Immunotherapy combined with high- and low-dose radiation to all sites leads to complete clearance of disease in a patient with metastatic vaginal melanoma.

A 73-year-old woman with metastatic vaginal mucosal melanoma that had progressed on ipilimumab and nivolumab experienced clinical and radiographic complete response to dual checkpoint inhibitor immunotherapy given in combination with high-dose plus low-dose radiation. General characteristics and treatment options in this disease are highlighted.

Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.

The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI.

Acute tryptophan depletion promotes an anterior-to-posterior fMRI activation shift during task switching in older adults.

Studies have long reported that aging is associated with declines in several functions modulated by the prefrontal cortex, including executive functions like working memory, set shifting, and inhibitory control. The neurochemical basis to this is poorly understood, but may include the serotonergic system. We investigated the modulatory effect of serotonin using acute tryptophan depletion (ATD) during a cognitive switching task involving visual-spatial set shifting modified for a functional MRI environment. Ten healthy women over 55 years were tested on two separate occasions in this within-group double-blind sham-controlled crossover study to compare behavioral and physiological brain functioning following ATD and following a ("placebo") sham depletion condition. ATD did not significantly affect task performance. It did modulate brain functional recruitment. During sham depletion women significantly activated the expected task-relevant brain regions associated with the Switch task including prefrontal and anterior cingulate cortices. In contrast, following ATD participants activated posterior regions of brain more during switch than repeat trials. In addition to the main effects of depletion condition, a comparison of the ATD relative to the sham condition confirmed this anterior-to-posterior shift in activation. The posterior (increased) activation clusters significantly and negatively correlated with the reduced prefrontal activation clusters suggesting a compensation mechanism for reduced prefrontal activation during ATD. Thus, serotonin modulates an anterior-to-posterior shift of activation during cognitive switching in older adults. Neural adaptation to serotonin challenge during cognitive control may prove useful in determining cognitive vulnerability in older adults with a predisposition for serontonergic down-regulation (e.g., in vascular or late life depression).

A comparison of psychosocial health in North American and Chinese Canadian cardiac outpatients, and ethnocultural correlates of quality of life.

OBJECTIVES: To: 1) compare sociodemographic, clinical and psychosocial characteristics of Chinese Canadian and North American cardiac outpatients, 2) describe the ethnocultural characteristics of Chinese Canadian cardiac outpatients, and 3) investigate ethnocultural correlates of quality of life among Chinese Canadian cardiac outpatients. DESIGN: Cross-sectional. SETTING: 11 hospitals and two outpatient clinics of a Chinese Canadian cardiologist in Ontario, Canada. PARTICIPANTS: 1404 (n = 96; 6.8% Chinese Canadian) cardiac outpatients. MAIN OUTCOMES MEASURES: Participants completed a survey assessing sociodemographic, ethnocultural and psychosocial characteristics. Quality of life was assessed with the MacNew instrument, which was translated to traditional Chinese character. RESULTS: Chinese Canadian cardiac outpatients were of significantly lower socioeconomic status, and were less likely to be working, had lower activity status, body mass index, were less likely to smoke, had better left ventricular function, and were less likely to have undergone bypass surgery than their North American counterparts. Chinese Canadians reported significantly lower quality of life and social support than North Americans. Of the Chinese Canadian participants, 13 (26.5%) felt they needed an interpreter during a cardiac medical visit but did not receive this service. Correlates of greater quality of life in Chinese Canadian cardiac outpatients were greater proficiency in both English and Chinese languages, as well as perceived ability to communicate with Canadians, to fit into social situations, and understand English jokes. CONCLUSION: Some characteristics of Chinese Canadian cardiac outpatients may put their health at a disadvantage when compared to their North American counterparts, however some protective factors were also observed. Language proficiency was a key correlate of quality of life.

The lethal and sublethal impacts of two tire rubber-derived chemicals on brook trout (Salvelinus fontinalis) fry and fingerlings.

Recent toxicity studies of stormwater runoff implicated N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) as the contaminant responsible for the mass mortality of coho salmon (Oncorhynchus kisutch). In the wake of this discovery, 6PPD-quinone has been measured in waterways around urban centers, along with other tire wear leachates like hexamethoxymethylmelamine (HMMM). The limited data available for 6PPD-quinone have shown toxicity can vary depending on the species. In this study we compared the acute toxicity of 6PPD-quinone and HMMM to Brook trout (Salvelinus fontinalis) fry and fingerlings. Our results show that fry are ∼3 times more sensitive to 6PPD-quinone than fingerlings. Exposure to HMMM ≤6.6 mg/L had no impact on fry survival. These results highlight the importance of conducting toxicity tests on multiple life stages of fish species, and that relying on fingerling life stages for species-based risk assessment may underestimate the impacts of exposure. 6PPD-quinone also had many sublethal effects on Brook trout fingerlings, such as increased interlamellar cell mass (ILCM) size, hematocrit, blood glucose, total CO2, and decreased blood sodium and chloride concentrations. Linear relationships between ILCM size and select blood parameters support the conclusion that 6PPD-quinone toxicity is an outcome of osmorespiratory challenges imposed by gill impairment.

Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance.

Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease and is now considered to be the hepatic manifestation of the metabolic syndrome. However, the role of steatosis per se and the precise factors required in the progression to steatohepatitis or insulin resistance remain elusive. The JAK-STAT pathway is critical in mediating signaling of a wide variety of cytokines and growth factors. Mice with hepatocyte-specific deletion of Janus kinase 2 (L-JAK2 KO mice) develop spontaneous steatosis as early as 2 weeks of age. In this study, we investigated the metabolic consequences of jak2 deletion in response to diet-induced metabolic stress. To our surprise, despite the profound hepatosteatosis, deletion of hepatic jak2 did not sensitize the liver to accelerated inflammatory injury on a prolonged high fat diet (HFD). This was accompanied by complete protection against HFD-induced whole-body insulin resistance and glucose intolerance. Improved glucose-stimulated insulin secretion and an increase in ß-cell mass were also present in these mice. Moreover, L-JAK2 KO mice had progressively reduced adiposity in association with blunted hepatic growth hormone signaling. These mice also exhibited increased resting energy expenditure on both chow and high fat diet. In conclusion, our findings indicate a key role of hepatic JAK2 in metabolism such that its absence completely arrests steatohepatitis development and confers protection against diet-induced systemic insulin resistance and glucose intolerance.

Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on ß-cell function and insulin sensitivity.

Dietary protein restriction during pregnancy and lactation in rats impairs ß-cell function and mass in neonates and leads to glucose intolerance in adult offspring. Maternal taurine (Tau) supplementation during pregnancy in rats restores ß-cell function and mass in neonates, but its long-term effects are unclear. The prevention of postnatal catch-up growth has been suggested to improve glucose tolerance in adult offspring of low-protein (LP)-fed mothers. The objective of this study was to examine the relative contribution of ß-cell dysfunction and insulin resistance to impaired glucose tolerance in 130-day-old rat offspring of LP-fed mothers and the effects of maternal Tau supplementation on ß-cell function and insulin resistance in these offspring. Pregnant rats were fed i) control, ii) LP, and iii) LP+Tau diets during gestation and lactation. Offspring were given a control diet following weaning. A fourth group consisting of offspring of LP-fed mothers, maintained on a LP diet following weaning, was also studied (LP-all life). Insulin sensitivity in the offspring of LP-fed mothers was reduced in females but not in males. In both genders, LP exposure decreased ß-cell function. Tau supplementation improved insulin sensitivity in females and ß-cell function in males. The LP-all life diet improved ß-cell function in males. We conclude that i) maternal Tau supplementation has persistent effects on improving glucose metabolism (ß-cell function and insulin sensitivity) in adult rat offspring of LP-fed mothers and ii) increasing the amount of protein in the diet of offspring adapted to a LP diet after weaning may impair glucose metabolism (ß-cell function) in a gender-specific manner.

Mapping glioma heterogeneity using multiparametric 18 F-choline PET/MRI in childhood and teenage-young adults.

OBJECTIVE: The heterogeneity of post-treatment imaging remains a significant challenge in children and teenagers/young adults (TYA) diagnosed with glioma. The aim of this study was to evaluate the utility of 18 F-choline PET/MRI in determining intratumoural heterogeneity in paediatric and TYA gliomas. METHODS: Twenty-six patients (mean age 16 years, range 8-22 years) with suspected glioma disease progression were evaluated with 18 F-choline PET/MRI. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUV max ) in enhancing (enh) and non-enhancing (ne) tumour volumes and normal-appearing white matter (wm) were calculated (rCBV enh , rCBV ne , rCBV wm , ADC enh , ADC ne , ADC wm , SUV enh , SUV ne and SUV wm ). RESULTS: Significantly higher SUV enh and SUV ne compared with SUV wm were observed [SUV enh 0.89 (0.23-1.90), SUV ne 0.36 (0.16-0.78) versus SUV wm 0.15 (0.04-1.19); P < 0.001 and P = 0.004, respectively]. Equivalent results were observed for ADV and rCBV (ADC enh , ADC ne : P < 0.001 versus ADC wm ; rCBV enh , rCBV ne : P < 0.001 versus rCBV wm ). The highest values for mean SUV max [0.89 (0.23-1.90)] and mean rCBV [2.1 (0.74-5.08)] were in the enhancing component, while the highest values for ADC [1780 mm 2 /s (863-2811)] were in the necrotic component. CONCLUSION: 18 F-choline PET/MRI is able map imaging heterogeneity in paediatric and TYA gliomas, detecting post-treatment enhancing, non-enhancing, and necrotic tumour components equivalent to ADC and DSC-derived rCBV. This offers potential in the response assessment of diffuse non-enhancing gliomas and in selected cases such as posterior fossa tumours where quantitative MRI is technically difficult.

Low recognition of attention deficit hyperactivity disorder in adult patients admitted to the Epilepsy Monitoring Unit.

INTRODUCTION: Adult patients with epilepsy (PWE) have an 18% prevalence of comorbid attention deficit hyperactivity disorder (ADHD) compared to a prevalence of 2%-5% in the general population. Recognition of this dual diagnosis is important since stimulant therapy is both safe and effective in this population. METHODS: Here, we aim to determine if PWE have adequate documentation for comorbid ADHD when being admitted to the Epilepsy Monitoring Unit (EMU). A retrospective review was conducted at the Baylor St. Luke's Medical Center EMU for patients presenting between July 2017 and November 2020. Patients were divided into two groups: Group I-patients without a documented ADHD diagnosis or ADHD medications and Group II-patients with a documented ADHD diagnosis and/or taking medications indicated specifically for ADHD. RESULTS: Of 524 individual patients who presented to the EMU, only 25 patients (4.8%) had documentation of a diagnosis of ADHD and/or ADHD medications (Group II). The proportion of patients in Group II did not significantly differ based on the EMU diagnosis. However, there was a significantly greater number of other psychiatric diagnoses (p = .005) and a greater number of psychiatric medications prescribed (p < .001) in patients in Group II. CONCLUSION: Our study suggests that ADHD is underrecognized and underdiagnosed in patients presenting to the EMU, and screening tools may be useful to help clinicians address seizure comorbidities such as ADHD.

Towards Understanding Sensory Substitution for Accessible Visualization: An Interview Study.

For all its potential in supporting data analysis, particularly in exploratory situations, visualization also creates barriers: accessibility for blind and visually impaired individuals. Regardless of how effective a visualization is, providing equal access for blind users requires a paradigm shift for the visualization research community. To enact such a shift, it is not sufficient to treat visualization accessibility as merely another technical problem to overcome. Instead, supporting the millions of blind and visually impaired users around the world who have equally valid needs for data analysis as sighted individuals requires a respectful, equitable, and holistic approach that includes all users from the onset. In this paper, we draw on accessibility research methodologies to make inroads towards such an approach. We first identify the people who have specific insight into how blind people perceive the world: orientation and mobility (O&M) experts, who are instructors that teach blind individuals how to navigate the physical world using non-visual senses. We interview 10 O&M experts-all of them blind-to understand how best to use sensory substitution other than the visual sense for conveying spatial layouts. Finally, we investigate our qualitative findings using thematic analysis. While blind people in general tend to use both sound and touch to understand their surroundings, we focused on auditory affordances and how they can be used to make data visualizations accessible-using sonification and auralization. However, our experts recommended supporting a combination of senses-sound and touch-to make charts accessible as blind individuals may be more familiar with exploring tactile charts. We report results on both sound and touch affordances, and conclude by discussing implications for accessible visualization for blind individuals.

The Impact of Compassion from Others and Self-compassion on Psychological Distress, Flourishing, and Meaning in Life Among University Students.

Objectives: Research shows that compassion from others and from the self may enable university students to face, overcome, and bounce back from adversity and generate a greater sense of thriving and meaning in life. However, the underlying processes are largely unknown. The present study aimed to examine the associations of compassion with psychological distress, flourishing, and meaning in life among university students and explore the mechanisms underlying these associations. Methods: A total of 536 Hong Kong university students completed questionnaires measuring their experiences of compassion from others, self-compassion, resilience, psychological distress, flourishing, and meaning in life. Results: Serial mediation analyses showed that compassion from others was associated positively with self-compassion, which was, in turn, linked to greater resilience and consequently lower levels of psychological distress and higher levels of flourishing and meaning in life. Conclusions: Our findings reveal the associations of compassion from others and self-compassion with the well-being and life meaning of university students. The findings highlight the importance of being open and receptive to love and kindness from others. The findings also point to the importance of developing a caring attitude toward oneself.

UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival.

In pancreatic beta-cells, uncoupling protein 2 (UCP2) influences mitochondrial oxidative phosphorylation and insulin secretion. Here, we show that alpha-cells express significantly higher levels of UCP2 than do beta-cells. Greater mitochondrial UCP2-related uncoupling was observed in alpha-cells compared with beta-cells and was accompanied by a lower oxidative phosphorylation efficiency (ATP/O). Conversely, reducing UCP2 activity in alpha-cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, the suppression of UCP2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in UCP2(-/-) mice. In addition to its effects on secretion, UCP2 played a cytoprotective role in islets, with UCP2(-/-) alpha-cells being more sensitive to specific death stimuli. In summary, we demonstrate a direct role for UCP2 in maintaining alpha-cell function at the level of glucose metabolism, glucagon secretion, and cytoprotection.

Metastatic Medullary Thyroid Cancer: The Role of 68Gallium-DOTA-Somatostatin Analogue PET/CT and Peptide Receptor Radionuclide Therapy.

CONTEXT: Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. OBJECTIVE: Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). METHODS: We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). RESULTS: Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years. CONCLUSIONS: The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.

Spectrum of neurovascular complications from central nervous system infections (viral, bacterial and fungal).

In the following pictorial review, common and uncommon neurovascular complications associated with a spectrum of viral, bacterial and fungal infections involving the central nervous system will be illustrated. These complications include cerebral vascular insult, venous thrombosis, vasculitis and aneurysm formation. They can occur as separate entities but are often inter-related. The imaging features of neurovascular complication related to infections can provide clues and aid diagnosis when considering the potential mode of infectious spread and the type of potential infectious organism involved. The radiological appearances vary from common features that are shared by several types of pathogens to typical characteristics of a type of infectious organism.

Complete Genome Sequences of 12 B1 Cluster Mycobacteriophages, Gareth, JangoPhett, Kailash, MichaelPhcott, PhenghisKhan, Phleuron, Phergie, PhrankReynolds, PhrodoBaggins, Phunky, Vaticameos, and Virapocalypse.

Twelve B1 cluster mycobacteriophages were isolated from soil samples collected in Philadelphia, PA, USA, using Mycobacterium smegmatis mc2 155 as a host, and were sequenced. The genome sequences range in size from 66,887 bp to 68,953 bp in length and have between 99 and 105 putative protein-coding genes.

Glucose-Induced ß-Cell Dysfunction In Vivo: Evidence for a Causal Role of C-jun N-terminal Kinase Pathway.

Prolonged elevation of glucose can adversely affect ß-cell function. Oxidative stress, which has been implicated in glucose-induced ß-cell dysfunction, can activate c-jun N-terminal kinase (JNK). However, whether JNK is causal in glucose-induced ß-cell dysfunction in vivo is unclear. Therefore, we aimed at investigating the causal role of JNK activation in in vivo models of glucose-induced ß-cell dysfunction. Glucose-induced ß-cell dysfunction was investigated in the presence or absence of JNK inhibition. JNK inhibition was achieved using either (i) the JNK-specific inhibitor SP600125 or (ii) JNK-1-null mice. (i) Rats or mice were infused intravenously with saline or glucose with or without SP600125. (ii) JNK-1 null mice and their littermate wild-type controls were infused intravenously with saline or glucose. Following the glucose infusion periods in rats and mice, ß-cell function was assessed in isolated islets or in vivo using hyperglycemic clamps. Forty-eight-hour hyperglycemia at ~20 mM in rats or 96-hour hyperglycemia at ~13 mM in mice impaired ß-cell function in isolated islets and in vivo. Inhibition of JNK using either SP600125 or JNK-1-null mice prevented glucose-induced ß-cell dysfunction in isolated islets and in vivo. Islets of JNK-1-null mice exposed to hyperglycemia in vivo showed an increase in Pdx-1 and insulin 2 mRNA, whereas islets of wild-type mice did not. Together, these data show that JNK pathway is involved in glucose-induced ß-cell dysfunction in vivo and is thus a potential therapeutic target for type 2 diabetes.

Analytical Platforms and Techniques to Study Stem Cell Metabolism.

Over the past decade, advances in systems biology or 'omics techniques have enabled unprecedented insights into the biological processes that occur in cells, tissues, and on the organism level. One of these technologies is the metabolomics, which examines the whole content of the metabolites in a given sample. In a biological system, a stem cell for instance, there are thousands of single components, such as genes, RNA, proteins, and metabolites. These multiple molecular species interact with each other and these interactions may change over the life-time of a cell or in response to specific stimuli, adding to the complexity of the system. Using metabolomics, we can obtain an instantaneous snapshot of the biological status of a cell, tissue, or organism and gain insights on the pattern(s) of numerous analytes, both known and unknown, that result because of a given biological condition. Here, we outline the main methods to study the metabolism of stem cells, including a relatively recent technology of mass spectrometry imaging. Given the abundant and increasing interest in stem cell metabolism in both physiological and pathological conditions, we hope that this chapter will provide incentives for more research in these areas to ultimately reach wide network of applications in biomedical, pharmaceutical, and nutritional research and clinical medicine.

Paradoxical embolism: a rare life- and limb-threatening emergency.

This article presents a case of a 43-year-old man with paradoxical embolism. The patient had simultaneous deep venous thrombosis, pulmonary embolism and bilateral limb-threatening arterial occlusions. The unifying diagnosis was paradoxical embolism through a previously undetected atrial septal defect. Suggestions for the evaluation and emergency management of paradoxical embolism are outlined, and the literature is briefly reviewed.

The provision of mental health treatment after screening: exploring the relationship between treatment setting and treatment intensity.

OBJECTIVE: Primary care screening programs for mental health disorders are designed to detect patients who might benefit from treatment. As such, the utility of these programs is predicated on the actions that take place in response to a positive screen. Our objective was to characterize the cascade of care delivery steps following a positive screen for a mental health disorder. METHOD: We examined the care received by primary care patients over the year following a new positive screen for depression, posttraumatic stress disorder (PTSD) or alcohol misuse. We characterized whether the care adhered to practice guidelines for related mental health disorders and whether involvement of mental health specialists led to higher use of guideline-adherent practices. RESULTS: Many patients received appropriate treatment in the primary care setting and those whose scores were consistent with more severe illness were more likely to receive care in a mental health setting. Patients with positive screens for depression and PTSD who went on to be seen in mental health clinics received care that was consistent with treatment guidelines for the related disorder most of the time. In the case of patients with positive screens for alcohol misuse, few received guideline-recommended medications in any setting. However, a substantial portion of patients received some alcohol-related counseling from their primary care physicians during the visit in which their alcohol misuse was detected. CONCLUSION: It appears that the treatment system for mental health problems, which extends from primary care settings to mental health subspecialty settings, can provide adequate care when patients' mental health problems are identified through screening. The care provided in all settings can be improved, and additional steps to enhance the quality of care are warranted. This should include additional efforts to align screening and treatment.