Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma.

PURPOSE: By taking advantage of 18F-FDG PET imaging and tissue nuclear magnetic resonance (NMR) metabolomics, we examined the dynamic metabolic alterations induced by liver irradiation in a mouse model for hepatocellular carcinoma (HCC). METHODS: After orthotopic implantation with the mouse liver cancer BNL cells in the right hepatic lobe, animals were divided into two experimental groups. The first received irradiation (RT) at 15 Gy, while the second (no-RT) did not. Intergroup comparisons over time were performed, in terms of 18F-FDG PET findings, NMR metabolomics results, and the expression of genes involved in inflammation and glucose metabolism. RESULTS: As of day one post-irradiation, mice in the RT group showed an increased 18F-FDG uptake in the right liver parenchyma compared with the no-RT group. However, the difference reached statistical significance only on the third post-irradiation day. NMR metabolomics revealed that glucose concentrations peaked on day one post-irradiation both, in the right and left lobes-the latter reflecting a bystander effect. Increased pyruvate and glutamate levels were also evident in the right liver on the third post-irradiation day. The expression levels of the glucose-6-phosphatase (G6PC) and fructose-1, 6-bisphosphatase 1 (FBP1) genes were down-regulated on the first and third post-irradiation days, respectively. Therefore, liver irradiation was associated with a metabolic shift from an impaired gluconeogenesis to an enhanced glycolysis from the first to the third post-irradiation day. CONCLUSION: Radiation-induced metabolic alterations in the liver parenchyma occur as early as the first post-irradiation day and show dynamic changes over time.

Multimodal imaging reveals transient liver metabolic disturbance and sinusoidal circulation obstruction after a single administration of ketamine/xylazine mixture.

A ketamine/xylazine (K/X) mixture is widely used before and during experiments in rodents. However, the impact of short-term use of K/X mixture and its influences on data interpretation have rarely been discussed. In this study, we administered one shot of a K/X mixture and examined acute hepatic responses using biochemical analysis, histopathological examination, and non-invasive imaging to determine the delay required prior to further assessment of the liver to avoid confounding effects triggered by anaesthesia. After the K/X injection, aspartate aminotransferase (AST) in serum was significantly elevated from 3 to 48 h. Obstructed sinusoidal circulation lasting for 24 or 36 h was revealed by DCE-MRI and drug distribution analysis, respectively. Metabolic alterations were detected at 3 h by NMR analysis and FDG-PET. Moreover, ultrasonography showed that lipid droplet accumulation increased from 1 to 16 h and declined thereafter. Taken together, our findings show that the K/X mixture induces acute hepatotoxicity and metabolic disturbance, and these disturbances cause hemodynamical disorders in the liver. The required time interval for recovery from K/X impact was dependent on the chosen assay. It took at least 16 h for metabolic recovery and 36 h for recovery of sinusoidal circulation. However, the liver was not fully recovered from the injury within 48 h.

Diffusion-weighted MRI and 18F-FDG PET correlation with immunity in early radiotherapy response in BNL hepatocellular carcinoma mouse model: timeline validation.

PURPOSE: Imaging probes/biomarkers that are correlated with molecular or microenvironmental alterations in tumors have been used not only in diagnosing cancer but also in assessing the efficacy of cancer treatment. We evaluated the early response of hepatocellular carcinoma (HCC) to radiation treatment using T2-weighted magnetic resonance imaging (MRI), diffusion-weighted (DW) MRI, and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). METHODS: Orthotopic HCC tumors were established in the right liver lobe of Balb/c mice. Mice were longitudinally scanned using T2-weighted/DW MRI and 18F-FDG PET 1 day before and on days 1, 3, 6, 9 and 13 after irradiation with 15 Gy to the right liver lobe to determine tumor size, apparent diffusion coefficient (ADC) value, and maximum standardized uptake value. Immunohistochemical (IHC) staining was performed to validate the tumor microenvironment. RESULTS: Irradiation markedly retarded tumor growth in the orthotopic HCC model and led to increaes in ADC values as early as on day 1 after irradiation. Irradiation also resulted in increases in 18F-FDG uptake on day 1 that were sustained until the end of the observation period. IHC staining revealed a decrease in the number of proliferative cells and a continuous macrophage influx into irradiated tumors, which dramatically altered the tumor microenvironment. Lastly, in vitro coculture of HCC cells and macrophages led to interaction between the cells and enhanced the cellular uptake of 18F-FDG. CONCLUSION: ADC values and 18F-FDG uptake measured using DW MRI and 18F-FDG PET serve as potential biomarkers for early assessment of HCC tumor responses to radiation therapy.

Low Persistence of Antithrombotic Agents is Associated with Poor Outcomes after First-ever Acute Ischemic Stroke.

OBJECTIVE: This study investigated the time-trend persistence with antithrombotic agents (AT) and assessed the impact of AT persistence on outcome events and adverse events (AE) within two years after first-ever acute ischemic stroke (IS). METHODS: Using Taiwan's National Health Insurance claims dataset, 7,341 IS subjects hospitalized between 2001 and 2005 with AT prescribed at discharge and survived at least 3 months were followed up for 2 years. Time-trends of AT usage were analyzed. Medication persistence was assessed as the proportion of days covered (PDC) for filled prescription, and categorized into low, intermediate and high persistence. Multivariate logistic regression analysis and multivariate Cox proportional hazard regression models were performed to identify factors associated with AT persistence and its impact on vascular outcomes. RESULTS: AT persistence rates declined sharply from 81% to 52% during the first 6 months. In addition to patient and facility-level characteristics, occurrence of AE (e.g., GI bleeding/ulceration, fractures/ major trauma, and iatrogenic/unspecific illness) was inversely related to AT persistence. Compared with patients with low persistence, the composite risk of recurrent stroke, cardiovascular disease, or death from any cause was significantly lower in patients with intermediate (Hazard Ratio [HR] 0.64, 0.57-0.71) or high AT persistence (0.74, 0.66-0.83).

Diminished Neural Responses to Emotionally Valenced Facial Stimuli: A Potential Biomarker for Unemotional Traits in Early Childhood.

Callous-unemotional (CU) traits are characterized by deficits in guilt/empathy, shallow affect, and the callous and manipulative use of others. Individuals showing CU traits have increased risk for behavior problems and reduced responses to displays of distress in others. To explore how deficits in emotion-processing are associated with CU traits, the current study examined the association between callous-unemotionality and a neural index of facial emotion processing, using the event-related potential technique in a group of 3-5 year olds. Children viewed a series of static emotional faces, depicting either fear or happiness, while electroencephalography data were collected. The N170 component, thought to index the neural processes associated with face perception, was examined along with CU traits. Findings suggest that the unemotional dimension of CU traits is associated with diminished emotion-processing responses to fearful faces. Reduced neural responses to facial depictions of fear could be a biomarker for unemotional traits in early childhood.

Rehabilitation Reduced Readmission and Mortality Risks in Patients With Stroke or Transient Ischemic Attack: A Population-based Study.

BACKGROUND: It remains unclear whether rehabilitation has an impact on reducing the long-term risk of mortality or readmission following stroke or transient ischemic attack (TIA). OBJECTIVES: To investigate the association between the dosage and continuation of rehabilitation and the risk of outcome events (OEs) after stroke or TIA. RESEARCH DESIGN: A retrospective cohort study using Taiwan's National Health Insurance database. SUBJECTS: In total, 4594 patients admitted with first-ever acute stroke or TIA were followed-up for 32 months. MEASURES: The occurrence of 3 OEs: (1) vascular readmissions/all-cause mortality [vascular event (VE)], (2) all-cause readmissions/mortality (OE1), and (3) all-cause mortality (OE2), in model 1: none, low-intensity, and high-intensity rehabilitation; and model 2: inpatient plus/or outpatient rehabilitation. RESULTS: Comparing with patients without rehabilitation, in model 1, patients receiving low-intensity rehabilitation had a lower risk of VE [Hazard ratio (HR), 0.77; 95% CI, 0.68-0.87] and OE1 (HR, 0.77; CI, 0.71-0.84), but not OE2 (HR, 0.91; CI, 0.77-1.07). Patients receiving high-intensity rehabilitation had lower risks of all VE (HR, 0.68; CI, 0.58-0.79), OE1 (HR, 0.79; CI, 0.71-0.88), and OE2 (HR, 0.56; CI, 0.44-0.71). In model 2, patients receiving inpatient plus outpatient rehabilitation had a lowest risk of VE (HR, 0.55; CI, 0.47-0.65), OE1 (HR, 0.65; CI, 0.58-0.72), and OE2 (HR, 0.45; CI, 0.35-0.59). Sensitivity analysis with TIA excluded rendered the similar trend. Subgroup analyses found that the positive effect was not demonstrated in hemorrhagic stroke patients. CONCLUSIONS: Rehabilitation use was associated with reduction of readmissions/mortality risks following stroke or TIA. The optimal intensity and duration of rehabilitation and the discrepancy shown in hemorrhagic stroke need further clarification.

Reduced neural responses to vocal fear: a potential biomarker for callous-uncaring traits in early childhood.

OBJECTIVE: Callous-unemotional (CU) traits are characterized by a lack of guilt and empathy, and low responsiveness to distress and fear in others. Children with CU traits are at-risk for engaging in early and persistent conduct problems. Individuals showing CU traits have been shown to have reduced neural responses to others' distress (e.g., fear). However, the neural components of distress responses in children with CU traits have not been investigated in early childhood. In the current study, we examined neural responses that underlie the processing of emotionally valenced vocal stimuli using the event-related potential technique in a group of preschoolers. METHOD: Participants between 2 and 5 years old took part in an auditory oddball task containing English-based pseudowords spoken with either a fearful, happy, or a neutral prosody while electroencephalography data were collected. The mismatch negativity (MMN) component, an index of the automatic detection of deviant stimuli within a series of stimuli, was examined in association with two dimensions of CU traits (i.e., callousness-uncaring and unemotional dimensions) reported by primary caregivers. RESULTS: Findings suggest that the callousness-uncaring dimension of CU traits in early childhood is associated with reduced responses to fearful vocal stimuli. CONCLUSIONS: Reduced neural responses to vocal fear could be a biomarker for callous-uncaring traits in early childhood. These findings are relevant for clinicians and researchers attempting to identify risk factors for early callous-uncaring traits.

Release of Doxorubicin by a Folate-Grafted, Chitosan-Coated Magnetic Nanoparticle.

In clinical tumor therapy, chemotherapeutic routes have caused severe side effects; current delivery methods are unsatisfactory. Successful design of a remotely folate (FA)-grafted chitosan (CS)-coated magnetic nanoparticle (MNP) with low toxicity, has been achieved. A chemotherapeutic drug such as doxorubicin (DOX), is loaded in the MNP-based matrix (FA-grafted CS-DOX-TPP-MNP), which is coated by an activated target tumor molecule of FA-grafted CS biopolymer with the inclusion of tripolyphosphate (TPP) as a linker. The resultant nano-complexes exhibited random aggregates (~240 nm) and zeta potential (-24.9 mV). In vivo experiments using athymic BALB/c nude mice with human glioblastoma U87 cells in a subcutaneous tumor model revealed that magnetic guidance of FA-grafted CS-DOX-TPP-MNP, injected via the tail vein, significantly decreased tumor growth. This manuscript demonstrates the feasibility of magnetizing control of FA-grafted CS-DOX-TPP-MNP to enhance the localization of drug release.

Highly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour.

Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments' inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours' acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.

Gonadotropin releasing hormone agonist treatment to increase final stature in children with precocious puberty: a meta-analysis.

In the setting of central precocious puberty (CPP), the motivation for hormonal intervention is to help the child to reach a taller adult stature than she would achieve otherwise. While gonadotropin-releasing hormone analogs (GnRHa) constitute an established treatment for improving adult stature in girls presenting with CPP up to age 6 (true precocious puberty), it is not yet clear whether or not the same is true in the setting of CPP presented in girls beyond age 6 (advance puberty). GnRHa may slow growth velocity, offsetting the anticipated improvement in final height that should have resulted from the increased time before growth plate fusion. Consequently, it's been suggested that growth hormone (GH) should be combined with GnRHa to improve the results.Few controlled prospective studies have been performed with GnRHa in children and many conclusions rely in part on collective expert opinion. Therefore, the literature was searched and relevant studies were selected using the search terms "gonadotropin releasing hormone agonist," "precocious puberty/early puberty," and "GnRH analogue." After selected articles were screened for relevance, the process yielded 8 studies, the results of which were then pooled in a meta-analysis aimed at evaluating the effects of GnRHa therapy both with and without added GH in the setting of early puberty. A significant difference was elucidated in final height and predicted adult height comparing GnRHa and combined GnRHa/GH groups. However, no significant difference was elucidated in final height standard deviation scores (SDS) and initial height SDS when comparing GnRHa and control groups. At the same time, the final analysis revealed no significant difference in final height SDS and initial height SDS when GnRHa and combined GnRHa/GH groups were compared.The results suggest GnRHa therapy may have a positive effect on final adult height in girls with early puberty, while adding GH to the treatment may suggest more advantage. Interpretation of the results requires extreme caution, given the complexity of the outcome analysis. Final height gain may prove to be a more appropriate measure of treatment efficacy in any case.

Gender differences in smoking behaviors in an Asian population.

BACKGROUND: Gender-sensitive tobacco control policies are being challenged, and new directions are being sought because public health efforts have reduced cigarette consumption more substantially among men than among women. To better target women, it would help to identify the protective cultural factors that promote resiliency in women and discourage them from smoking. Whereas western cultures have generated a great deal of gender-specific research and programs on the prevention of smoking in women, Asian cultures have not. Taking a personal and sociocultural perspective, this study examines the effect of gender on smoking behaviors in Taiwan. METHODS: In a 2004 cross-sectional random-sampled interview survey, 827 adult men and 90 adult women smokers in Taiwan were queried about the time they began smoking, maintenance of their habits, and their readiness to change. RESULTS: The male/female smoking rate ratio was 9.5 (45.7% vs. 4.8%). Men smoked significantly more cigarettes per day than women (18 vs. 11). We found Taiwanese women started smoking around 20 years old, much later than their western counterparts. We also found that whereas the smoking behavior of the men was very sensitive to social environment and structural factors, that of women revolved around their desire to control their weight and handle their emotions. CONCLUSIONS: Differences in the smoking behavior of men and women are a result of a different sociocultural environment and the life trajectories and social circumstances embedded within it. Comprehensive tobacco control policies need to be tailored to not just smoking behavior alone or one population alone but to the determinants of smoking behavior in specific groups, for example, women. Even when targeting women, some effort may be needed on targeting women of different ethnicities, for instance, Asian women in whom the prevalence is increasing at alarming rates.

The effect of changing reimbursement policies on quality of in-patient care, from fee-for-service to prospective payment.

OBJECTIVE: Using insurance claims for hemorrhoidectomies, we examined the effect of Taiwan's Bureau of National Health Insurance's case payment system, a fixed case payment rate method used to reimburse health care providers for in-patient care. DESIGN: This observational natural experimental study examined changes in medical care that occurred between two phases: the 9 months before case payment system was implemented on 1 October 1997 and the 9 months afterwards. The changes were analyzed by performing linear regressions with interaction between hospital type and the implementation of case payment system. SETTING: This study was based on total claim data from National Health Insurance. STUDY PARTICIPANTS: A total of 23 638 hemorrhoidectomy insurance claims. MAIN OUTCOME MEASURES: Length of stay, number of medical services, and number of drug prescriptions. Medical services were stratified into those that were considered minimal requirements and those considered optional by the Bureau of National Health Insurance. RESULTS: Over the 18-month period, the number of patients increased by 23.7%. After the case payment system was implemented, length of stay decreased by 0.59 days (P < 0.0001), the number of minimally required services increased by 2.19 to 4.24 items (P < 0.0001), the number of optional service items decreased by 0.32 items (P < 0.0001), and drug prescription decreased slightly by 0.58 to 0.99 items (P < 0.0001) per hospitalization. CONCLUSIONS: The case payment system successfully shortened length of stay without significantly sacrificing the provision of services.

The effect of Taiwan's tax-induced increases in cigarette prices on brand-switching and the consumption of cigarettes.

The effect of raising cigarette taxes to reduce smoking has been the subject of several studies, which often treat the price of cigarettes as an exogenous factor given to smokers who respond to it by adjusting their smoking behavior. However, cigarette prices vary with brand and quality, and smokers can and do switch to lower-priced brands to reduce the impact of the tax on the cost of cigarettes as they try to consume the same number of cigarettes as they had before a tax hike. Using data from a two-year follow-up interview survey conducted before and after a new cigarette tax scheme was imposed in Taiwan in 2002, this study examines three behavioral changes smokers may make to respond to tax-induced cigarette price increase: brand-switching, amount consumed, and amount spent on smoking. These changes were studied in relation to smoker income, before-tax cigarette price, level of addiction, exposure to advertizing, and consumer loyalty. We found that smokers, depending upon exposure to advertizing, level of consumer loyalty and initial price of cigarettes, switched brands to maintain current smoking habits and control costs. We also found that the initial amount smoked and level of addiction, not price, at least not at the current levels in Taiwan, determined whether a smoker reduced the number of cigarettes he consumed.

Public opinion regarding earmarked cigarette tax in Taiwan.

BACKGROUND: Cigarette taxation has been perceived by academics and policy-makers as one of the most effective ways of reducing the use of cigarettes. On January 1 2002, the Taiwan government imposed a New Taiwan (NT) 5 dollars per pack tax earmarked for the purpose of tobacco control. This study uses a survey collected prior to taxation to assess public attitudes toward cigarette taxation, public beliefs about the effectiveness of cigarette taxation at reducing cigarette use and public opinions about the allocation of this tax revenue. METHODS: Data were drawn from a national face-to-face interview on cigarette consumption in 2000. A total of 3,279 adults were aged 18 to 64 years; 49.9% of whom were male and 50.1% female, and with a smoking prevalence of 49.1% and 4.1%, respectively. The attitudes toward cigarette tax were analysed using multi-logit regressions. We analysed by logistic regression the potential changes in smoking behaviour that smokers might make in response to the five NT (New Taiwan) dollar earmarked tax on cigarettes per pack. We summarized public opinions about the allocation of earmarked tax revenue using descriptive statistics. RESULTS: Current smokers (OR = 0.34) and former smokers (OR = 0.68) were less likely to support the cigarette tax than non-smokers. A favourable attitude toward the tax was positively associated with personal monthly income, especially among females. Among male smokers, the possibility of reducing/quitting smoking in response to the five-NT-dollar tax was negatively associated with the monthly expense for smoking. The two most frequently-suggested areas to receive money from the revenue collected from the earmarked tax were health education and cancer subsidy. CONCLUSIONS: Smoking status and economic factors determine the attitude and potential responses of people toward the cigarette tax. Taiwan's five NT-dollar earmarked tax for cigarettes may have only a limited effect upon the reduction in cigarette use.