. RESULTS: We demonstrate that treatment of mice with established disease using mAb PC61 and DC/tumor fusion significantly reduced counts of pulmonary metastases compared to treatment with PC61 alone (p=0.002) or treatment with control antibody plus fusion vaccine (p=0.0397). Furthermore, IFN-gamma ELISPOT analyses reveal that the increase in cancer immunity was mediated by anti-tumor specific CD4+ T-helper cells, without concomitant induction of CD8+ cytotoxic T cells. Lastly, our data provide proof of principle that combination treatment with mAb PC61 and systemic IL-12 can lower the dose of IL-12 necessary to obtain maximal therapeutic efficacy. CONCLUSIONS: To our knowledge, this is the first report investigating the effects of anti-CD25 mAb administration on DC/tumor-fusion vaccine efficacy in a murine melanoma model, and our results may aide the design of future clinical trials with enhanced therapeutic impact.

Recent advances in artificial intelligence applications for supportive and palliative care in cancer patients.

PURPOSE OF REVIEW: Artificial intelligence (AI) is a transformative technology that has the potential to improve and augment the clinical workflow in supportive and palliative care (SPC). The objective of this study was to provide an overview of the recent studies applying AI to SPC in cancer patients. RECENT FINDINGS: Between 2020 and 2022, 29 relevant studies were identified and categorized into two applications: predictive modeling and text screening. Predictive modeling uses machine learning and/or deep learning algorithms to make predictions regarding clinical outcomes. Most studies focused on predicting short-term mortality risk or survival within 6 months, while others used models to predict complications in patients receiving treatment and forecast the need for SPC services. Text screening typically uses natural language processing (NLP) to identify specific keywords, phrases, or documents from patient notes. Various applications of NLP were found, including the classification of symptom severity, identifying patients without documentation related to advance care planning, and monitoring online support group chat data. SUMMARY: This literature review indicates that AI tools can be used to support SPC clinicians in decision-making and reduce manual workload, leading to potentially improved care and outcomes for cancer patients. Emerging data from prospective studies supports the clinical benefit of these tools; however, more rigorous clinical validation is required before AI is routinely adopted in the SPC clinical workflow.

Emerging technologies in adipose tissue research.

Technologies are transforming the understanding of adipose tissue as a complex and dynamic tissue that plays a critical role in energy homoeostasis and metabolic health. This mini-review provides a brief overview of the potential impact of novel technologies in biomedical research and aims to identify areas where these technologies can make the most significant contribution to adipose tissue research. It discusses the impact of cutting-edge technologies such as single-cell sequencing, multi-omics analyses, spatial transcriptomics, live imaging, 3D tissue engineering, microbiome analysis, in vivo imaging, and artificial intelligence/machine learning. As these technologies continue to evolve, we can expect them to play an increasingly important role in advancing our understanding of adipose tissue and improving the treatment of related diseases.

The Microbiome in the Obesity-Breast Cancer Axis: Diagnostic and Therapeutic Potential.

A growing body of evidence has demonstrated a relationship between the microbiome, adiposity, and cancer development. The microbiome is emerging as an important factor in metabolic disease and cancer pathogenesis. This review aimed to highlight the role of the microbiome in obesity and its association with cancer, with a particular focus on breast cancer. This review discusses how microbiota dysbiosis may contribute to obesity and obesity-related diseases, which are linked to breast cancer. It also explores the potential of the gut microbiome to influence systemic immunity, leading to carcinogenesis via the modulation of immune function. This review underscores the potential use of the microbiome profile as a diagnostic tool and treatment target, with strategies including probiotics, fecal microbiota transplantation, and dietary interventions. However, this emphasizes the need for more research to fully understand the complex relationship between the microbiome, metabolic disorders, and breast cancer. Future studies should focus on elucidating the mechanisms underlying the impact of the microbiome on breast cancer and exploring the potential of the microbiota profile as a biomarker and treatment target.

The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.

Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.

Post-stroke periodic estrogen receptor-beta agonist improves cognition in aged female rats.

Women have a higher risk of having an ischemic stroke and increased cognitive decline after stroke as compared to men. The female sex hormone 17ß-estradiol (E2) is a potent neuro- and cognitive-protective agent. Periodic E2 or estrogen receptor subtype-beta (ER-ß) agonist pre-treatments every 48 h before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study aims to investigate the efficacy of post-stroke ER-ß agonist treatments in reducing ischemic brain damage and cognitive deficits in RS female rats. Retired breeder (9-10 months) Sprague-Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min and treated with either ER-ß agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 h after induction of tMCAO. Subsequently, rats were treated with either ER-ß agonist or DMSO vehicle every 48 h for ten injections. Forty-eight hours after the last treatment, animals were tested for contextual fear conditioning to measure post-stroke cognitive outcome. Neurobehavioral testing, infarct volume quantification, and hippocampal neuronal survival were employed to determine severity of stroke. Periodic post-stroke ER-ß agonist treatment reduced infarct volume, improved recovery of cognitive capacity by increasing freezing in contextual fear conditioning, and decreased hippocampal neuronal death in RS female rats. These data suggest that periodic post-stroke ER-ß agonist treatment to reduce stroke severity and improve post-stroke cognitive outcome in menopausal women has potential for future clinical investigation.

Multilaboratory particle image velocimetry analysis of the FDA benchmark nozzle model to support validation of computational fluid dynamics simulations.

This study is part of a FDA-sponsored project to evaluate the use and limitations of computational fluid dynamics (CFD) in assessing blood flow parameters related to medical device safety. In an interlaboratory study, fluid velocities and pressures were measured in a nozzle model to provide experimental validation for a companion round-robin CFD study. The simple benchmark nozzle model, which mimicked the flow fields in several medical devices, consisted of a gradual flow constriction, a narrow throat region, and a sudden expansion region where a fluid jet exited the center of the nozzle with recirculation zones near the model walls. Measurements of mean velocity and turbulent flow quantities were made in the benchmark device at three independent laboratories using particle image velocimetry (PIV). Flow measurements were performed over a range of nozzle throat Reynolds numbers (Re(throat)) from 500 to 6500, covering the laminar, transitional, and turbulent flow regimes. A standard operating procedure was developed for performing experiments under controlled temperature and flow conditions and for minimizing systematic errors during PIV image acquisition and processing. For laminar (Re(throat)=500) and turbulent flow conditions (Re(throat)≥3500), the velocities measured by the three laboratories were similar with an interlaboratory uncertainty of ∼10% at most of the locations. However, for the transitional flow case (Re(throat)=2000), the uncertainty in the size and the velocity of the jet at the nozzle exit increased to ∼60% and was very sensitive to the flow conditions. An error analysis showed that by minimizing the variability in the experimental parameters such as flow rate and fluid viscosity to less than 5% and by matching the inlet turbulence level between the laboratories, the uncertainties in the velocities of the transitional flow case could be reduced to ∼15%. The experimental procedure and flow results from this interlaboratory study (available at http://fdacfd.nci.nih.gov) will be useful in validating CFD simulations of the benchmark nozzle model and in performing PIV studies on other medical device models.

Successful rescue treatment of right posterior inferior cerebellar artery (PICA) vascular stasis with tirofiban following endovascular coil implantation.

This report describes a patient who developed intraprocedural vascular stasis immediately following elective endovascular coil emboliation. Urgent antiplatelet treatment with the GpIIb/IIIa agent tirofiban was used. It was infused intra-arterially during the procedure, followed by a fixed rate intravenous continuous infusion, and successfully restored normal circulation. There were no reports of further bleeding or haemodynamic compromise during the hospital stay. The patient's condition returned to baseline and he was discharged the following day with no neurological deficits.

Memantine Usage for Management of Korsakoff Syndrome in the Setting of Chronic Alcohol Use and Unspecified Eating Disorder.

Korsakoff syndrome is a neuropsychiatric condition frequently seen as a progression of Wernicke's encephalopathy and is often associated with long-term alcohol abuse. It is characterized by further cognitive impairments, such as indiscriminate anterograde and retrograde amnesia, in addition to executive function deficits. As the syndrome is a result of severe thiamine deficiency, its management primarily focuses on nutritional replenishment and electrolyte maintenance. In recent years, a few published reports have detailed the off-label use of Food and Drug Administration (FDA) approved drugs for Alzheimer's in an attempt to treat neurocognitive deficits associated with Korsakoff patients. In this particular case, we note subjective improvement in cognition after initiating memantine, an N-Methyl-d-aspartate (NMDA) receptor antagonist.

Pheochromocytoma Presenting as Testicular Pain: An Unusual Case Report.

Pheochromocytoma (PCC) is a rare catecholamine-secreting tumor that arises from chromaffin cells of the adrenal medulla which are derived from the neural crest. This report illustrates a 51-year-old Caucasian male with a history of hypertension diagnosed two years ago who presented to the hospital due to acute onset of right testicular pain of 3-day duration. Laboratory results and imaging revealed a presumptive diagnosis of PCC. The patient had undergone robot-assisted laparoscopic right adrenalectomy 14 days after being diagnosed with PCC due to perioperative management with phenoxybenzamine. The final pathology report revealed a PCC. At follow-up two weeks after discharge, the patient reported complete resolution of his testicular pain.

Case Report: Glaucoma in an Infant With Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness that occurs due to incomplete development of retinal blood vessels in preterm infants. Glaucoma is an ocular comorbidity in some patients with ROP, and it may be associated with immature anterior chamber development, ROP itself, or the treatment for ROP. There have been a few reports of narrow-angle glaucoma after laser treatment for ROP. In this case report, we describe the course of a female infant born at 24 weeks and 5 days of gestational age with treatment-requiring ROP treated with laser photocoagulation who subsequently developed very elevated intraocular pressure and shallow anterior chambers without pupillary block. The patient required bilateral ab externo trabeculotomy for elevated intraocular pressure, which normalized after the procedure. The patient has remained stable at the last follow-up at 51 weeks postmenstrual age. Differing from previous glaucoma presentations in this setting, we illustrate a case of elevated intraocular pressure and anterior chamber narrowing after laser therapy without pupillary block or synechiae. The possible multifactorial etiology of glaucoma in this patient, including incomplete angle development, ischemia, and laser treatment, highlight the need for glaucoma screening in patients with ROP, both in the short and long term.

Corpus callosum deficits in antipsychotic-naïve schizophrenia: evidence for neurodevelopmental pathogenesis.

The corpus callosum (CC), the largest inter-hemispheric tract connecting the association cortices, has been shown to be affected in disorders with aberrant neurodevelopment. Previous studies that investigated CC abnormalities in schizophrenia have reported mixed findings potentially due to various confounding factors. In this study, we used magnetic resonance imaging to examine a large sample of antipsychotic-naïve schizophrenia patients (n=66) in comparison with age-, sex-, and handedness-matched (as a group) healthy comparison subjects (n=46). Mid-sagittal areas of CC sub-regions--namely, the genu, body, isthmus and splenium--were measured based on Witelson's method with good inter- and intra-rater reliability. The genu and body of the CC were significantly smaller in schizophrenia patients in comparison to healthy subjects after controlling for the potential confounding effects of age, sex and intracranial area. In male schizophrenia patients, there was a significant positive correlation between the age at onset of psychosis and the area of the genu. Together, these findings suggest neurodevelopmentally mediated hypoconnectivity in schizophrenia.

Hyperammonemic Encephalopathy: A Complication of Gastric Bypass Surgery.

Hyperammonemia is a metabolic abnormality characterized by elevated levels of ammonia in the blood. This case report illustrates a 72-year-old Caucasian female with a history of prior gastric bypass surgery done 15 years ago, who was admitted multiple times for acute encephalopathy over the course of a few months. The patient was found to have a gastro-gastric fistula seen on a CT scan of the abdomen, which was the culprit of her acute encephalopathy. The patient underwent fistula closure via esophagogastroduodenoscopy.

Lateral Pinning of the Pediatric Phalangeal Neck Fracture.

Closed reduction and percutaneous pinning is the treatment of choice for displaced pediatric phalangeal neck fractures. Multiple techniques have been described to address challenges in managing these unstable fractures. We describe our technique of closed reduction and percutaneous pinning, which avoids the physis and increases the wire insertion accuracy, minimizing the number of attempts and wire passes made at percutaneous pinning.

Validation of a CFD methodology for positive displacement LVAD analysis using PIV data.

Computational fluid dynamics (CFD) is used to asses the hydrodynamic performance of a positive displacement left ventricular assist device. The computational model uses implicit large eddy simulation direct resolution of the chamber compression and modeled valve closure to reproduce the in vitro results. The computations are validated through comparisons with experimental particle image velocimetry (PIV) data. Qualitative comparisons of flow patterns, velocity fields, and wall-shear rates demonstrate a high level of agreement between the computations and experiments. Quantitatively, the PIV and CFD show similar probed velocity histories, closely matching jet velocities and comparable wall-strain rates. Overall, it has been shown that CFD can provide detailed flow field and wall-strain rate data, which is important in evaluating blood pump performance.

Vitreoretinal lymphoma, secondary to non-CNS systemic lymphoma, masquerading as an infectious retinitis.

PURPOSE: To report an atypical case of vitreoretinal lymphoma, secondary to non-central nervous system (non-CNS) systemic lymphoma, masquerading as an infectious retinitis. OBSERVATIONS: A 76-year-old female with a history of cecal diffuse large B-cell lymphoma with two prior occurrences of posterior segment ocular involvement presented with a complaint of blurry vision in the right eye. Exam findings were significant for large areas of retinal whitening and retinal hemorrhages in the absence of choroidal lesions or significant vitritis. The clinical suspicion of an infectious retinitis, was supported by a presumptive immunosuppressive state secondary to her recent treatment (within 1 month) with both intravitreal and systemic rituximab plus high-dose methotrexate. Aggressive treatment with intravitreal and systemic antivirals and antibiotics was initiated. However, polymerase chain reaction (PCR) testing of aqueous fluid was negative for cytomegalovirus (CMV), herpes simplex virus, herpes zoster virus and toxoplasma, and her condition continued to worsen, so suspicion was raised for a masquerading recurrent malignancy. She was treated empirically with serial intravitreal injections of methotrexate and showed dramatic clinical improvement. A subsequent relapse occurred that responded rapidly to intravitreal methotrexate in the absence of antiviral/antibiotics. CONCLUSION: It is important for clinicians to be aware of atypical presentations of vitreoretinal lymphoma. This case emphasizes the fact that secondary ocular lymphoma after systemic lymphoma can have a vitreoretinal presentation rather than the more common choroidal involvement. Furthermore, it shows that recurrences of this disease in the same patient can have very different manifestations, including an appearance indistinguishable from a viral retinitis.