Investigations Towards Tryptophan Uptake and Transport Across an In Vitro Model of the Oral Mucosa Epithelium.

Tryptophan is an essential amino acid and plays an important role in several metabolic processes relevant for the human health. As the main metabolic pathway for tryptophan along the kynurenine axis is involved in inflammatory responses, changed metabolite levels can be used to monitor inflammatory diseases such as ulcerative colitis. As a progenitor of serotonin, altered tryptophan levels have been related to several neurogenerative diseases as well as depression or anxiety. While tryptophan concentrations are commonly evaluated in serum, a non-invasive detection approach using saliva might offer significant advantages, especially during long-term treatments of patients or elderly. In order to estimate whether active transport processes for tryptophan might contribute to a potential correlation between blood and saliva tryptophan concentrations, we investigated tryptophan's transport across an established oral mucosa in vitro model. Interestingly, treatment with tryptophan revealed a concentration dependent secretion of tryptophan and the presence of a saturable transporter while transport studies with deuterated tryptophan displayed increased permeability from the saliva to the blood compartment. Protein analysis demonstrated a distinct expression of L-type amino acid transporter 1 (LAT1), the major transporter for tryptophan, and exposure to inhibitors (2 -amino-2-norbornanecarboxylic acid (BCH), L-leucine) led to increased tryptophan levels on the saliva side. Additionally, exposure to tryptophan in equilibrium studies resulted in a regulation of LAT1 at the mRNA level. The data collected in this study suggest the participation of active transport mechanisms for tryptophan across the oral mucosa epithelium. Future studies should investigate the transport of tryptophan across salivary gland epithelia in order to enable a comprehensive understanding of tryptophan exchange at the blood-saliva barrier.

Development of 3D-iNET ORION: a novel, pre-clinical, three-dimensional in vitro cell model for modeling human metastatic neuroendocrine tumor of the pancreas.

Neuroendocrine tumors (NETs) of the pancreas are rare neoplasms that present complex challenges to diagnosis and treatment due to their indolent course. The incidence of pancreatic neuroendocrine tumors has increased significantly over the past two decades. A limited number of pancreatic neuroendocrine cell lines are currently available for the research. Here, we present 3D-iNET ORION, a novel 3-dimensional (spheroid) cell line, isolated from human pancreatic neuroendocrine tumor liver metastasis. Three-dimensionally grown (3D) cancer cell lines have gained interest over the past years as 3D cancer cell lines better recapitulate the in vivo structure of tumors, and are more suitable for in vitro and in vivo experiments. 3D-iNET ORION cancer cell line showed high potential to form tumorspheres when embedded in Matrigel matrix and expresses synaptophysin and EpCAM. Electron microscopy analysis of cancer cell line proved the presence of dense neurosecretory granules. When xenografted into athymic mice, 3D-iNET ORION cells produce slow-growing tumors, positive for chromogranin and synaptophysin. Human Core Exome Panel Analysis has shown that 3DiNET ORION cell line retains the genetic aberration profile detected in the original tumor. In conclusion, our newly developed neuroendocrine cancer cell line can be considered as a new research tool for in vitro and in vivo experiments.

Valvular Endocarditis and Biventricular Heart Failure in the Setting of Tropheryma whipplei Disease.

Whipple disease is a rare systemic illness associated with weight loss, diarrhea, and arthralgia. Asymptomatic carriage is common, but the disease can be complicated by cardiac involvement and may result in culture-negative endocarditis. Cardiac manifestations of the disease can lead to death. This report presents the case of a 66-year-old man with Whipple disease and biventricular heart failure with cardiogenic shock. Medical therapy followed by successful replacement of the aortic and mitral valves resulted in substantial improvement.

Prevalence, Incidence, and Outcomes of Diastolic Dysfunction in Isolated Tricuspid Regurgitation: Perhaps Not Really "Isolated"?

BACKGROUND: In the absence of left-sided cardiac/pulmonary disease, functional tricuspid regurgitation (FTR) is referred to as isolated or idiopathic. Relationships between left ventricular diastolic dysfunction (DD) and FTR remain unknown. OBJECTIVES: The purpose of this study was to investigate the prevalence, incidence, and outcome of DD in patients with idiopathic FTR. METHODS: Adults without structural heart disease were identified. Severe DD was defined by ≥3 of 4 abnormal DD parameters (medial e', medial E/e', TR velocity, left atrial volume index) and ≥ moderate DD by ≥2. Propensity-score matching was performed (3:1) between each less-than-severe TR group and severe TR based on age, sex, body mass index, and comorbidities. RESULTS: Among 30,428 patients, FTR was absent in 73%, mild in 22%, moderate in 4%, and severe in 0.4%. In the propensity-matched sample, severe DD was present in 2%, 6%, 9%, and 13% patients, and ≥ moderate DD in 11%, 18%, 28%, and 48%, respectively (P < 0.001). The probability of heart failure with preserved ejection fraction using the H2FPEF score increased with increasing FTR (median 29.7%, 45.5%, 61.4%, and 88.7%, respectively), as did the prevalence of impaired left atrial strain <24% (35%, 48%, and 69% in mild, moderate, and severe TR). Incident severe and ≥ moderate DD developed more frequently with increasing FTR (HR: 8.45 [95% CI: 2.60-27.50] and HR: 2.82 [95% CI: 1.40-5.69], respectively for ≥ moderate vs no FTR) over a median of 3.0 years. Findings were confirmed in patients without lung disease or right ventricular enlargement. Over a median of 5.0 years, patients with ≥ moderate FTR and DD had the greatest risk of worse outcomes (multivariable P < 0.001). The association between TR and adverse outcomes was significantly diminished in the absence of DD. CONCLUSIONS: Diastolic dysfunction, increased heart failure with preserved ejection fraction probability, and impaired left atrial strain are commonly present in patients with idiopathic FTR, suggesting that the latter may not be truly isolated. Patients with FTR without DD or heart failure are at increased risk of incident DD. Patients with FTR and DD display worse outcomes.

Analyzing the Shortcomings in Smart Healthcare for Remote Home Care-A Case Study of the Taiwan Market.

In Taiwan, remote healthcare initially focused on telemedicine, with systematic development starting in 2007 through the "Remote Care Pilot Program" and subsequent initiatives. Significant advancements came with the "Remote Health Care Services Development Plan" in 2010, which integratedArtificial intelligence and Information and communications technologies, enhancing smart healthcare in home care. This study investigated strategic gaps in smart healthcare applications for remote home care using a mixed-methods approach, particularly the Analytic Hierarchy Process (AHP). This study identified and ranked strategic gaps, including "legal regulations", "economic factors", "user behavior habits", "policy and culture", and "environment and technology". Findings, based on in-depth interviews with 6 experts and 16 AHP questionnaire samples, highlight "legal regulations" and "user behavior habits" as critical areas needing attention. Addressing these gaps can improve user acceptance and the effectiveness of smart healthcare applications, providing valuable insights for future research and practice in making remote home care more comprehensive and efficient.

Secondary tricuspid regurgitation: incidence, types, and outcomes in atrial fibrillation vs. sinus rhythm.

BACKGROUND AND AIMS: Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. METHODS: Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. RESULTS: Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P < .001), larger right atrial size (median 78 vs. 53 mL, P < .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P < .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. CONCLUSIONS: New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.

Impact of a patient-centered tool to reduce misconceptions about coronary artery disease and its treatment: The CAD roadmap.

Objective: Health misinformation is common and can lead to harmful behaviors such as medication non-adherence. We assessed the impact of a novel patient educational tool focused on overcoming misconceptions among patients with coronary artery disease (CAD). Methods: We developed the CAD Roadmap, an educational tool aimed at explaining the disease trajectory and overcoming common disease misconceptions (such as that statin medications are not beneficial). We designed a pilot survey to assess patients' 1) CAD-related knowledge, 2) medication-taking behavior, and 3) acceptability of the Roadmap. Survey participants were recruited online. CAD knowledge scores were compared with repeated measures t-tests. Results: Among 114 patients with CAD (mean age 67 years, 63% male), average CAD-related knowledge was 79.0% pre-test and 89.7% after review of the CAD Roadmap (p < .001). After review of the Roadmap, 24% indicated they planned to take their medications more regularly, 93% agreed it was helpful in understanding medication benefits, and 77% felt more empowered to participate in medical decisions. Conclusion: The CAD Roadmap was evaluated positively, improved disease-related knowledge, and has the potential to improve adherence to treatments. Innovation: Unlike many other interventions, the CAD Roadmap is specifically designed to overcome common misconceptions to improve health behaviors.

Pulmonary Hypertension and Anastrozole (PHANTOM): A Randomized, Double-Blind, Placebo-Controlled Trial.

RATIONALE: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. OBJECTIVES: We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH). METHODS: We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. MEASUREMENTS AND MAIN RESULTS: Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups. CONCLUSIONS: Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03229499.

The State of State Biomarker Testing Insurance Coverage Laws.

This Viewpoint discusses laws mandating insurance coverage of biomarker testing to broaden access to care for patients with cancer.

New Approaches to Assessment and Management of Tricuspid Regurgitation Before Intervention.

Severe tricuspid regurgitation (TR) is a progressive condition associated with substantial morbidity, poor quality of life, and increased mortality. Patients with TR commonly have coexisting conditions including congestive heart failure, pulmonary hypertension, chronic lung disease, atrial fibrillation, and cardiovascular implantable electronic devices, which can increase the complexity of medical and surgical TR management. As such, the optimal timing of referral for isolated tricuspid valve (TV) intervention is undefined, and TV surgery has been associated with elevated risk of morbidity and mortality. More recently, an unprecedented growth in TR treatment options, namely the development of a wide range of transcatheter TV interventions (TTVI) is stimulating increased interest and referral for TV intervention across the entire medical community. However, there are no stepwise algorithms for the optimal management of symptomatic severe TR before TTVI. This article reviews the contemporary assessment and management of TR with addition of a medical framework to optimize TR before referral for TTVI.

Transport of Non-Steroidal Anti-Inflammatory Drugs across an Oral Mucosa Epithelium In Vitro Model.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell® model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured.

Low-grade mucoepidermoid carcinoma mimicking benign cystic lesions in the salivary gland: A diagnostic dilemma.

Mucoepidermoid carcinoma (MEC) is a common malignancy arising in the parotid gland. The diagnosis of MEC is typically based on its morphological features alone, characteristically containing mucocytes, intermediate cells and epidermoid cells. However, when cystic degeneration is diffuse, it is challenging to distinguish MEC from other benign cystic tumors. This is a case report of a 58-year-old Caucasian man who presented with a parotid mass. H&E sections of the mass reveal multiloculated cysts lined by bland-looking epithelium with only rare papillary architectures. The papillary proliferation contains mucocytes, and epidermoid cells highlighted by the p63 immunohistochemistry study. The diagnosis was confirmed by FISH result of positive MAML2 (11q21) rearrangement. Patient underwent parotidectomy and is disease-free 6 months post-surgery. MEC with cystic degeneration is a common diagnostic pitfall which can mimic many benign lesions in the salivary gland. We present a rare case with MEC with extensive cystic change, its molecular and pathologic findings and review the diagnostic features of MEC, its benign mimickers and useful tools for distinguishing these entities.

Imaging of Cardiac Sarcoidosis: An Update and Future Aspects.

Cardiac sarcoidosis (CS), an increasingly recognized disease of unknown etiology, is associated with significant morbidity and mortality. Given the limited diagnostic yield of traditional endomyocardial biopsy (EMB), there is increasing reliance on multimodality cardiovascular imaging in the diagnosis and management of CS, with EMB being largely supplanted by the use of 18F-fluorodeoxyglucose (FDG-PET) and cardiac magnetic resonance imaging (CMR). This article aims to provide a comprehensive review of imaging modalities currently utilized in the screening, diagnosis, and monitoring of CS, while highlighting the latest developments in each area.

The Natural History of Atrial Functional Mitral Regurgitation.

BACKGROUND: The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown. OBJECTIVES: The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality. METHODS: Adults with left atrial (LA) volume index ≥40 mL/m2, ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up. RESULTS: A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures. CONCLUSIONS: In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased.