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We have developed a Mathematica application package to perform dynamic simulations of the red blood cell (RBC) metabolic network. The package relies on, and integrates, many years of mathematical modeling and biochemical work on red blood cell metabolism. The extensive data regarding the red blood cell metabolic network and the previous kinetic analysis of all the individual components makes the human RBC an ideal 'model' system for mathematical metabolic models. The Mathematica package can be used to understand the dynamics and regulatory characteristics of the red blood cell.

Evaluation of the bone marrow is a routine part of staging of many hematologic malignancies including lymphoma. Bishop et al. (J. Clin. Path. 1992:45;1105) determined that there was a relationship between the length of a trephine biopsy and the likelihood of identifying tumor in the specimen. They found that the yield of malignancy reached a plateau when specimens were greater than or equal to 1.6 cm length, prior to fixation. In a yearlong audit of the results from Christie Hospital 58% of trephine biopsies were found to be inadequate based on this criterion. Though there have been improvements to trephine needles for bone marrow biopsy they all require manual insertion of the needle into the bone to obtain a core. Furthermore, significant variation has been reported among individuals performing trephine biopsies with respect to adequacy of resulting sample. OnControl has introduced a bone marrow biopsy system that uses a power driver to assist in the insertion of the needle into the marrow. In the fall of 2009, 9 physicians were trained on the system. Over the next six months, physicians could choose at their discretion to use a disposable Jamshidi needle with a crown tip or the OnControl bone marrow biopsy system. The results were recorded in a registry as part of a hospital Quality Assurance Project.A prospective registry recorded the date of the procedure, operator, needle type, length of the specimen as determine by pathology, overall cellularity, and involvement of the specimen by tumor. Complications, if any, were to be recorded. For the manual procedures, concurrent aspirate were obtained with an Illinois needle at an adjacent site. With the OnControl system the aspirate and biopsy were performed sequential through a single bone marrow puncture.From January to July, 2010, 142 bone marrow biopsies were performed by the attendings on the Lymphoma Service, 77 with a Jamshidi needle and 65 with the OnControl system. Length: The median lengths were 12mm (0-26) with the Jamshidi and 18mm (6-32) with the OnControl system (p<0.001). The median biopsy length among individual operators ranged from 6 to 15 mm and 11 to 21 mm for the Jamshidi and OnControl system, respectively. Cellularity: For marrow specimens uninvolved by lymphoma, the median cellularity was not different between the two methods; 40% with the Jamshidi (N=59) and 45% with the OnControl (N=45) (p=0.575). Safety: There were no reported procedures-related complications reported with either technique. In three cases, there was some difficulty in removing the marrow core from the OnControl needle (4.6%). Biopsy Adequacy: Using the data driven length of 16mm for adequacy, only 42% of all bone marrows were of an adequate length. However, 60% of the biopsies from the OnControl system were ≥ 16mm compared to 27% of the biopsies obtained with the traditional Jamshidi needle (p<0.001).The OnContol bone marrow biopsy system resulted is a significantly higher proportion of adequate trephine biopsies avoiding the need for repeat or bilateral procedures. The sequential aspirate and biopsy through a single needle did not result in focal hypocellularity of the marrow. The OnControl bone marrow biopsy system is safe and a more effective alternative to conventional Jamshidi biopsy needle.Zelenetz: Communicore: Honoraria.

Aim and Background: To explore how children and adolescents perceive hope, maintain it, and use it in their lives during challenging times, specifically in the context of the COVID-19 pandemic. The pandemic presented a worldwide multifac-torial impact on the mental and physical health of children and adolescents. Design and Methods: A descriptive phenomenological qualitative approach was used. Semi-structured audio-taped interviews were conducted with children (ages 8 to 12 years) and adolescents (ages 13 to 17 years) from varied settings following obtainment of written consent from parent(s) and assent from participants. Transcriptions of the audio-taped interviews were analyzed following Colaizzi's method of analysis. Lincoln and Guba's framework served as the guide for establishing trustworthiness of data and findings. Results: Forty-two interviews were conducted with 22 children and 20 adolescents at which point data saturation was obtained. Five themes representing the children's and adolescents' understanding and use of hope in their lives emerged from the data: internal light, connectedness, unique/one's own/other centered, wavering/challenged/rekindled, and a kaleidoscope of color and facets. These findings support the complex and multidimensional nature of hope in children and adolescents. Conclusions: Findings provide important data for nurses, other health care professionals, teachers, and parents to help them understand children's and adolescents' perception of hope, and how they maintained and used it within the context of the COVID-19 pandemic. Practice Implications: This study could potentially provide a basis upon which to develop hope-focused, developmentally informed interventions and programs to assist children and adolescents in cultivating, strengthening, and engaging their hope. Keywords: Hope, qualitative, COVID-19, children, adolescents, mental health, pandemic., Hope is universally experienced and essential for individuals' positive health and well-being across the lifespan. Research examining hope from the perspective of children or adolescents is currently limited. Hope is [...]

Objective: To investigate the drug loading and release rate of epirubicin-loaded thermosensitive liquid embolic agents in vitro. Materials and Methods: The drug loading and stability of epirubicin-loaded thermosensitive liquid embolic agents with or without iopromide were determined by high-performance liquid chromatography, and the same method was used to determine the drug release rate of thermosensitive liquid embolic agents at different time points. Results: For epirubicin-loaded thermosensitive liquid embolic agents without iopromide, the average drug loading after filtration by membrane was (0.78 ± 0.02) mg and the drug loading rate was (16.1 ± 0.35)%, while the average drug loading without membrane was (0.73 ± 0.06) mg and the drug loading rate was (15.07 ± 1.17)%. After adding iopromide, the drug loading capacity was measured from 0 h-24 h solution and the drug loading was calculated indirectly and conclude that the drug loading capacity of thermosensitive liquid embolic agents decreased or disappeared. The sustained release rate of epirubicin from 0 to 48 hours was 42.65% in 48 hours. Conclusion: Epirubicin can be successfully loaded into the thermosensitive liquid embolic agents with good stability and sustained release. After adding iopromide, the drug loading capacity of thermosensitive liquid embolic agents decreased or disappeared. Keywords: Drug loading, drug release rate, epirubicin, liquid embolic agent, Author(s): Ji'an He [1,2]; Mei Li [1]; Yan Xu [1]; Ning Fan [1,2]; Chong Tian [1,3]; Tianye Lv [1,4]; Wenge Xing (corresponding author) [1]; Haipeng Yu (corresponding author) [1] Transcatheter [...]

Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens--derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered guotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology., We have coevolved with microbes in the environment, and each body habitat has a unique set of microorganisms (microbiota) (1). The most abundant and well-studied microbiota are found in the [...]

OBJECTIVE--The beneficial effects of the inactivation of endocannabinoid system (ECS) by administration of antagonists of the cannabinoid receptor (CB) 1 on several pathological features associated with obesity is well demonstrated, but the relative contribution of central versus peripheral mechanisms is unclear. We examined the impact of CB1 antagonism on liver and adipose tissue lipid metabolism in a mouse model of diet-induced obesity. RESEARCH DESIGN AND METHODS--Mice were fed either with a standard diet or a high-sucrose high-fat (HSHF) diet for 19 weeks and then treated with the CB1-specific antagonist SR141716 (10 mg x [kg.sup.-1] x [day.sup.-1]) for 6 weeks. RESULTS--Treatment with SR141716 reduced fat mass, insulin levels, and liver triglycerides primarily increased by HSHF feeding. Serum adiponectin levels were restored after being reduced in HSHF mice. Gene expression of scavenger receptor class B type I and hepatic lipase was induced by CB1 blockade and associated with an increase in HDL-cholesteryl ether uptake. Concomitantly, the expression of CB1, which was strongly increased in the liver and adipose tissue of HSHF mice, was totally normalized by the treatment. Interestingly, in visceral but not subcutaneous fat, genes involved in transport, synthesis, oxidation, and release of fatty acids were upregulated by HSHF feeding, while this effect was counteracted by CB1 antagonism. CONCLUSIONS--A reduction in the CB1-mediated ECS activity in visceral fat is associated with a normalization of adipocyte metabolism, which may be a determining factor in the reversion of liver steatosis induced by treatment with SR141716. Diabetes 59:926-934, 2010, Obesity results from an imbalance between energy intake and expenditure and is characterized by increased body weight and abnormal development of adipose tissue with excessive fat storage (1). Recently, evidence [...]

OBJECTIVE--We investigated the regulation of adipose tissue gene expression during different phases of a dietary weight loss program and its relation with insulin sensitivity. RESEARCH DESIGN AND METHODS--Twenty-two obese women followed a dietary intervention program composed of an energy restriction phase with a 4-week very-low-calorie diet and a weight stabilization period composed of a 2-month low-calorie diet followed by 3-4 months of a weight maintenance diet. At each time point, a euglycemic-hyperinsulinemic clamp and subcutaneous adipose tissue biopsies were performed. Adipose tissue gene expression profiling was performed using a DNA microarray in a subgroup of eight women. RT-quantitative PCR was used for determination of mRNA levels of 31 adipose tissue macrophage markers (n = 22). RESULTS--Body weight, fat mass, and C-reactive protein level decreased and glucose disposal rate increased during the dietary intervention program. Transcriptome profiling revealed two main patterns of variations. The first involved 464 mostly adipocyte genes involved in metabolism that were downregulated during energy restriction, upregulated during weight stabilization, and unchanged during the dietary intervention. The second comprised 511 mainly macrophage genes involved in inflammatory pathways that were not changed or upregulated during energy restriction and downregulated during weight stabilization and dietary intervention. Accordingly, macrophage markers were upregulated during energy restriction and downregulated during weight stabilization and dietary intervention. The increase in glucose disposal rates in each dietary phase was associated with variation in expression of sets of 80-110 genes that differed among energy restriction, weight stabilization, and dietary intervention. CONCLUSIONS--Adipose tissue macrophages and adipocytes show distinct patterns of gene regulation and association with insulin sensitivity during the various phases of a dietary weight loss program., Obesityis a major risk factor for diabetes and cardiovascular disease. The excess of fat mass is linked to an impairment of insulin sensitivity through complex multifactorial and still poorly understood [...]

OBJECTIVE--Obesity is associated with an overactive endocannabinoid (EC) system. The mechanisms responsible for increased ECs in obese individuals are poorly understood. Therefore, we examined the role of adipocyte insulin resistance in intracellular EC metabolism. METHODS--We used 3T3-L1 adipocytes and diet-induced obese (DIO) mice to examine the role of obesity and insulin resistance in the regulation and/or dysregulation of intracellular ECs. RESULTS--For the first time, we provide evidence that insulin is a major regulator of EC metabolism. Insulin treatment reduced intracellular ECs (2-arachidonylglycerol [2-AG] and anandamide [AEA]) in 3T3-L1 adipocytes. This corresponded with insulin-sensitive expression changes in enzymes of EC metabolism. In insulin-resistant adipocytes, patterns of insulin-induced enzyme expression were disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation. Expression profiling of adipocytes from DIO mice largely recapitulated in vitro changes, suggesting that insulin resistance affects the EC system in vivo. In mice, expression changes of EC synthesis and degradation enzymes were accompanied by increased plasma EC concentrations (2-AG and AEA) and elevated adipose tissue 2-AG. CONCLUSIONS--Our findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation. These novel observations offer a mechanism whereby obese insulin-resistant individuals exhibit increased concentrations of ECs. Diabetes 57:1262-1268, 2008, Growing evidence suggests that the endocannabinoid (EC) system plays an important role in obesity and metabolic disease. ECs are endogenous lipid-derived molecules that act similarly to the active ingredient in [...]

Reactive oxygen species (ROS) influence many physiological processes including host defense, hormone biosynthesis, fertilization, and cellular signaling. Increased ROS production (termed 'oxidative stress') has been implicated in various pathologies, including [...]

The effects of the cannabinoid-1 receptor (C[B.sub.1]) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of C[B.sub.1] antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of C[B.sub.1] antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum-fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that C[B.sub.1] blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent C[B.sub.1] antagonism from exerting beneficial effects on energy and glucose metabolism., Obesity results from a prolonged energy imbalance during which intake exceeds expenditure. The difficulty to lose excess weight is tightly linked to the ability of the systems regulating energy balance [...]

The endocannabinoid system has been suspected to contribute to the association of visceral fat accumulation with metabolic diseases. We determined whether circulating endocannabinoids are related to visceral adipose tissue mass in lean, subcutaneous obese, and visceral obese subjects (10 men and 10 women in each group). We further measured expression of the cannabinoid type 1 (C[B.sub.1]) receptor and fatty acid amide hydrolase (FAAH) genes in paired samples of subcutaneous and visceral adipose tissue in all 60 subjects. Circulating 2-arachidonoyl glycerol (2-AG) was significantly correlated with body fat (r = 0.45, P = 0.03), visceral fat mass (r = 0.44, P = 0.003), and fasting plasma insulin concentrations (r = 0.41, P = 0.001) but negatively correlated to glucose infusion rate during clamp (r = 0.39, P = 0.009). In visceral adipose tissue, C[B.sub.1] mRNA expression was negatively correlated with visceral fat mass (r = 0.32, P = 0.01), fasting insulin (r = 0.48, P < 0.001), and circulating 2-AG (r = 0.5, P < 0.001), whereas FAAH gene expression was negatively correlated with visceral fat mass (r = 0.39, P = 0.01) and circulating 2-AG (r = 0.77, P < 0.001). Our findings suggest that abdominal fat accumulation is a critical correlate of the dysregulation of the peripheral endocannabinoid system in human obesity. Thus, the endocannabinoid system may represent a primary target for the treatment of abdominal obesity and associated metabolic changes. Diabetes 55:3053-3060, 2006, Endocannabinoids are lipid mediators derived from membrane phospholipids or triglycerides with complex effects on body weight and metabolic regulation (1,2). Several enzymes are involved in the synthesis and degradation of [...]

Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity., Obesity is one of the main risk factors for the development of type 2 diabetes, and weight loss may be a successful means of reducing the number of patients affected [...]

Interleukin (IL)-10, an anti-inflammatory cytokine, preserves endothelial function during acute inflammation. We tested the hypotheses that IL-10 plays a protective role in blood vessels during diabetes by suppressing impairment of endothelium-dependent relaxation and that protection by IL-10 is mediated by effects on superoxide ([O.sub.2.sup.-]). Streptozotocin (150 mg/kg i.p.) or citrate buffer was injected into IL-10-deficient (IL-[10.sup.-/-]) mice and wild-type controls (IL-[10.sup.+/+]). In IL[10.sup.+/+] and IL-[10.sup.-/-] mice, blood glucose levels were ~120 mg/dl after citrate administration and ~400 mg/dl after streptozotocin administration. Vasorelaxation was examined in arteries in vitro 12-16 weeks later. Maximum relaxation to acetylcholine (30 µmol/l) was 88 ± 3% (means ± SE) in nondiabetic mice and 84 ± 3% in diabetic IL-[10.sup.+/+] mice (P > 0.05). Thus, at this time point, diabetes did not impair endothelium-dependent relaxation in vessels in wild-type mice. In contrast, maximum relaxation in vessels from diabetic IL-[10.sup.-/-] mice was significantly decreased (74 ± 5%) compared with nondiabetic IL-[10.sup.-/-] mice (93 ± 2%, P < 0.05). Superoxide dismutase with polyethylene glycol (PEG-SOD) restored impaired responses to acetylcholine to levels seen in controls. Responses to acetylcholine also were improved by allopurinol (an inhibitor of xanthine oxidase) in vessels from diabetic IL-[10.sup.-/-] mice. Thus, diabetes produces greater impairment of relaxation to acetylcholine in IL-[10.sup.-/-] mice than in IL-[10.sup.+/+] mice. These findings provide direct evidence that IL-10 impedes mechanisms of endothelial dysfunction during diabetes. Restoration of vasorelaxation with PEG-SOD or allopurinol suggests that the mechanism(s) by which IL-10 preserves endothelium-dependent vasorelaxation involves [O.sub.2.sup.-], perhaps by reducing production of [O.sub.2.sup.-] by xanthine oxidase. Diabetes 51:1931-1937, 2002, Endothelium-dependent vasorelaxation is impaired by proinflammatory cytokines during inflammation (1,2). Interleukin (IL)-10 attenuates expression and/or production of proinflammatory cytokines (3). IL-10 preserves vascular function, including endothelium-dependent relaxation, during acute inflammation [...]