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RATIONALE AND OBJECTIVES: The total number of procedures and their relative value units (RVUs) were used to measure the productivity of radiologists. Besides variations in productivity due to differences in the percentage of clinical effort, baseline productivity also varies among clinical subspecialty sections. The authors' previous research used the full-time equivalent (FTE) as the unit to adjust for differences in the percentage of clinical effort and a set of adjustment factors (or calibration constants) to modify the default work RVUs according to types of procedures. These adjustments led to comparable average productivity measurements across subspecialty sections. Since 2003, radiology practice has continued to change, including the introduction of positron emission tomography/computed tomography into clinical practice, suggesting a need to update the understanding of clinical productivity and refine the authors' adjustment procedure. In this study, the authors analyzed the most recent survey of academic departments and derived updated adjustment factors for differences in workload among subspecialty sections. The results can be used to determine faculty staffing requirements and evaluate radiologists' performance. MATERIALS AND METHODS: A survey performed by the Society of Chairmen of Academic Radiology Departments collected data in 2006 for 1,134 radiologists in 24 departments, including 10 departments that also reported productivity in an earlier 2003 survey. These data included the numbers of procedures (represented by Current Procedural Terminology [CPT] codes) performed by radiologists, percentage clinical effort, subspecialty sections, and the number of clinical days. The numbers of CPT codes were converted into total work RVUs per FTE faculty member. By grouping the CPT codes into 6 prespecified examination categories, adjustment factors were created to adjust the RVUs for CPT categories to ensure that the median total adjusted work RVUs from different subspecialty sections were comparable. RESULTS: Overall, the mean clinical workload in 2006 was 9,671 examinations, a statistically significant 15% increase from 2003. The mean number of work RVUs per FTE was 7,136, a 22% increase from 2003. The adjustment factors have been modified from those presented in the authors' earlier paper, including reductions for interventional radiology, computed tomography, magnetic resonance imaging, nuclear medicine, and a new adjustment factor for 'special procedures.' These adjustments reduced differences in adjusted RVUs per FTE between subspecialty sections. CONCLUSIONS: Clinical workload, as measured by RVUs per FTE and adjusted RVUs per FTE, is very useful for determining optimal staffing in subspecialty sections and in radiology departments in general. Workload continues to increase, both in examination complexity and in numbers of overall procedures. Adjustment factors make workload comparisons between subspecialty sections more valid and meaningful. [ABSTRACT FROM AUTHOR]

Background: Medicare data may be a useful source for determining the utilization of mammography among elderly women, but the accuracy of these data has not been established. Objective: We determined whether Medicare physician billing claims are an accurate reflection of mammography utilization among women ages 65 and older and whether they can be used to assess the use of screening as compared with diagnostic mammography. Data Sources: Mammography use was assessed using Medicare billing claims and radiology reports from 2 mammography registries; the San Francisco Mammography Registry and the New Mexico Mammography Registry. Methods: Completeness of the Medicare data was assessed by comparing mammography use based on Medicare, with radiology reports from the mammography registries, which served as the referent standard. Capture rates for Medicare claims for individual mammograms were examined, and women were characterized as having undergone at least 1 mammogram within each 2-year period based on the Medicare data, and these rates were compared with the referent standard. To determine whether Medicare data can distinguish between screening and diagnostic mammography, we performed a classification analysis using the mammography registries screening/diagnostic designation as the referent standard (dependent variable) and Medicare claim information as the independent/predictor variable. On the basis of the mammogram level classification analysis, women were categorized as having been frequently screened (at least 2 screening mammograms spaced by 12 to 36 months), screened (at least 1 screening mammogram), or not screened. Subjects: Women ages 65 and older, diagnosed with breast cancer between 1992-1999, who had at least 1 mammogram between 1992-1999 were examined. Results: A total of 3340 mammograms were obtained in 1371 women between 1992 and 1999. Overall, 83% of mammograms obtained by these women had a corresponding billing claim in Medicare. This increased from 65% in 1992 to 90% in 1999. Of women who underwent at least 1 mammogram during each 2-year period per the referent standard, 94% of women were accurately classified by Medicare claims as also having undergone mammography during the same 2-year period. In multivariable analysis, a mammogram was more likely to be associated with a billing claim over time, for women 80 years or older, and for white and Asian as compared with Hispanic women. Neither socioeconomic status nor screening/diagnostic designation affected the likelihood that a mammogram would be associated with a billing claim. The Medicare data accurately categorized a given mammogram as screening or diagnostic for 87.5% of mammograms. Lastly, there was moderate to substantial agreement in the categorization of women as frequently screened, screened or not screened between the 2 data sets (weighted kappa 0.74, 95% confidence interval 0.70-0.78). Conclusion: Medicare administrative claims are reliable for assessment of mammography utilization and have become more accurate over time. Medicare claims data also provide a mechanism for designating mammography as screening or diagnostic, which subsequently may allow accurate description of a woman's screening history. [ABSTRACT FROM AUTHOR]

A previous study (Haley RW, Marshall WW, McDonald GG, Daugherty MA, Petty F, Fleckenstein JL: Brain abnormalities in Gulf War syndrome: evaluation with 1H MR spectroscopy. Radiology 2000; 215: 807-817) suggested that individuals with Gulf War Illness (GWI) had reduced quantities of the neuronal marker N-acetylaspartate (NAA) in the basal ganglia and pons. This study aimed to determine whether NAA is reduced in these regions and to investigate correlations with other possible causes of GWI, such as psychological response to stress in a large cohort of Gulf War veterans. Individuals underwent tests to determine their physical and psychological health and to identify veterans with (n=81) and without (n=97) GWI. When concentrations of NAA and ratios of NAA to creatine- and choline-containing metabolites were measured in the basal ganglia and pons, no significant differences were found between veterans with or without GWI, suggesting that GWI is not associated with reduced NAA in these regions. Veterans with GWI had significantly higher rates of post-traumatic stress disorder, supporting the idea that GWI symptoms are stress related. [ABSTRACT FROM AUTHOR]

Objectives: The Centers for Medicare and Medicaid Services funded the development of a computed tomography (CT) quality measure for use in pay-for-performance programs, which balances automated assessments of radiation dose with image quality to incentivize dose reduction without compromising the diagnostic utility of the tests. However, no existing quantitative method for assessing CT image quality has been validated against radiologists' image quality assessments on a large number of CT examinations. Thus to develop an automated measure of image quality, we tested the relationship between radiologists' subjective ratings of image quality with measurements of radiation dose and image noise., Materials and Methods: Board-certified, posttraining, clinically active radiologists rated the image quality of 200 diagnostic CT examinations from a set of 734, representing 14 CT categories. Examinations with significant distractions, motion, or artifact were excluded. Radiologists rated diagnostic image quality as excellent, adequate, marginally acceptable, or poor; the latter 2 were considered unacceptable for rendering diagnoses. We quantified the relationship between ratings and image noise and radiation dose, by category, by analyzing the odds of an acceptable rating per standard deviation (SD) increase in noise or geometric SD (gSD) in dose., Results: One hundred twenty-five radiologists contributed 24,800 ratings. Most (89%) were acceptable. The odds of an examination being rated acceptable statistically significantly increased per gSD increase in dose and decreased per SD increase in noise for most categories, including routine dose head, chest, and abdomen-pelvis, which together comprise 60% of examinations performed in routine practice. For routine dose abdomen-pelvis, the most common category, each gSD increase in dose raised the odds of an acceptable rating (2.33; 95% confidence interval, 1.98-3.24), whereas each SD increase in noise decreased the odds (0.90; 0.79-0.99). For only 2 CT categories, high-dose head and neck/cervical spine, neither dose nor noise was associated with ratings., Conclusions: Radiation dose and image noise correlate with radiologists' image quality assessments for most CT categories, making them suitable as automated metrics in quality programs incentivizing reduction of excessive radiation doses., Competing Interests: Conflicts of interest and sources of funding: A.B.B., M.K., and R.S.-B. are co-founders of Alara Imaging, Inc, a company focused on improving the clinical and operational aspects of health systems, including collecting and reporting radiation dose and image quality associated with computed tomography as part of payer-led quality programs. T.P.S. is a consultant for Alara Imaging. Alara Imaging played no role in any aspect of the article. The other authors have no conflicts of interests relevant to this article to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The most accurate method for estimating patient effective dose (a principal metric for tracking patient radiation exposure) from computed tomography (CT) requires time-intensive Monte Carlo simulation. A simpler method multiplies a scalar coefficient by the widely available scanner-reported dose length product (DLP) to estimate effective dose. We developed new adult effective dose coefficients using actual patient scans and assessed their agreement with Monte Carlo simulation., Methods: A multicenter sample of 216,906 adult CT scans was prospectively assembled in 2015-2020 from the University of California San Francisco International CT Dose Registry and the University of Florida library of computational phantoms. We generated effective dose coefficients for eight body regions, stratified by patient sex, diameter, and scanner manufacturer. We applied the new coefficients to DLPs to calculate effective doses and assess their correlations with Monte Carlo radiation transport-generated effective dose., Results: Effective dose coefficients varied by body region and decreased in magnitude with increasing patient diameter. Coefficients were approximately twofold higher for torso scans in smallest compared with largest diameter categories. For example, abdomen and pelvis coefficients decreased from 0.027 to 0.013 mSv/mGy-cm between the 16-20 cm and 41+ cm categories. There were modest but consistent differences by sex and manufacturer. Diameter-based coefficients used to estimate effective dose produced strong correlations with the reference standard (Pearson correlations 0.77-0.86). The reported conversion coefficients differ from previous studies, particularly in neck CT., Conclusions: New effective dose coefficients derived from empirical clinical scans can be used to easily estimate effective dose using scanner-reported DLP., Clinical Relevance Statement: Scalar coefficients multiplied by DLP offer a simple approximation to effective dose, a key radiation dose metric. New effective dose coefficients from this study strongly correlate with gold standard, Monte Carlo-generated effective dose, and differ somewhat from previous studies., Key Points: • Previous effective dose coefficients were derived from theoretical models rather than real patient data. • The new coefficients (from a large registry/phantom library) differ from previous studies. • The new coefficients offer reasonably reliable values for estimating effective dose., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: To characterize the use and impact of radiation dose reduction techniques in actual practice for routine abdomen CT., Methods: We retrospectively analyzed consecutive routine abdomen CT scans in adults from a large dose registry, contributed by 95 hospitals and imaging facilities. Grouping exams into deciles by, first, patient size, and second, size-adjusted dose length product (DLP), we summarized dose and technical parameters and estimated which parameters contributed most to between-protocols dose variation. Lastly, we modeled the total population dose if all protocols with mean size-adjusted DLP above 433 or 645 mGy-cm were reduced to these thresholds., Results: A total of 748,846 CTs were performed using 1033 unique protocols. When sorted by patient size, patients with larger abdominal diameters had increased dose and effective mAs (milliampere seconds), even after adjusting for patient size. When sorted by size-adjusted dose, patients in the highest versus the lowest decile in size-adjusted DLP received 6.4 times the average dose (1680 vs 265 mGy-cm) even though diameter was no different (312 vs 309 mm). Effective mAs was 2.1-fold higher, unadjusted CTDI vol 2.9-fold, and phase 2.5-fold for patients in the highest versus lowest size-adjusted DLP decile. There was virtually no change in kV (kilovolt). Automatic exposure control was widely used to modulate mAs, whereas kV modulation was rare. Phase was the strongest driver of between-protocols variation. Broad adoption of optimized protocols could result in total population dose reductions of 18.6-40%., Conclusion: There are large variations in radiation doses for routine abdomen CT unrelated to patient size. Modification of kV and single-phase scanning could result in substantial dose reduction., Clinical Relevance: Radiation dose-optimization techniques for routine abdomen CT are routinely under-utilized leading to higher doses than needed. Greater modification of technical parameters and number of phases could result in substantial reduction in radiation exposure to patients., Key Points: • Based on an analysis of 748,846 routine abdomen CT scans in adults, radiation doses varied tremendously across patients of the same size and optimization techniques were routinely under-utilized. • The difference in observed dose was due to variation in technical parameters and phase count. Automatic exposure control was commonly used to modify effective mAs, whereas kV was rarely adjusted for patient size. Routine abdomen CT should be performed using a single phase, yet multi-phase was common. • kV modulation by patient size and restriction to a single phase for routine abdomen indications could result in substantial reduction in radiation doses using well-established dose optimization approaches., (© 2023. The Author(s).)

Background: The most accurate method for estimating effective dose (the most widely understood metric for tracking patient radiation exposure) from computed tomography (CT) requires time-intensive Monte Carlo simulation. A simpler method multiplies a scalar coefficient by the widely available scanner-reported dose length product (DLP) to estimate effective dose., Objective: Develop pediatric effective dose coefficients and assess their agreement with Monte Carlo simulation., Materials and Methods: Multicenter, population-based sample of 128,397 pediatric diagnostic CT scans prospectively assembled in 2015-2020 from the University of California San Francisco International CT Dose Registry and the University of Florida library of highly realistic hybrid computational phantoms. We generated effective dose coefficients for seven body regions, stratified by patient age, diameter, and scanner manufacturer. We applied the new coefficients to DLPs to calculate effective doses and assessed their correlations with Monte Carlo radiation transport-generated effective doses., Results: The reported effective dose coefficients, generally higher than previous studies, varied by body region and decreased in magnitude with increasing age. Coefficients were approximately 4 to 13-fold higher (across body regions) for patients  <1 year old compared with patients 15-21 years old. For example, head CT (54% of scans) dose coefficients decreased from 0.039 to 0.003 mSv/mGy-cm in patients  <1 year old vs. 15-21 years old. There were minimal differences by manufacturer. Using age-based conversion coefficients to estimate effective dose produced moderate to strong correlations with Monte Carlo results (Pearson correlations 0.52-0.80 across body regions)., Conclusions: New pediatric effective dose coefficients update existing literature and can be used to easily estimate effective dose using scanner-reported DLP., (© 2023. The Author(s).)

Inflammation has been associated with numerous neurological disorders. Inflammatory environments trigger a series of cellular and physiological alterations in the brain. However, how inflammatory milieu affects neuronal physiology and how neuronal alterations progress in the inflammatory environments are not fully understood. In this study, we examined the effects of pro-inflammatory milieu on mitochondrial functions and neuronal activities in the hypothalamic POMC neurons. Treating mHypoA-POMC/GFP1 with the conditioned medium collected from LPS activated macrophage were employed to mimic the inflammatory milieu during hypothalamic inflammation. After a 24-h treatment, intracellular ROS/RNS levels were elevated, and the antioxidant enzymes were reduced. Mitochondrial respiration and mitochondrial functions, including basal respiratory rate, spared respiration capacity, and maximal respiration, were all significantly compromised by inflammatory milieu. Moreover, pro-inflammatory cytokines altered mitochondrial dynamics in a time-dependent manner, resulting in the elongation of mitochondria in POMC neurons after a 24-h treatment. Additionally, the increase of C-Fos and Pomc genes expression indicated that the neurons were activated upon the stimulation of inflammatory environment. This neuronal activation of were confirmed on the LPS-challenged mice. Collectively, a short-term to midterm exposure to inflammatory milieu stimulated metabolic switch and neuronal activation, whereas chronic exposure triggered the elevation of oxidative stress, the decrease of the mitochondrial respiration, and the alterations of mitochondrial dynamics., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Drug-resistant tuberculosis (DR-TB) is a major contributor to global cases of antimicrobial resistance and remains a public health challenge. To understand the extent and trend of DR-TB under an enhanced multidrug-resistant TB (MDR-TB) management program, we conducted a population-based retrospective study of 1511 Taiwanese MDR-TB cases reported from 2008 to 2019., Methods: We obtained patient demographics and clinical and bacteriological information from the National TB Registry and the Infectious Disease Notification System., Results: Of the 1511 MDR-TB patients, 941 were new cases, 485 were previously treated, and 85 had an unknown history of treatment. The male to female ratio was 2.75, and the median age of the patients was 57 years (IQR: 45-72). We observed a significant decline in MDR-TB cases, with annual percentage change (APC) of -4.17%. However, new and previously treated MDR-TB cases had APCs of -1.41% and -9.18%, respectively. The rates of MDR-TB resistance to ethambutol, streptomycin and pyrazinamide were 47.2%, 42.4% and 28.9%, respectively, whereas the rates of resistance to fluoroquinolones and second-line injectable drugs (SLIDs) were 4.1-7.1%, 9.0-14.1%; and the rate of extensively drug-resistant TB was 1.9%, respectively. Furthermore, we observed a decreasing trend of resistance to SLIDs (APCs -7.0% to -8.2%) in new cases and a significant decreasing trend of resistance to moxifloxacin (-24.6%) and levofloxacin (-23.3%) in previously treated cases., Conclusion: The decreasing trend of MDR-TB and resistance to second-line drugs suggested that our programmatic management of TB was effective and that the impact on TB control was profound., Competing Interests: Conflict of interest None., (Copyright © 2022. Published by Elsevier B.V.)

Background: Advances in CT have facilitated widespread use of medical imaging while increasing patient lifetime exposure to ionizing radiation., Purpose: To describe dose optimization strategies used by health care organizations to optimize radiation dose and image quality., Materials and Methods: A qualitative study of semistructured interviews conducted with 26 leaders from 19 health care systems in the United States, Europe, and Japan. Interviews focused on strategies that were used to optimize radiation dose at the organizational level. A directed content analysis approach was used in data analysis., Results: Analysis identified seven organizational strategies used by these leaders for optimizing CT dose: (1) engaging radiologists and technologists, (2) establishing a CT dose committee, (3) managing organizational change, (4) providing leadership and support, (5) monitoring and benchmarking, (6) modifying CT protocols, and (7) changes in equipment and work rules., Conclusions: Leaders in these health systems engaged in specific strategies to optimize CT dose within their organizations. The strategies address challenges health systems encounter in optimizing CT dose at the organizational level and offer an evolving framework for consideration in dose optimization efforts for enhancing safety and use of medical imaging., (Copyright © 2022 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: Radiation dose metrics vary by the calibration reference phantom used to report doses. By convention, 16-cm diameter cylindrical polymethyl-methacyrlate phantoms are used for head imaging and 32-cm diameter phantoms are used for body imaging in adults. Actual usage patterns in children remain under-documented., Objective: This study uses the University of California San Francisco International CT Dose Registry to describe phantom selection in children by patient age, body region and scanner manufacturer, and the consequent impact on radiation doses., Materials and Methods: For 106,837 pediatric computed tomography (CT) exams collected between Jan. 1, 2015, and Nov. 2, 2020, in children up to 17 years of age from 118 hospitals and imaging facilities, we describe reference phantom use patterns by body region, age and manufacturer, and median and 75th-percentile dose-length product (DLP) and volume CT dose index (CTDI vol ) doses when using 16-cm vs. 32-cm phantoms., Results: There was relatively consistent phantom selection by body region. Overall, 98.0% of brain and skull examinations referenced 16-cm phantoms, and 95.7% of chest, 94.4% of abdomen and 100% of cervical-spine examinations referenced 32-cm phantoms. Only GE deviated from this practice, reporting chest and abdomen scans using 16-cm phantoms with some frequency in children up to 10 years of age. DLP and CTDI vol values from 16-cm phantom-referenced scans were 2-3 times higher than 32-cm phantom-referenced scans., Conclusion: REFERENCE PHANTOM SELECTION IS HIGHLY CONSISTENT, WITH A SMALL BUT SIGNIFICANT NUMBER OF ABDOMEN AND CHEST SCANS (~5%) USING 16-CM PHANTOMS IN YOUNGER CHILDREN, WHICH PRODUCES DLP VALUES APPROXIMATELY TWICE AS HIGH AS EXAMS REFERENCED TO 32-CM PHANTOMS., (© 2021. The Author(s).)

Systemic and intracellular metabolic states are critical factors affecting immune cell functions. The metabolic regulator AMP-activated protein kinase (AMPK) senses AMP levels and mediates cellular responses to energy-restrained conditions. The ubiquitously expressed AMPK participates in various biological functions in numerous cell types, including innate immune cell macrophages and osteoclasts, which are their specialized derivatives in bone tissues. Previous studies have demonstrated that the activation of AMPK promotes macrophage polarization toward anti-inflammatory M2 status. Additionally, AMPK acts as a negative regulator of osteoclastogenesis, and upregulation of AMPK disrupts the differentiation of osteoclasts. However, the regulation and roles of AMPK in differentiated osteoclasts have not been characterized. Here, we report that inflammatory stimuli-regulated-AMPK activation of differentiated and undifferentiated osteoclasts in opposite ways. Lipopolysaccharide (LPS) inhibited the phosphorylation of AMPK in macrophages and undifferentiated osteoclasts, but it activated AMPK in differentiated osteoclasts. Inactivating AMPK decreased cellular responses against the activation of toll-like receptor signaling, including the transcriptional activation of proinflammatory cytokines and the bone resorption genes TRAP, and MMP9. The elevation of bone resorption by LPS stimulation was disrupted by AMPK inhibitor, indicating the pivotal roles of AMPK in inflammation-induced activities in differentiated osteoclasts. The AMPK activator metformin did not increase proinflammatory responses, possibly because other factors are also required for this regulation. Notably, changing the activation status of AMPK did not alter the expression levels of bone resorption genes in unstimulated osteoclasts, indicating the essential roles of AMPK in cellular responses to inflammatory stimuli but not in the maintenance of basal levels. Unlike its M2-polarizing roles in macrophages, AMPK was not responsive to the M2 stimulus of interleukin-4. Our observations revealed differences in the cellular properties of macrophages and osteoclasts as well as the complexity of regulatory mechanisms for osteoclast functions., (© 2021 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Hypercholesterolemia induces intracellular accumulation of cholesterol in macrophages and other immune cells, causing immunological dysfunctions. On cellular levels, cholesterol enrichment might lead to mitochondrial metabolic reprogramming and change macrophage functions. Additionally, as cholesterol is permeable to the plasma membrane and might integrate into the membranous organelles, such as endoplasmic reticulum or mitochondria, cholesterol enrichment might change the functions or properties of these organelles, and ultimately alters the cellular functions. In this study, we investigate the mitochondrial alterations and intracellular oxidative stress induced by accumulation of cholesterol in the macrophages, and the possible immunological impacts caused by these alterations. Macrophage cells RAW264.7 were treated with cholesterol to induce intracellular accumulation of cholesterol, which further triggered the reduced production of reactive oxygen/nitrogen species, as well as decrease of oxidative phosphorylation. Basal respiration rate, ATP production and non-mitochondrial oxygen consumption are all suppressed. In contrast, glycolysis remained unaltered in this cholesterol-enriched condition. Previous studies demonstrated that metabolic profiles are associated with macrophage polarization. We further verified whether this metabolic reprogramming influences the macrophage responses to pro-inflammatory or anti-inflammatory stimuli. Our results showed the changes of transcriptional regulations in both pro-inflammatory and anti-inflammatory genes, but not specific toward M1 or M2 polarization. Collectively, the accumulation of cholesterol induced mitochondrial metabolic reprogramming and suppressed the production of oxidative stress, and induced the alterations of macrophage functions., (© 2021 The Authors.)

An outbreak of pneumonia associated with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, China, in December 2019, and has been spread worldwide rapidly now. Over 5.3-million confirmed cases and 340,000 disease-associated deaths have been found till May 25, 2020. The potential pathophysiology for SARS-CoV-2 to affect the target is via the receptor, angiotensin-converting enzyme 2 (ACE2). ACE2 can be found in the respiratory, cardiovascular, gastrointestinal tract, urinary tract, and reproductive organs such as human ovaries and Leydig cells in the testis. This receptor plays a dominant role in the fertility function. Considering the crucial roles of testicular cells of the male reproductive system, increasing numbers of studies focus on the effects of SARS-CoV-2 on the testis. In this literature, we reviewed several studies to evaluate the relevance between SARS-CoV-2, ACE receptor, and female and male reproductive system and found that the risk of being attacked by SARS-CoV-2 is higher in males than in females. Since men infected with SARS-CoV-2 virus may have the risk of impaired reproductive performance, such as the orchitis and an elevated of luteinizing hormone (LH), and additionally, SARS-CoV-2 virus may be found in semen, although the latter is still debated, all suggest that we should pay much attention to sexual transmitted disease and male fertility after recovering from COVID-19.

Background: Pyruvate kinase M2 (PKM2) is a regulator of the processes of glycolysis and oxidative phosphorylation, but the roles that it plays in endometrial cancer remain largely unknown. This study evaluated the PKM2 expression in normal endometrium, endometrial hyperplasia, and endometrial carcinoma, and its prognostic value was investigated in endometrial carcinoma patients., Methods: A hospital-based retrospective review was conducted to examine the immunohistochemical PKM2 distribution in 206 endometrium samples from biopsies or hysterectomies. The immunoreactivity of PKM2 was divided into groups of low and high scores according to the extent and intensity of staining., Results: Intense cytoplasmic staining was observed for the PKM2 protein in malignant endometrial lesions. A high PKM2 score was observed in many endometrial carcinoma samples (50.0%), but there was a low percentage in endometrial atypical hyperplasia (12.5%). High PKM2 expression was not found in the normal endometrium (0.0%) nor endometrial hyperplasia without atypia (0.0%). The PKM2 protein score was significantly higher in endometrial carcinoma samples than premalignant endometrial lesions (p < 0.001). Notably, higher PKM2 scores in cases of endometrial carcinoma correlated with poor overall survival (p = 0.006), and the hazard ratio for death was 3.40 (95% confidence interval, 1.35-8.56)., Conclusions: Our results indicate that the prevalence of PKM2 high tumor cells in endometrial carcinoma is significantly associated with worse prognostic factors and favors a poor prognosis. The expression of PKM2 is also a potential histopathological biomarker for use in the differential diagnosis of malignant and premalignant endometrial lesions., Competing Interests: The authors declare no conflict of interest.

Background: The treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients in the 1990s in Taiwan was not satisfactory. To strengthen programmatic management of drug-resistant tuberculosis (PMDT), Taiwan MDR-TB Consortium (TMTC) was established in 2007. We assess the performance and epidemiologic impact of TMTC., Methodology/principle Findings: We analyzed the trends of proportion of TB cases with drug susceptibility testing, enrollment of MDR-TB patients into TMTC and outcomes of treatment of all MDR-TB patients in Taiwan from 2007-2016. We computed the trends of both incidence and prevalence of MDR-TB from 2007-2016. We assessed the trends of MDR-TB among both new and recurrent TB cases. The proportion of TB cases with drug susceptibility testing results increased from 24.2% in 2007 to 97.9% in 2016. Of the 1,452 MDR-TB patients who were eligible for TMTC care, 1,197 (82.4%) were enrolled in TMTC, in whom 82.9% had treatment success. MDR-TB incidence was 9.0 cases per million in 2007, which declined to 4.6 cases per million in 2016 (p<0.0001). MDR-TB prevalence decreased from 19.4 cases per million in 2007 to 8.4 cases per million in 2016 (p<0.0001). The proportion of MDR-TB among new TB cases decreased from 1.4% in 2010 to 1.0% in 2016 (p = 0.039); and that among recurrent TB cases from 9.0% in 2010 to 1.8% in 2016 (p<0.0001)., Conclusions: We concluded that effective PMDT have had a significant impact on the epidemic of drug-resistant TB in Taiwan., Competing Interests: The authors have declared that no competing interests exist.

Oxidation of pure Ti sputtered with a 250 nm layer of amorphous SiO 2 and bulk Ti 5 Si 3 was conducted at 800 °C for 2 or 32 h in a 1 standard cubic centimeter per minute (SCCM) O 2 /4 SCCM Ar environment (approximately pO 2 = 0.2 atm/20.3 kPa). Specimens were characterized using transmission electron microscopy, scanning transmission electron microscopy, and energy dispersive spectroscopy. The data in this article accompanies research article "Early oxidation behavior of Si-coated titanium" [1], which contains further discussion. The data for this article is hosted at the Materials Commons data repository and is available for download at https://materialscommons.org/mcapp/#/data/dataset/b8bc8038-a735-4cb9-9a9e-a0fb912b248c.

Bisphenol A (BPA) is an industrial material used for many plastic products and is considered an endocrine disruptor. BPA can be released into the environment and can spread through the food chain. It is well known that BPA exposure leads to lesions, especially in the reproductive system. According to previous studies, BPA reduces newborn numbers in pregnant mice and affects placentation. The placenta is a special endocrine organ during pregnancy. It secretes important hormones, such as progesterone and estrogen, to maintain gestation. In steroid hormone synthesis, two specific enzymes are important: P450scc (CYP11A1) converts cholesterol to pregnenolone and aromatase (CYP19) induces androgen conversion to estrogen.To determine the effects of a low dose of BPA on hormone synthesis in the placenta, we used JEG-3 cells as a model. We found that the steroidogenic genes CYP11A1 and CYP19 were downregulated in human tissues by detectable concentrations of BPA (1-1000 nM), which do not affect cell viability. Furthermore, we demonstrated that BPA influenced the ERK signaling pathway and resulted in hormone reductions. An analysis of trophoblasts in primary culture from a term human placenta showed the same phenomena. Our data demonstrate that treatment with a low dose of BPA does not affect human placental cell survival, but decreases hormone production via to the downregulation of steroidogenic genes and ERK signaling pathway changes.

Plasma membrane-localized pattern recognition receptors (PRRs) such as FLAGELLIN SENSING2 (FLS2), EF-TU RECEPTOR (EFR), and CHITIN ELICITOR RECEPTOR KINASE1 (CERK1) recognize microbe-associated molecular patterns (MAMPs) to activate pattern-triggered immunity (PTI). A reverse genetics approach on genes responsive to the priming agent β-aminobutyric acid (BABA) revealed IMPAIRED OOMYCETE SUSCEPTIBILITY1 (IOS1) as a critical PTI player. Arabidopsis thaliana ios1 mutants were hypersusceptible to Pseudomonas syringae bacteria. Accordingly, ios1 mutants showed defective PTI responses, notably delayed upregulation of the PTI marker gene FLG22-INDUCED RECEPTOR-LIKE KINASE1, reduced callose deposition, and mitogen-activated protein kinase activation upon MAMP treatment. Moreover, Arabidopsis lines overexpressing IOS1 were more resistant to bacteria and showed a primed PTI response. In vitro pull-down, bimolecular fluorescence complementation, coimmunoprecipitation, and mass spectrometry analyses supported the existence of complexes between the membrane-localized IOS1 and BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1)-dependent PRRs FLS2 and EFR, as well as with the BAK1-independent PRR CERK1. IOS1 also associated with BAK1 in a ligand-independent manner and positively regulated FLS2-BAK1 complex formation upon MAMP treatment. In addition, IOS1 was critical for chitin-mediated PTI. Finally, ios1 mutants were defective in BABA-induced resistance and priming. This work reveals IOS1 as a novel regulatory protein of FLS2-, EFR-, and CERK1-mediated signaling pathways that primes PTI activation., (© 2016 American Society of Plant Biologists. All rights reserved.)

Objective: To evaluate how the accuracy of present-on-admission (POA) reporting affects hospital 30-day acute myocardial infarction (AMI) mortality assessments., Data Sources: A total of 2005 California patient discharge data (PDD) and vital statistics death files., Study Design: We compared hospital performance rankings using an established model assessing hospital performance for AMI with (1) a model incorporating POA indicators of whether a secondary condition was a comorbidity or a complication of care, and (2) a simulation analysis that factored POA indicator accuracy into the hospital performance assessment. For each simulation, we changed POA indicators for six major acute risk factors of AMI mortality. The probability of POA being changed depended on patient and hospital characteristics., Principal Findings: Comparing the performance rankings of 268 hospitals using the established model with that using the POA indicator, 67 hospitals' (25 percent) rank differed by ≥10 percent. POA reporting inaccuracy due to overreporting and underreporting had little additional impact; POA overreporting contributed to 4 percent of hospitals' difference in rank compared to the POA model and POA underreporting contributed to <1 percent difference., Conclusion: Incorporating POA indicators into risk-adjusted models of AMI care has a substantial impact on hospital rankings of performance that is not primarily attributable to inaccuracy in POA hospital reporting., (© Health Research and Educational Trust.)

Background: Src-family kinases (SFKs) are involved in neuronal survival and their aberrant regulation contributes to neuronal death. However, how they control neuronal survival and death remains unclear., Objective: To define the effect of inhibition of Src activity and expression on neuronal survival., Results: In agreement with our previous findings, we demonstrated that Src was cleaved by calpain to form a 52-kDa truncated fragment in neurons undergoing excitotoxic cell death, and expression of the recombinant truncated Src fragment induced neuronal death. The data confirm that the neurotoxic signaling pathways are intact in the neurons we used for our study. To define the functional role of neuronal SFKs, we treated these neurons with SFK inhibitors and discovered that the treatment induced cell death, suggesting that the catalytic activity of one or more of the neuronal SFKs is critical to neuronal survival. Using small hairpin RNAs that suppress Src expression, we demonstrated that Src is indispensable to neuronal survival. Additionally, we found that neuronal death induced by expression of the neurotoxic truncated Src mutant, treatment of SFK inhibitors or knock-down of Src expression caused inhibition of the neuroprotective protein kinases Erk1/2, or Akt., Conclusions: Src is critical to both neuronal survival and death. Intact Src sustains neuronal survival. However, in the excitotoxic condition, calpain cleavage of Src generates a neurotoxic truncated Src fragment. Both intact Src and the neurotoxic truncated Src fragment exert their biological actions by controlling the activities of neuroprotective protein kinases., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Plasma membrane-localized pattern recognition receptors such as FLAGELLIN SENSING2 (FLS2) and EF-TU RECEPTOR (EFR) recognize microbe-associated molecular patterns (MAMPs) to activate the first layer of plant immunity termed pattern-triggered immunity (PTI). A reverse genetics approach with genes responsive to the priming agent β-aminobutyric acid (BABA) revealed IMPAIRED OOMYCETE SUSCEPTIBILITY1 (IOS1) as a critical PTI player. Arabidopsis thaliana ios1 mutants were hypersusceptible to Pseudomonas syringae bacteria. Accordingly, ios1 mutants demonstrated defective PTI responses, notably delayed upregulation of PTI marker genes, lower callose deposition, and mitogen-activated protein kinase activities upon bacterial infection or MAMP treatment. Moreover, Arabidopsis lines overexpressing IOS1 were more resistant to P. syringae and demonstrated a primed PTI response. In vitro pull-down, bimolecular fluorescence complementation, coimmunoprecipitation, and mass spectrometry analyses supported the existence of complexes between the membrane-localized IOS1 and FLS2 and EFR. IOS1 also associated with BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1) in a ligand-independent manner and positively regulated FLS2/BAK1 complex formation upon MAMP treatment. Finally, ios1 mutants were defective in BABA-induced resistance and priming. This work reveals IOS1 as a regulatory protein of FLS2- and EFR-mediated signaling that primes PTI activation upon bacterial elicitation., (© 2014 American Society of Plant Biologists. All rights reserved.)

Pethidine is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, pethidine may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, pethidine potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity.

This article evaluates the accuracy of reporting do not resuscitate (DNR) orders in administrative data for use in risk-adjusted hospital assessments. We compared DNR reporting by 48 California hospitals in 2005 patient discharge data (PDD) with gold-standard assessments made by registered nurses (RNs) who reabstracted 1,673 records of patients with myocardial infarction, pneumonia, or heart failure. The PDD agreed with the RN reabstraction in 1,411 (84.3%) cases. The administrative data did not reflect a DNR order in 71 of 512 records where the RN indicated there was (14% false negative rates), and reflected a DNR order in 191 of 1,161 records where the RN indicated there was not (16% false positive rate). The accuracy of DNR was more problematic for patients who died, suggesting that hospital-reported DNR is problematic for capturing patient preferences for resuscitation that can be used for risk-adjusted outcomes assessments.

Background: The 2010 Affordable Care Act relies on Federally Qualified Health Centers (FQHCs) and FQHC look-alikes (look-alikes) to provide care for newly insured patients, but ties increased funding to demonstrated quality and efficiency., Purpose: To compare FQHC and look-alike physician performance with private practice primary care physicians (PCPs) on ambulatory care quality measures., Methods: The study was a cross-sectional analysis of visits in the 2006-2008 National Ambulatory Medical Care Survey. Performance of FQHCs and look-alikes on 18 quality measures was compared with private practice PCPs. Data analysis was completed in 2011., Results: Compared to private practice PCPs, FQHCs and look-alikes performed better on six measures (p<0.05); worse on diet counseling in at-risk adolescents (26% vs 36%, p=0.05); and no differently on 11 measures. Higher performance occurred in ACE inhibitors use for congestive heart failure (51% vs 37%, p=0.004); aspirin use in coronary artery disease (CAD; 57% vs 44%, p=0.004); β-blocker use for CAD (59% vs 47%, p=0.01); no use of benzodiazepines in depression (91% vs 84%, p=0.008); blood pressure screening (90% vs 86%, p<0.001); and screening electrocardiogram (EKG) avoidance in low-risk patients (99% vs 93%, p<0.001). Adjusting for patient characteristics yielded similar results, except that private practice PCPs no longer performed better on any measures., Conclusions: FQHCs and look-alikes demonstrated equal or better performance than private practice PCPs on select quality measures despite serving patients who have more chronic disease and socioeconomic complexity. These findings can provide policymakers with some reassurance as to the quality of chronic disease and preventive care at Federally Qualified Health Centers and look-alikes, as they plan to use these health centers to serve 20 million newly insured individuals., (Copyright © 2012 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Plant cells can be sensitized toward a subsequent pathogen attack by avirulent pathogens or by chemicals such as β-aminobutyric acid (BABA). This process is called priming. Using a reverse genetic approach in Arabidopsis thaliana, we demonstrate that the BABA-responsive L-type lectin receptor kinase-VI.2 (LecRK-VI.2) contributes to disease resistance against the hemibiotrophic Pseudomonas syringae and the necrotrophic Pectobacterium carotovorum bacteria. Accordingly, LecRK-VI.2 mRNA levels increased after bacterial inoculation or treatments with microbe-associated molecular patterns (MAMPs). We also show that LecRK-VI.2 is required for full activation of pattern-triggered immunity (PTI); notably, lecrk-VI.2-1 mutants show reduced upregulation of PTI marker genes, impaired callose deposition, and defective stomatal closure. Overexpression studies combined with genome-wide microarray analyses indicate that LecRK-VI.2 positively regulates the PTI response. LecRK-VI.2 is demonstrated to act upstream of mitogen-activated protein kinase signaling, but independently of reactive oxygen production and Botrytis-induced kinase1 phosphorylation. In addition, complex formation between the MAMP receptor flagellin sensing2 and its signaling partner brassinosteroid insensitive1-associated kinase1 is observed in flg22-treated lecrk-VI.2-1 mutants. LecRK-VI.2 is also required for full BABA-induced resistance and priming of PTI. Our work identifies LecRK-VI.2 as a novel mediator of the Arabidopsis PTI response and provides insight into molecular mechanisms governing priming.

Objective: To test the accuracy of reporting present-on-admission (POA) and to assess whether POA reporting accuracy differs by hospital characteristics., Data Sources: We performed an audit of POA reporting of secondary diagnoses in 1,059 medical records from 48 California hospitals., Study Design: We used patient discharge data (PDD) to select records with secondary diagnoses that are powerful predictors of mortality and could potentially represent comorbidities or complications among patients who either had a primary procedure of a percutaneous transluminal coronary angioplasty or a primary diagnosis of acute myocardial infarction, community-acquired pneumonia, or congestive heart failure. We modeled the relationship between secondary diagnoses POA reporting accuracy (over-reporting and under-reporting) and hospital characteristics., Data Collection: We created a gold standard from blind reabstraction of the medical records and compared the accuracy of the PDD against the gold standard., Principal Findings: The PDD and gold standard agreed on POA reporting in 74.3 percent of records, with 13.7 percent over-reporting and 11.9 percent under-reporting. For-profit hospitals tended to overcode secondary diagnoses as present on admission (odds ratios [OR] 1.96; 95 percent confidence interval [CI] 1.11, 3.44), whereas teaching hospitals tended to undercode secondary diagnoses as present on admission (OR 2.61; 95 percent CI 1.36, 5.03)., Conclusions: POA reporting of secondary diagnoses is moderately accurate but varies by hospitals. Steps should be taken to improve POA reporting accuracy before using POA in hospital assessments tied to payments., (© Health Research and Educational Trust.)

Objective: To investigate the relationship between the Notch 1 signaling pathway and the embryo implantation rate., Design: Mouse embryos were cultured in vitro, and implantation competency was quantified., Setting: Tertiary fertility center of a university teaching hospital., Animal(s): Outbred ICR strain mouse embryos., Intervention(s): The expression of Notch 1 was altered by adding a γ-secretase inhibitor to the culture medium. We quantified the consequent effect on embryo implantation., Main Outcome Measure(s): We measured the messenger RNA level of Notch 1 gene at different embryonic stages, embryo implantation rate under different culture conditions, the amount of Notch 1, and related implantation competency., Result(s): Quantitative polymerase chain reaction showed that the expression of Notch 1 increased during the implantation window. Adding γ-secretase inhibitor in the culture medium decreased the percentage of blastocysts in a dose-dependent manner. A Matrigel invasion assay showed that the competency of implantation required adequate expression of Notch 1 intracellular domain., Conclusion(s): Expression of Notch 1 at the proper time is required for the competency of embryo implantation; this effect is mediated through regulation of Notch 1 intracellular domain expression., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant "binge" treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.

A new certified reference material (CRM) of melamine in milk GLHK-11-02 was developed aiming to address the great demand from the testing community after the melamine crises. The material was prepared by adding an appropriate quantity of melamine into the skimmed milk samples and the final product was in the form of fine lyophilized powder. Characterization of the material relied on two newly developed gravimetric isotope dilution mass spectrometry (IDMS) methods, one using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and another gas chromatography-mass spectrometry (GC-MS). Experimental parameters with crucial effects on the performance of the two IDMS methods were thoroughly investigated. These included purity of standard used, equilibration time of isotopes, efficiency of extraction methods as well as possible interferences from the matrix and melamine analogues. Precision was found to be excellent with a coefficient of variation of 2.5% for the LC-IDMS/MS (n=46) and 1.9% for the GC-IDMS (n=30) respectively. Using one-tail Student's t-test at 95% confidence interval, analytical data sets generated from the two methods were found to exhibit no significant difference. Measurement accuracy of the methods was further verified through an Asia Pacific Metrology Program (APMP) pilot study. Analytical results of the present LC-IDMS/MS for the two milk test samples at the concentration level of about 0.45 and 3.5 mg kg(-1) were proven to be very good. There were excellent overlaps between our results and the assigned reference values, and the absolute deviation was less than 3.2%. Both the LC-IDMS/MS and GC-IDMS methods were shown to be sufficiently reliable and accurate for certification of the melamine CRM. Certified value of melamine in dry mass fraction in GLHK-11-02 was 1.14 mg kg(-1). Expanded uncertainty due to sample inhomogeneity, long term and short term stability and variability in the characterization procedure was at 7.1% or 0.08 mg kg(-1). The CRM is primarily used to provide a complete method validation for and to improve the technical competence of melamine analysis to food and chemical testing laboratories., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Breast cancer has a long natural history. Established and emerging biologic markers address overall risk but not necessarily timing of recurrence. 346 adjuvant naïve breast cancer cases from Guy's Hospital with 23 years minimum follow-up and archival blocks were recut and reassessed for hormone-receptors (HR), HER2-receptor and grade. Disease-specific survival (DSS) was analyzed by recursive partitioning. To validate insights from this analysis, gene-signatures (proliferative and HR-negative) were evaluated for their ability to predict early versus late metastatic risk in 683 node-negative, adjuvant naïve breast cancers annotated with expression microarray data. Risk partitioning showed that adjuvant naïve node-negative outcome risk was primarily partitioned by tumor receptor status and grade but not tumor size. HR-positive and HER2-negative (HRpos) risk was partitioned by tumor grade; low grade cases have very low early risk but a 20% fall-off in DSS 10 or more years after diagnosis. Higher grade HRpos cases have risk over >20 years. Triple-negative (Tneg) and HER2-positive (HER2pos) cases DSS events occurred primarily within the first 5 years. Among node-positive cases, only low grade conferred late risk, suggesting that proliferative gene signatures that identify proliferation would be important for predicting early but not late recurrence. Using pooled data from four publicly available data sets for node-negative tumors annotated with gene expression and outcome data, we evaluated four prognostic gene signatures: two proliferation-based and two immune function-based. Tumor proliferative capacity predicted early but not late metastatic risk for HRpos cases. The immune function or HRneg specific signatures predicted only early metastatic risk in Tneg and HER2pos cases. Breast cancer prognostic signatures need to inform both risk and timing of metastatic events and may best be applied within subsets. Current signatures predict for outcome risk within 5 years of diagnosis. Predictors of late risk for HR positive disease are needed.

Objective: Physicians' fears of being sued may lead to defensive medical practices, such as ordering nonindicated medical imaging. We investigated the association between states' medical malpractice tort reforms and neurologic imaging rates for patients seen in the emergency department with mild head trauma., Methods: We assessed neurologic imaging among a national sample of 8588 women residing in 10 US states evaluated in an emergency setting for head injury between January 1, 1992, and December 31, 2001. We assessed the odds of imaging as it varied by the enactment of medical liability reform laws., Results: The medical liability reform laws were significantly associated with the likelihood of imaging. States with laws that limited monetary damages (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.40-0.99), mandated periodic award payments (OR, 0.64; 95% CI, 0.43-0.97), or specified collateral source offset rules (OR, 0.62; 95% CI, 0.40-0.96) had an approximately 40% lower odds of imaging, whereas states that had laws that limited attorney's contingency fees had significantly higher odds of imaging (OR, 1.5; 95% CI, 0.99-2.4), compared to states without these laws. When we used a summation of the number of laws in place, the greater the number of laws, the lower the odds of imaging. In the multivariate analysis, after adjusting for individual and community factors, the total number of laws remained significantly associated with the odds of imaging, and the effect of the individual laws was attenuated, but not eliminated., Conclusion: The tort reforms we examined were associated with the propensity to obtain neurologic imaging. If these results are confirmed in larger studies, tort reform might mitigate defensive medical practices., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To study choline metabolism in biopsies from nonenhancing Grade 2 (AS2) and Grade 3 (AS3) astrocytomas to determine whether (1) phosphocholine (PC) dominates in AS3, and (2) PC is associated with proliferation or angiogenesis. PC and glycerophosphocholine (GPC) are involved in phospholipid metabolism that accompanies mitosis. PC is the predominant peak in Grade 4 astrocytoma (GBM) while GPC dominates in AS2., Materials and Methods: We used high resolution magic angle spinning magnetic resonance spectroscopy to compare the concentrations of 10 metabolites in 41 biopsies (16 AS2 and 25 AS3) from 24 tumors. Immunohistochemistry was performed on paired biopsies to determine the cell density, Ki-67 proliferation index, and vascular endothelial growth factor (VEGF) angiogenic marker expression., Results: AS3 had higher PC than AS2; however, the PC:GPC was less than 1 in all cases irrespective of tumor grade. Within tumors, GPC increased with Ki-67 and PC and tCho increased with cell density. There was no association between any choline compound and VEGF., Conclusion: These data suggest that PC:GPC less than 1 is not unique to low grade glioma. Furthermore, the PC concentration that is a marker of aggressive glial tumors is not tightly linked to cell proliferation or angiogenesis in nonenhancing astrocytomas., (Copyright © 2011 Wiley-Liss, Inc.)

Background. A patient- and assessor-blinded randomized controlled trial was conducted to examine the effectiveness of auricular transcutaneous electrical nerve stimulation (TENS) in relieving posthysterectomy pain. Method. Forty-eight women who had undergone a total abdominal hysterectomy were randomly assigned into three groups (n = 16 each) to receive either (i) auricular TENS to therapeutic points (the true TENS group), (ii) auricular TENS to inappropriate points (the sham TENS group), or (iii) 20 minutes of bed rest with no stimulation (the control group). The intervention was delivered about 24 hours after the operation. A visual analogue scale was used to assess pain while resting (VAS-rest) and upon huffing (VAS-huff) and coughing (VAS-cough), and the peak expiratory flow rate (PEFR) was assessed before and at 0, 15, and 30 minutes after the intervention. Result. As compared to the baseline, only the true TENS group reported a significant reduction in VAS-rest (P = .001), VAS-huff (P = .004), and VAS-cough (P = .001), while no significant reduction in any of the VAS scores was seen in the sham TENS group (all P > .05). In contrast, a small rising trend was observed in the VAS-rest and VAS-huff scores of the control group, while the VAS-cough score remained largely unchanged during the period of the study. A between-group comparison revealed that all three VAS scores of the true TENS group were significantly lower than those of the control group at 15 and 30 minutes after the intervention (all P < .02). No significant between-group difference was observed in PEFR at any point in time. Conclusion. A single session of auricular TENS applied at specific therapeutic points significantly reduced resting (VAS-rest) and movement-evoked pain (VAS-huff, VAS-cough), and the effects lasted for at least 30 minutes after the stimulation. The analgesic effects of auricular TENS appeared to be point specific and could not be attributed to the placebo effect alone. However, auricular TENS did not produce any significant improvement in the performance of PEFR.

Methamphetamine (METH) abuse is a serious public health issue. Of particular concern are findings that repeated high-dose administrations of METH cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. Previous studies have also revealed that METH treatment causes alterations in the dopamine transporter (DAT), including the formation of higher molecular mass DAT-associated complexes. The current study extends these findings by examining mechanisms underlying DAT complex formation. The association among DAT complex formation and other METH-induced phenomena, including alterations in vesicular monoamine transporter 2 (VMAT2) immunoreactivity, astrocytic activation [as assessed by increased glial fibrillary acidic protein (GFAP) immunoreactivity], and persistent dopaminergic deficits was also explored. Results revealed that METH-induced DAT complex formation and reductions in VMAT2 immunoreactivity precede increases in GFAP immunoreactivity. Furthermore, and as reported previously for DAT complexes, pretreatment with the D2 receptor antagonist eticlopride [S-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride] attenuated the decrease in VMAT2 immunoreactivity as assessed 24 h after METH treatment. DAT complexes distinct from those present 24 h after METH treatment, decreases in VMAT2 immunoreactivity, and increased GFAP immunoreactivity were present 48 to 72 h after METH treatment. Pretreatment with eticlopride attenuated each of these phenomena. Finally, DAT complexes were present 7 days after METH treatment, a time point at which VMAT2 and DAT monomer immunoreactivity were also reduced. Eticlopride pretreatment attenuated each of these phenomena. These findings provide novel insight into not only receptor-mediated mechanisms underlying the effects of METH but also the interaction among factors that probably are associated with the persistent dopaminergic deficits caused by the stimulant.

This report demonstrates that a repeated 'challenge' high-dose methamphetamine (METH) injection regimen rapidly decreases striatal K(+)-stimulated dopamine (DA) release concurrent with decreases in both synaptosomal membrane-associated (referred to herein as membrane-associated) and previously reported decreases in non-synaptosomal membrane-associated (presumably cytoplasmic) vesicular DA uptake and content. Resembling previously reported effects involving cytoplasmic vesicles wherein uptake was decreased 48 h after treatment, the decrease in membrane-associated uptake persisted 72 h. Cytoplasmic and membrane-associated vesicular DA uptakes were decreased 7 days after the challenge regimen. A single METH injection also rapidly decreased K(+)-stimulated DA release, membrane-associated DA content, and membrane-associated DA uptake; however, unlike after the challenge regimen, the decrease in uptake recovered by 24 h. Pre-treatment with the D(2) receptor antagonist, eticlopride, did not attenuate the decrease in membrane-associated uptake as assessed 1 h after either a single or challenge treatment. However, eticlopride attenuated the decrease in membrane-associated uptake caused by the challenge regimen as assessed 24 h later. These data reveal complex effects of METH on vesicular function that vary according to the vesicle population under study, dosing regimen, and time after treatment. These may contribute to both the decrease in K(+)-stimulated DA release and the persistent dopaminergic deficits caused by METH., (© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.)

Astronauts experience bone loss after the long spaceflight missions. Identifying specific regions that undergo the greatest losses (e.g. the proximal femur) could reveal information about the processes of bone loss in disuse and disease. Methods for detecting such regions, however, remains an open problem. This paper focuses on statistical methods to detect such regions. We perform statistical parametric mapping to get t-maps of changes in images, and propose a new cross-validation method to select an optimum suprathreshold for forming clusters of pixels. Once these candidate clusters are formed, we use permutation testing of longitudinal labels to derive significant changes.

Tolerance to brain injury involves hypoxia-inducible factor-1 (HIF-1) and its target genes as the key pathway mediating a cascade of events including cell survival, energetics, and angiogenesis. In this study, we established the treatment paradigms for an in vitro model of tolerance to oxidative injury in primary astrocytic cultures and further examined the roles for the HIF-1 signalling cascade. Isolated murine astrocytes were preconditioned with sub-toxic concentrations of HIF-1 inducers and subsequently exposed to a H(2)O(2) insult, where changes in cell viability and protein expression were determined. Preconditioning with non-damaging concentrations of desferrioxamine (DFO) and ethyl-3,4-dihydroxybenzoate (EDHB) significantly improved cellular viability after H(2)O(2) injury treatment. Time course studies revealed that DFO and EDHB treatments alone induced sequential activation of HIF-1 signal transduction where nuclear HIF-1alpha protein accumulation was detected as early as 2h, followed by downstream upregulation of intracellular and released VEGF from 4h and 8h onwards, respectively. The protective effects of DFO and EDHB preconditioning against H(2)O(2) injury were abolished by co-treatment with cycloheximide, an inhibitor of protein synthesis. Importantly, when the anti-HIF-1 compound, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was used, the cytoprotection and VEGF accumulation produced by DFO and EDHB preconditioning were diminished. These results indicate the essential role of the HIF-1 pathway in our model of tolerance against oxidative injury in cultured astrocytes, and suggest roles for astrocytic HIF-1 expression and VEGF release which may influence the function of surrounding cells and vasculature during oxidative stress-related brain diseases., (Copyright 2010 Elsevier B.V. All rights reserved.)

GABAergic striatal neurons are compromised in basal ganglia pathologies and we analysed how insult nature determined their patterns of injury and recruitment of the intrinsic mitochondrial pathway during programmed cell death (PCD). Stressors affecting targets implicated in striatal neurodegeneration [3-morpholinylsydnoneimine (SIN-1), 3-nitropropionic acid (3-NP), NMDA, 3,5-dihydroxyphenylglycine (DHPG), and staurosporine (STS)] were compared in cultured GABAergic neurons from murine striatum by analyzing the progression of injury and its correlation with mitochondrial involvement, the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Stressors produced PCD exhibiting slow-onset kinetics with time-dependent annexin-V labeling and eventual DNA fragmentation. IMS proteins including cytochrome c were differentially distributed, although stressors except STS produced early redistribution of apoptosis-inducing factor and Omi, suggestive of early recruitment of both caspase-dependent and caspase-independent signaling. In general, Bax mobilization to mitochondria appeared to promote IMS protein redistribution. Caspase 3 activation was prominent after STS, whereas NMDA and SIN-1 produced mainly calpain activation, and 3-NP and DHPG elicited a mixed profile of protease activation. PCD and redistribution of IMS proteins in striatal GABAergic neurons were canonical and insult-dependent, reflecting differential interplay between the caspase cascade and alternate cell death pathways.

Objective: The objective of this retrospective study was to compare the diagnostic value of 2-[(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography ((18)F-FDG PET)/CT versus (18)F-FDG PET and CT alone for staging and restaging of pediatric solid tumors., Methods: Forty-three children and adolescents (19 females and 24 males; mean age, 15.2 years; age range, 6-20 years) with osteosarcoma (n = 1), squamous cell carcinoma (n = 1), synovial sarcoma (n = 2), germ cell tumor (n = 2), neuroblastoma (n = 2), desmoid tumor (n = 2), melanoma (n = 3), rhabdomyosarcoma (n = 5), Hodgkin's lymphoma (n = 7), non-Hodgkin-lymphoma (n = 9), and Ewing's sarcoma (n = 9) who had undergone (18)F-FDG PET/CT imaging for primary staging or follow-up of metastases were included in this study. The presence, location, and size of primary tumors was determined separately for PET/CT, PET, and CT by two experienced reviewers. The diagnosis of the primary tumor was confirmed by histopathology. The presence or absence of metastases was confirmed by histopathology (n = 62) or clinical and imaging follow-up (n = 238)., Results: The sensitivities for the detection of solid primary tumors using integrated (18)F-FDG PET/CT (95%), (18)F-FDG PET alone (73%), and CT alone (93%) were not significantly different (p > 0.05). Seventeen patients showed a total of 153 distant metastases. Integrated PET/CT had a significantly higher sensitivity for the detection of these metastases (91%) than PET alone (37%; p < 0.05), but not CT alone (83%; p > 0.05). When lesions with a diameter of less than 0.5 cm were excluded, PET/CT (89%) showed a significantly higher specificity compared to PET (45%; p < 0.05) and CT (55%; p < 0.05). In a sub-analysis of pulmonary metastases, the values for sensitivity and specificity were 90%, 14%, 82% and 63%, 78%, 65%, respectively, for integrated PET/CT, stand-alone PET, and stand-alone CT. For the detection of regional lymph node metastases, (18)F-FDG PET/CT, (18)F-FDG PET alone, and CT alone were diagnostically correct in 83%, 61%, and 42%. A sub-analysis focusing on the ability of PET/CT, PET, and CT to detect osseous metastases showed no statistically significant difference between the three imaging modalities (p > 0.05)., Conclusion: Our study showed a significantly increased sensitivity of PET/CT over that of PET for the detection of distant metastases but not over that of CT alone. However, the specificity of PET/CT for the characterization of pulmonary metastases with a diameter > 0.5 cm and lymph node metastases with a diameter of <1 cm was significantly increased over that of CT alone.

Objective: A significant segment of women remains underscreened with mammography. We sought to summarize literature related to factors associated with receipt of mammography. For data sources, we used English language papers published between 1988 and 2007, including 221 studies describing 4,957,347 women., Methods: We calculated odds ratios (ORs) associated with receipt of mammography. Random effects modeling was used to assess trends in mammography utilization and to calculate summary multivariate point estimates. Results were stratified by age, race/ethnicity, and study year. We summarized results between 1988 and 2004 and compared recent years with these results., Results: Physician access barriers, such as not having a physician-recommend mammography (adjusted OR 0.16, 95% CI 0.08-0.33) and having no primary care provider (OR 0.41, 95% CI 0.32-0.53), were highly predictive of not obtaining mammography. Past screening behavior correlated strongly with receipt of mammography (clinical breast examination, adjusted OR 9.15, 95% CI 3.49-23.98) and Pap test (adjusted OR 3.45, 95% CI 2.12-5.62). With the exception of having no insurance (adjusted OR 0.47, 95% CI 0.39-0.57), several potential socioeconomic barriers did not appear to have an important impact on screening. Racial and ethnic differences were seen. Concerns about cost, mammography safety, and pain were more important to African American and Latina women, and having no insurance was more important to white and Chinese women. Cost concerns and the presence of a family history of breast cancer were less important to older women, whereas screening knowledge had a stronger impact on mammography use in women aged > or =65 years. When we compared study results before 2004 with those later, we found very little difference in the multivariate, adjusted ORs over time., Conclusions: Women with poor access to physicians are much less likely to undergo mammography. Improving the frequency and scope of mammography recommendation by primary care providers is the single most important direct contribution the medical community can make toward increasing mammography use.

Multiple high-dose methamphetamine administrations cause long-lasting (>1 week) deficits in striatal dopaminergic neuronal function. This stimulant likewise causes rapid (within 1 h) and persistent (at least 48 h) decreases in activities of striatal: 1) dopamine transporters, as assessed in synaptosomes; and 2) vesicular monoamine transporter -2 (VMAT-2), as assessed in a non-membrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction. Importantly, not all brain areas are vulnerable to methamphetamine-induced long-lasting deficits. Similarly, the present study indicates that methamphetamine exerts differential acute effects on monoaminergic transporters according to brain region. In particular, results revealed that in the nucleus accumbens, methamphetamine rapidly, but reversibly (within 24 h), decreased plasmalemmal dopamine transporter function, without effect on plasmalemmal dopamine transporter immunoreactivity. Methamphetamine also rapidly and reversibly (within 48 h) decreased cytoplasmic VMAT-2 function in this region, with relatively little effect on cytoplasmic VMAT-2 immunoreactivity. In contrast, methamphetamine did not alter either dopamine transporter or VMAT-2 activity in the hypothalamus. Noteworthy, the nucleus accumbens and hypothalamus did not display the persistent long-lasting striatal dopamine depletions caused by the stimulant. Taken together, these data suggest that deficits in plasmalemmal and vesicular monoamine transporter activity lasting greater than 24-48 h may be linked to the long-lasting dopaminergic deficits caused by methamphetamine and appear to be region specific.

This study characterized cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) cell lines, tumor specimens, and blood samples. The CD90+ cells, but not the CD90(-) cells, from HCC cell lines displayed tumorigenic capacity. All the tumor specimens and 91.6% of blood samples from liver cancer patients bore the CD45(-)CD90+ population, which could generate tumor nodules in immunodeficient mice. The CD90+CD44+ cells demonstrated a more aggressive phenotype than the CD90+CD44(-) counterpart and formed metastatic lesions in the lung of immunodeficient mice. CD44 blockade prevented the formation of local and metastatic tumor nodules by the CD90+ cells. Differential gene expression profiles were identified in the CD45(-)CD90+ and CD45(-)CD90(-) cells isolated from tissue and blood samples from liver cancer patients and controls.

A human neuroblastoma cell line, IMR-32, was used as an in vitro model system to study the effects of arsenic trioxide (As(2)O(3)) on aggressive human neuroblastoma. From 0.5 micro M, As(2)O(3) exhibited a dose-dependent inhibition of IMR-32 proliferation. At concentrations of 1.5 micro M or higher, As(2)O(3) up-regulated caspase 3, leading to cellular apoptosis. However, neurofilament-200 kDa and tyrosine hydroxylase were not up-regulated, implying minimal neuronal differentiation. Concomitantly, TrkA was down-regulated and TrkB up-regulated. Pre-treatment with the protein kinase C (PKC) inhibitor Ro-31-8220 partially blocked As(2)O(3)-mediated apoptosis, meaning that As(2)O(3) might signal through PKC activation. The results suggest that As(2)O(3) might be potentially useful in neuroblastoma.

Objective: A solitary fibrous tumor is an uncommon soft-tissue tumor and rarely occurs in the uterus. We present such a case., Case Report: A 78-year-old woman presented with low abdominal pain, and pelvic computed tomography showed a pelvic mass attached to the uterus. As malignancy could not be ruled out, exploratory laparotomy with complete surgical staging was performed. The results of frozen section showed benign mesothelioma-like tumor. Unexpectedly, further histopathologic results of the lesion revealed a solitary fibrous tumor, an outcome that was subsequently confirmed by means of CD34 immunohistochemical stain., Conclusion: The behavior of solitary fibrous tumors arising from the uterus is difficult to evaluate; therefore, complete surgical excision featuring clear margins and comprehensive follow-up is recommended.