Cell Death Induced by the Combination of Ephedra sinica Extract and Radiation in HNSCC is Positively Related to BAX and p-MLKL Expression.

BACKGROUND: Numerous studies have proven the efficacy and safety of natural products, and are widely used as attractive cancer treatments. The investigation of effective natural products for improving cancer treatment is a promising strategy. Combination treatment with radiosensitizers and radiotherapy (RT) is considered necessary for therapeutic improvement in head and neck squamous cell carcinoma(HNSCC). OBJECTIVE: This study aims to investigate whether Ephedra sinica (ES) extract could induce selective cell death in cancer cells and serve as a radiosensitizer for HNSCC. METHODS: HNSCC cells were pretreated with ES extract before radiation, and the radiosensitizing activity was assessed using a colony formation assay. Radiation-induced cell death was evaluated using an annexinV-FITC assay. Western blotting was performed to confirm cell death-related gene expression, including apoptosis and necrosis markers. RESULTS: ES extract significantly inhibited HNSCC cell viability (FaDu and SNU1076), while having minimal effect on normal HaCaT cells. When HNSCC cells were irradiated with 2, 4, or 8 Gy and cultured with ES extract (25 µg/mL), they exhibited increased radiation sensitivity compared to non-treated cells. The combination of ES extract and radiation resulted in increased cell death compared to non-treated, ES-treated, or irradiated cells. The apoptosis marker BAX and necrosis marker p-MLKL expression levels were also elevated following the combination treatment. CONCLUSION: ES extract demonstrated significant cytotoxic potential in HNSCC cells without affecting normal cells. It enhanced the radiosensitivity of HNSCC cells by upregulating BAX and p-MLKL expression, leading to increased cell death. These results suggest ES extract exhibits a potential radiosensitizing capacity in HNSCC.

What drives the use of wearable healthcare devices? A cross-country comparison between the US and Korea.

Objective: Given the rapid growth of the wearable healthcare device market, we examined the associations among health-related and technology-related characteristics of using wearable healthcare devices and demonstrated how the associations differ between the US and Korean users. Methods: Online self-administered surveys were conducted with 4098 participants (3035 in the US and 1063 in Korea) who were recruited through two online survey service providers based on quota sampling. The primary outcome was the use of wearable healthcare devices. Seven health-related, two technology-related, and five socio-demographic factors were included as explanatory variables. Binary logistic regression analyses and a Chow test were conducted. Results: The health-related characteristics that were significantly associated with using wearable healthcare devices included disease-related worries (ß = 0.11**), health information seeking (ß = 0.26***), physical activity (ß = 0.62***), and health-related expenditures ($50-$199, ß = 0.38***; $200 or more, ß = 0.56***). Hedonic (ß = 0.33***), social (ß = 0.31***), and cognitive innovativeness (ß = 0.14*) also exhibited positive relationships. Younger, higher earner, and individuals with a child were more likely to use wearable healthcare devices. However, for Korean users, several associations disappeared including health information seeking, hedonic and social innovativeness, age, and household income. Conclusions: Key drivers of using wearable healthcare devices include greater concern about a specific illness, active engagement in health-promoting behaviors, and hedonic and social motivation to adopt new technologies. However, more country-specific considerations are needed in future studies to identify the main benefits for target markets.

Safety and efficacy of sucroferric oxyhydroxide in pediatric patients with chronic kidney disease.

BACKGROUND: Pediatric patients with advanced chronic kidney disease (CKD) are often prescribed oral phosphate binders (PBs) for the management of hyperphosphatemia. However, available PBs have limitations, including unfavorable tolerability and safety. METHODS: This phase 3, multicenter, randomized, open-label study investigated safety and efficacy of sucroferric oxyhydroxide (SFOH) in pediatric and adolescent subjects with CKD and hyperphosphatemia. Subjects were randomized to SFOH or calcium acetate (CaAc) for a 10-week dose titration (stage 1), followed by a 24-week safety extension (stage 2). Primary efficacy endpoint was change in serum phosphorus from baseline to the end of stage 1 in the SFOH group. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: Eighty-five subjects (2-18 years) were randomized and treated (SFOH, n = 66; CaAc, n = 19). Serum phosphorus reduction from baseline to the end of stage 1 in the overall SFOH group (least squares [LS] mean ± standard error [SE]) was - 0.488 ± 0.186 mg/dL; p = 0.011 (post hoc analysis). Significant reductions in serum phosphorus were observed in subjects aged ≥ 12 to ≤ 18 years (LS mean ± SE - 0.460 ± 0.195 mg/dL; p = 0.024) and subjects with serum phosphorus above age-related normal ranges at baseline (LS mean ± SE - 0.942 ± 0.246 mg/dL; p = 0.005). Similar proportions of subjects reported ≥ 1 TEAE in the SFOH (75.8%) and CaAc (73.7%) groups. Withdrawal due to TEAEs was more common with CaAc (31.6%) than with SFOH (18.2%). CONCLUSIONS: SFOH effectively managed serum phosphorus in pediatric patients with a low pill burden and a safety profile consistent with that reported in adult patients.

HIV-Associated CKDs in Children and Adolescents.

INTRODUCTION: Limited information is available describing the current prevalence of proteinuria and HIV-associated CKDs (HIV-CKDs) in children and adolescents living with HIV and receiving antiretroviral therapy in the United States. METHODS: To address this issue, we performed a retrospective study of children and adolescents living with HIV who received medical care at Children's National Hospital in Washington, DC, between January 2012 and July 2019. Demographic data, clinical parameters (mode of HIV transmission, viral loads, CD4 cell counts, serum creatinine, glomerular filtration rate [GFR], plasma lipid levels, proteinuria, blood pressure, renal biopsies), and medical treatments, all done as a standard of clinical care, were collected and analyzed. RESULTS: The majority of the 192 patients enrolled were of African descent (88%) and acquired HIV through vertical transmission (97%). The prevalence of all HIV-CKDs was 6%. Of these patients, 39% had intermittent or persistent proteinuria, and 7% percent had proteinuria with a mild decline in GFR (60-80 ml/min per 1.73 m2), and 6% had a mild decline in GFR without proteinuria. Documented hypertension was present in 6% of the patients, mainly in association with HIV-CKD. Patients with persistent proteinuria (3%) and biopsy-proven HIV-CKD had a slow but constant progression of their renal diseases. CONCLUSIONS: The prevalence of persistent proteinuria and HIV-CKD was lower than that reported in previous studies conducted in the United States. However, intermittent proteinuria, mild reductions in GFR, and progression of established HIV-CKD were common findings in this group of patients with predominantly vertically acquired HIV who were receiving antiretroviral therapy.

Quality Improvement Initiative to Reduce Admissions for Nephrotic Syndrome Relapse in Pediatric Patients.

Introduction: Childhood nephrotic syndrome is frequently seen in pediatric nephrology practice and often requires patient hospitalization for management. Numerous complications of this disease can be managed in an outpatient setting if brought to the attention of the medical team in a timely manner. Outpatient management will reduce healthcare cost and improve patient safety. The goal of this quality improvement initiative was to reduce admissions for nephrotic syndrome relapse from 8 to <5 admissions at a single center in a 3-month period. Methods: Fish-bone analysis was used to determine barriers to early recognition of relapse and successful outpatient care. Patient education about the disease process was identified as the primary barrier. A standardized approach to patient education as well as educational materials were developed. Champions were identified within each stakeholder group to train and disseminate the new process. Admission counts were compared from 3 years prior to implementation to 2 years post-implementation. Clinic visits for nephrotic syndrome were tallied as a balancing measure. Patients were surveyed in the outpatient clinics about whether they had ever received the education as a process measure. Results: Admission counts were reduced and met goal for the first 3 quarters that were examined; however, the number of admissions went above target in the last quarter. Clinic visit numbers did not change over the study period. Process measure showed that 75-80% of families were provided with nephrotic syndrome education. Conclusion: A standardized approach to patient and family education about idiopathic nephrotic syndrome can reduce admissions for management of relapse. This will reduce healthcare expenditure as well as improve patient safety.

Hyponatremia: An Unusual Presentation in a Neonate With Chromosome 1q21.1 Deletion Syndrome.

Chromosome 1q21.1 deletion syndrome is associated with a wide variety of clinical features including mild to moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. We report an unusual case of a premature neonate with persistent hyponatremia, markedly elevated plasma arginine vasopressin level (32.7 pg/mL), and clinical findings consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The patient, who also had microcephaly and dextrocardia, was subsequently diagnosed with chromosome 1q21.1 deletion syndrome. Further evaluation revealed hypothalamic abnormalities, features not previously described with this syndrome. To our knowledge, this is the first report of SIADH associated with congenital hypothalamic anomalies in a neonate with chromosome 1q21.1 deletion syndrome. We also report our experience using tolvaptan, a vasopressin receptor antagonist, in this patient to effectively maintain eunatremia.

Bosentan and Rifampin Interactions Modulate Influx Transporter and Cytochrome P450 Expression and Activities in Primary Human Hepatocytes.

The incidence of polypharmacy-which can result in drug-drug interactions-has increased in recent years. Drug-metabolizing enzymes and drug transporters are important polypharmacy modulators. In this study, the effects of bosentan and rifampin on the expression and activities of organic anion-transporting peptide (OATP) and cytochrome P450 (CYP450) 2C9 and CYP3A4 were investigated in vitro. HEK293 cells and primary human hepatocytes overexpressing the target genes were treated with bosentan and various concentrations of rifampin, which decreased the uptake activities of OATP transporters in a dose-dependent manner. In primary human hepatocytes, CYP2C9 and CYP3A4 gene expression and activities decreased upon treatment with 20 µM bosentan+200 µM rifampin. Rifampin also reduced gene expression of OATP1B1, OATP1B3, and OATP2B1 transporter, and inhibited bosentan influx in human hepatocytes at increasing concentrations. These results confirm rifampin- and bosentan-induced interactions between OATP transporters and CYP450.

Genetic Programming of Hypertension.

The heritability of hypertension (HTN) is widely recognized and as a result, extensive studies ranging from genetic linkage analyses to genome-wide association studies are actively ongoing to elucidate the etiology of both monogenic and polygenic forms of HTN. Due to the complex nature of essential HTN, however, single genes affecting blood pressure (BP) variability remain difficult to isolate and identify and have rendered the development of single-gene targeted therapies challenging. The roles of other causative factors in modulating BP, such as gene-environment interactions and epigenetic factors, are increasingly being brought to the forefront. In this review, we discuss the various monogenic HTN syndromes and corresponding pathophysiologic mechanisms, the different methodologies employed in genetic studies of essential HTN, the mechanisms for epigenetic modulation of essential HTN, pharmacogenomics and HTN, and finally, recent advances in genetic studies of essential HTN in the pediatric population.

The effect of lipopolysaccharide-induced obesity and its chronic inflammation on influenza virus-related pathology.

Obese individuals show increased susceptibility to infection, low vaccine efficacy, and worse pathophysiology. However, it is unclear how obesity affects these events. The aim of this study was to investigate the effect of obesity-triggered chronic inflammation on immune cells after influenza virus infection. Control and lipopolysaccharide mice, in which an osmotic pump continually released Tween saline or lipopolysaccharide, were prepared and 3 weeks later were infected with pandemic H1N1 2009 influenza A virus. In lipopolysaccharide mice, we found a reduction in macrophage activation markers in the steady state, and reduced production of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1ß, and interleukin-6, in restimulated peritoneal macrophages. Interestingly, lipopolysaccharide-triggered chronic inflammation exacerbated the severity of pathological symptoms in the lungs after challenge with influenza virus. Taken together, the increased severity of virus-induced symptoms in obese individuals with chronic inflammation may be, at least partially, caused by macrophage dysfunction.

Tracking Study About Adenovirus 36 Infection: Increase of Adiposity.

This study investigated the cross-sectional and longitudinal association between adenovirus 36 (Ad36) and obesity in 79 Korean adolescent boys over 1 year. We analyzed the changes in body composition and metabolic risk factors according to the presence of Ad36 antibodies. Ad36 antibodies in serum were detected using the constant virus-decreasing serum method. We found that the fat percentage and fasting insulin in the Ad36-seropositive group were greater than the Ad36-seronegative group. These results suggest that Ad36 infection is associated with an increase of adiposity, and the experience of Ad36 infection may affect the future fat gain of adolescents.

Alleviation of kainic acid-induced brain barrier dysfunction by 4-o-methylhonokiol in in vitro and in vivo models.

This experiment was designed to investigate whether 4-O-methylhonokiol (MH), a principal ingredient of Magnolia (M.) officinalis bark, alleviated acute intraperitoneal (i.p.) kainic acid- (KA-) induced brain blood barrier dysfunction (BBBD) via pathological examination and cytological analyses of the brain tissues of mice. KA (10-30 mg/kg) time- and dose-dependently increased the water content of brain tissues and induced edema and encephalopathy. However, pretreatment with MH (5 and 20 mg/kg, i.p.) significantly reduced the water content of the brain compared to that observed in the KA control group. Furthermore, MH significantly and dose-dependently reversed the remarkable variations in evan's blue dye (EBD) staining and malondialdehyde (MDA) levels that were induced by KA (10 mg/kg, i.p.). MH also decreased the elevated seizure scores that were induced by KA (10 mg/kg, i.p.) in mice in a manner similar to scavengers such as DMTU and trolox. Additionally, MH significantly scavenged intracellular ROS and Ca2+ within hippocampal cells. The tight junction seals mediated by claudin (Cld-5) were also found to be modulated by MH. MH efficiently reduced 1,1-diphenyl-2-picrylhydrazyl (DPPH) (IC50, 52.4 mM) and •OH with an electron spin resonance (ESR) signal rate constant of 4×10(9) M(-1)·S(-1), which is close to the reactivity of the vitamin E analog trolox. Taken together, these results suggest that MH may enhance radical scavenging in lipid and hydrophobic environments, which may be important for the physiological activity of the barrier.

Prospective validation of Baveno V definitions and criteria for failure to control bleeding in portal hypertension.

UNLABELLED: New definitions and criteria were released at the Baveno V consensus meeting. The purposes of this study were to verify Baveno V definitions and criteria for failure to control bleeding and to determine the usefulness of the combined use of the Adjusted Blood Requirement Index [ABRI: (number of blood units)/(final hematocrit-initial hematocrit)+0.01] with Baveno V criteria. In all, 246 consecutive liver cirrhosis patients with acute bleeding associated with portal hypertension were enrolled prospectively between January 2010 and October 2012. The treatment outcome on day 5 was assessed by endoscopy. For the ABRI calculation, two hematocrit levels were used as the initial hematocrit: the first level measured upon patient arrival (ABRI-A) and the lowest level measured before transfusion (ABRI-B). Treatment failures were identified in 53 patients, of whom 24 died. Based on repeated endoscopic findings, 29 patients were identified as treatment failures, while according to Baveno V criteria, 47 patients were regarded as treatment failures. The area under the receiver operating characteristic curve (AUROC) of Baveno V criteria was 0.906, and the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio were 83.0%, 98.4%, 93.6%, 95.5%, 53.41, and 0.17, respectively. The AUROC of Baveno V criteria was significantly greater than those of Baveno IV (P=0.0001) and Baveno II/III (P<0.0001) criteria. Adding ABRI-A or -B to Baveno V criteria resulted in a significant reduction of the AUROC (P<0.05). CONCLUSION: The Baveno V criteria are good predictors of treatment failure of early-stage acute gastrointestinal bleeding in patients with portal hypertension, while the addition of ARBI does not improve the prediction accuracy of the outcome of bleeding.

The organic anion transporter (OAT) family: a systems biology perspective.

The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Nuclear receptors and other transcription factors, such as Hnf4α and Hnf1α, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling.

Gastric endoscopic submucosal dissection is safe for day patients.

BACKGROUND/AIMS: Although the advantages of endoscopic submucosal dissection (ESD) are well established, there are important limitations that relate to its higher cost and higher rate of complications compared with endoscopic mucosal resection. This study assessed the therapeutic safety and efficacy of ESD in the treatment of small gastric dysplasia and early gastric cancer (EGC) located within the antrum in an outpatient setting, and it compared the results with those from patients admitted to hospital for ESD treatment. METHODS: This study was a retrospective analysis of a prospectively maintained database. We reviewed consecutive patients with EGC or gastric dysplasia who underwent ESD between October 2007 and May 2008. The lesions were smaller than 2 cm and were located in the antrum. We analyzed 105 lesions in 105 patients. The patients were assigned to two groups according to each patient's preference. RESULTS: The overall rates of complete resection were 98.1% in the inpatients group and 94.3% in the outpatients group. Immediate bleeding occurred in four inpatients, which included one patient in the outpatient group. Delayed bleeding occurred in one inpatient within 24 hours of the procedure. Macroperforations did not occur in either group. A microperforation was found in one outpatient. CONCLUSIONS: The safety and efficacy of ESD used to treat small gastric tumors in the antrum in an outpatient setting appeared to be similar to the safety and efficacy of ESD used to treat patients who were admitted to the hospital.

Endoscopic Management of Rectal Dieulafoy's Lesion: A Case Series and Optimal Treatment.

Rectal Dieulafoy's lesion (DL) is rare cause of lower gastrointestinal bleeding. Because of its rarity, there is no consensus on the optimal endoscopic hemostasis technique for rectal DL. We analyzed six patients who underwent endoscopic management for rectal DL after presenting with hematochezia at a single institute over 10 years. Of the six patients, three underwent endoscopic band ligation (EBL) and three underwent endoscopic hemoclip placement (EHP). Only one patient was treated with thermocoagulation. There were no immediate complications in any of the patients. None of the patients required a procedure or surgery for the treatment of rebleeding. Mean procedure times of EBL and EHP were 5.25 minutes and 7 minutes, respectively. Both EHP and EBL are shown to be effective in the treatment of bleeding rectal DL. We suggest that EBL may have potential as the preferred therapy owing to its superiority in technical and economic aspects, especially in elderly and high-risk patients.

A tailored approach for endoscopic treatment of small rectal neuroendocrine tumor.

INTRODUCTION: Resection of rectal neuroendocrine tumors (NETs) less than 1 cm in diameter can be performed using various endoscopic techniques. Endoscopic mucosal resection (EMR) traditionally had suboptimal complete resection rate compared to endoscopic submucosal resection with band ligation (ESMR-L). However, the previous studies did not consider the characteristics of rectal NETs. The aim of our study is to compare the efficacy of ESMR-L and EMR using tailored approach according to the characteristics of rectal NETs. METHODS: 82 rectal NETs in 77 patients treated by ESMR-L (n = 48) or EMR (n = 34) between September 2007 and October 2012 were retrospectively analyzed. ESMR-L was used for flat-type tumors or tumors with non-lifting sign after submucosal injection. Conventional EMR was used for elevated-type tumors or tumors with well-lifting sign after submucosal injection. RESULTS: The pathological complete resection rate was higher in the ESMR-L group (45 lesions, 93.8%) compared with the EMR group (30 lesions, 88.2%); however, this difference was not significant (p = 0.441). Overall complication did not differ significantly between the ESMR-L group and the EMR group (p = 0.774). There was one case of a remnant lesion in the ESMR-L group, which was managed by EMR after circumferential pre-cutting (EMR-P), and no recurrence has been detected in either the ESMR-L or EMR group. CONCLUSIONS: ESMR-L and EMR procedures could have a similar excellent complete resection rate, if we select the endoscopic resection technique according to the characteristics of the small rectal NETs.