Quantifying initial cellular events of mouse radiation lymphomagenesis and its tumor prevention in vivo by positron emission tomography and magnetic resonance imaging.
Radiation-induced thymic lymphoma (RITL) in mice is induced by fractionated whole-body X-irradiation (FX) and has served as a useful model for studying radiation carcinogenesis. In this model, the initial postirradiation cellular events in the thymus and bone marrow (BM) are critically important for tumorigenesis, and BM transplantation (BMT) prevents RITL. However, direct assessment of these events is so far restricted by the lack of noninvasive monitoring techniques. Here, we have developed positron emission tomography (PET) and magnetic resonance imaging (MRI) methods to quantify the events critical for RITL development and the effects of BMT in living animals. Apparent diffusion coefficients (ADCs) were calculated from diffusion-weighted MRI to evaluate the changes in the BM of mice receiving FX. ADC values dramatically changed in the irradiated BM, corresponding to pathological findings of the irradiated BM, returning to normal levels following BMT sooner than with spontaneous recovery. PET with 4'-[methyl-(11)C]thiothymidine, a novel tracer for cell proliferation, revealed that the irradiated thymus showed significantly higher tracer uptake than the unirradiated thymus 1 week after FX. Interestingly, its increased uptake was completely abolished by BMT, even with very few donor-derived cells in the thymus. Thereafter, the thymus receiving BMT had significantly increased tracer uptake. These findings suggest that BMT first suppresses FX-induced aberrant thymocyte proliferation and then accelerates thymic regeneration. This study demonstrates the feasibility of using PET and MRI for noninvasive monitoring of tumorigenic cellular processes in an animal model of radiation-induced cancer.


Correlation between Cobb angle, spinous process angle (SPA) and apical vertebrae rotation (AVR) on posteroanterior radiographs in adolescent idiopathic scoliosis (AIS).
To investigate the accuracy and reliability of the Cobb angle, the spinous process angle (SPA), and apical vertebral rotation (AVR) for measuring adolescent idiopathic scoliosis (AIS), and to evaluate the correlations between these measurements. A retrospective study of two sets of standing posteroanterior radiographs of patients with AIS was performed. The first set was 59 consecutive patients with AIS with Cobb angles <45° and the second set was 25 patients with Cobb angles >45°. The Cobb angle, SPA and AVR of each curve was measured twice by three observers with varying measurement experience. The mean absolute difference, standard deviation, and intra- and inter-rater reliability coefficients for each measurement were examined. The Pearson correlation coefficients between any two parameters were reported. The association of the Cobb angle with the SPA and AVR was examined using a multiple regression model. The average intra- and inter-observer reliabilities (ICC [2, 1]) of the Cobb angle, SPA, and AVR were 0.99, 0.95, 0.92 and 0.98, 0.88, 0.83, respectively. The correlation coefficients (r) between Cobb angle and SPA, Cobb angle and AVR, and SPA and AVR were 0.93, 0.68, and 0.60, respectively. Using multiple regression, the association between the Cobb angle and SPA combined with AVR was R (2) = 0.90. The resulting regression model was: [Formula: see text]. The SPA has high correlation with the Cobb angle. Including the AVR as an additional factor in multiple regression improves the prediction of the Cobb angle.


With the Advent of Tomosynthesis in the Workup of Mammographic Abnormality, is Spot Compression Mammography Now Obsolete? An Initial Clinical Experience.
To determine if the routine use of spot compression mammography is now obsolete in the assessment of screen detected masses, asymmetries and architectural distortion since the availability of digital breast tomosynthesis. We introduced breast tomosynthesis in the workup of screen detected abnormalities in our screening center in January 2015. During an initial learning period with tomosynthesis standard spot compression views were also performed. Three consultant breast radiologists retrospectively reviewed all screening mammograms recalled for assessment over the first 6-month period. We assessed retrospectively whether there was any additional diagnostic information obtained from spot compression views not already apparent on tomography. All cases were also reviewed for any additional lesions detected by tomosynthesis, not detected on routine 2-view screening mammography. 548 women screened with standard 2-view digital screening mammography were recalled for assessment in the selected period and a total of 565 lesions were assessed. 341 lesions were assessed by both tomosynthesis and routine spot compression mammography. The spot compression view was considered more helpful than tomosynthesis in only one patient. This was because the breast was inadequately positioned for tomosynthesis and the area in question was not adequately imaged. Apart from this technical error there was no asymmetry, distortion or mass where spot compression provided more diagnostic information than tomosynthesis alone. We detected three additional cancers on tomosynthesis, not detected by routine screening mammography. From our initial experience with tomosynthesis we conclude that spot compression mammography is now obsolete in the assessment of screen detected masses, asymmetries and distortions where tomosynthesis is available.


IRF-5 is a mediator of the death receptor-induced apoptotic signaling pathway.
The efficient and regulated response to cellular stress is coordinated by a genetic regulatory network in which a given transcription factor controls the expression of diverse target genes depending on the cell type and/or nature of the stimuli. The tumor suppressor p53 is thought to preferentially regulate the balance between cell survival and death. The interferon regulatory factor 5 (IRF-5), known to be involved in the innate immune response to pathogens, is also a critical regulator of DNA damage-induced apoptosis. Here, we provide direct evidence that IRF-5 promotes apoptosis upon signaling through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors (DR). We report that IRF-5 sensitizes tumor cells to TRAIL-induced apoptosis and cell death that is further enhanced by type I interferons. Cells deficient of IRF-5 gave a significantly diminished response to these agents. IRF-5 is involved in DR signaling upstream of caspase 8, in part because of an IRF-5-dependent increase in caspase 8 activation. We provide evidence that TRAIL induces a signaling cascade that leads to the phosphorylation and nuclear localization of IRF-5, resulting in transactivation of key DR signaling components. The results presented here identify IRF-5 as a new mediator of DR signaling and provides molecular insight into the mechanism of TRAIL-induced IRF-5 signaling.


Psychosexual function and impact of gynaecological cancer.
A diagnosis of gynaecological cancer and its treatment are usually associated with many physical and psychological changes, both as a result of the diagnosis itself and of the usual treatments of surgery, radiotherapy and/or several months of chemotherapy. Patients often experience symptoms such as fatigue, abdominal swelling and pain, and suffer from emotional distress and disturbances of their life style. Sexual functioning can also be affected. Often there are physiological difficulties, such as vaginal dryness, together with psychological distress and relationship problems. This chapter discusses the ways in which gynaecological cancer can impact sexual functioning, and presents findings from a research project that was undertaken to begin to understand how sexual functioning can be affected by ovarian cancer. The article also makes recommendations for how health-care professionals can help women to cope better with psychosexual dysfunction following a diagnosis of a gynaecological cancer.


Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women.
Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial. Two major vaginal bacterial community types-one dominated by Lactobacillus (59.2%) and the other where Gardnerella vaginalis predominated with other anaerobic bacteria (40.8%)-were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61% (P = 0.013) in Lactobacillus-dominant women but only 18% (P = 0.644) in women with non-Lactobacillus bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non-Lactobacillus women, negatively correlating with G. vaginalis and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism.


Axl receptor tyrosine kinase is a regulator of apolipoprotein E.
Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL-/- CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXL-deficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.


Sex-Dependent Effects of HO-1 Deletion from Adipocytes in Mice.
Induction of heme oxygenase-1 (HO-1) has been demonstrated to decrease body weight and improve insulin sensitivity in several models of obesity in rodents. To further study the role of HO-1 in adipose tissue, we created an adipose-specific HO-1 knockout mouse model. Male and female mice were fed either a control or a high-fat diet for 30 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were determined every six weeks. Adipocyte-specific knockout of HO-1 had no significant effect on body weight in mice fed a high-fat diet but increased body weight in female mice fed a normal-fat diet. Although body weights were not different in females fed a high fat diet, loss of HO-1 in adipocytes resulted in significant alterations in body composition. Adipose-specific HO-1 knockout resulted in increased fasting hyperglycemia and insulinemia in female but not male mice on both diets. Adipose-specific knockout of HO-1 resulted in a significant loss of HO activity and a decrease in the protein levels of adiponectin in adipose tissue. These results demonstrate that loss of HO-1 in adipocytes has greater effects on body fat and fasting hyperglycemia in a sex-dependent fashion and that expression of HO-1 in adipose tissue may have a greater protective role in females as compared to males.


Stage-specific effects of Plasmodium falciparum-derived hemozoin on blood mononuclear cell TNF-alpha regulation and viral replication.
The molecular immunological interactions between HIV and malaria are largely undefined. Since tumor necrosis factor (TNF)-alpha is elevated during acute malaria and increases with HIV-1 disease progression, TNF-alpha production may be an important mediator for interactions between malaria and HIV-1. To examine the stage-specific immunological interactions between HIV and malaria, peripheral blood mononuclear cells (PBMC) and CD14 cells were isolated and cultured from rhesus macaques at different stages of SIV infection. Cultures were stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma in the presence of Plasmodium falciparum-derived hemozoin (Hz) or synthetic Hz (sHz). TNF-alpha transcripts and soluble protein were examined by real time reverse transcription-PCR and ELISA, respectively. The effects of Hz on viral replication were determined by measurement of p27 antigen with varying concentrations of TNF-alpha neutralizing antibodies. Hz and sHz significantly increased LPS- and IFN-gamma-induced TNF-alpha protein and transcripts in PBMC from animals with late stage SIV infection (i.e., AIDS). Hz and sHz also induced high levels of sustained TNF-alpha transcripts in PBMC from the AIDS group. During the late stage of disease, CD14 cells were the primary source of TNF-alpha production. Stimulation of PBMC with Hz and sHz significantly increased viral replication that was dose-dependently reduced by the addition of TNF-alpha neutralizing antibodies. Hz promotes high levels of TNF-alpha production from PBMC during AIDS and increases viral replication in SIV-infected animals.


Fulminant orbital inflammatory syndrome in a patient with relapsing polychondritis: case report and review of the literature.
We describe a 75-year-old woman with rapid onset orbital inflammatory syndrome as her initial manifestation of relapsing polychondritis. Patient presented after the development of right eyelid swelling, erythema, and proptosis over a 48-hour period. Visual acuity was 20/30 in both eyes. Intraocular pressure was elevated in her right eye along with severe restriction of extraocular motility. Magnetic resonance imaging of the orbits revealed thickened right medial and inferior recti muscles. Serologic laboratory data was unrevealing. Patient demonstrated marked improvement within 12 hours of administration of intravenous corticosteroids. She was symptom-free after 1 week. A diagnosis of relapsing polychondritis was confirmed 3 weeks later after new onset complaints of right ear pain and a rash.


Understanding long-term primate community dynamics: implications of forest change.
Understanding the causes of population declines often involves comprehending a complex set of interactions linking environmental and biotic changes, which in combination overwhelm a population's ability to persist. To understand these relationships, especially for long-lived large mammals, long-term data are required, but rarely available. Here we use 26-36 years of population and habitat data to determine the potential causes of group density changes for five species of primates in Kibale National Park, Uganda, in areas that were disturbed to varying intensities in the late 1960s. We calculated group density from line transect data and quantified changes in habitat structure (cumulative diameter at breast height [dbh] and food availability [cumulative dbh of food trees]) for each primate species, and for one species, we evaluated change in food nutritional quality. We found that mangabeys and black-and-white colobus group density increased, blue monkeys declined, and redtails and red colobus were stable in all areas. For blue monkeys and mangabeys, there were no significant changes in food availability over time, yet their group density changed. For redtails, neither group density measures nor food availability changed over time. For black-and-white colobus, a decrease in food availability over time in the unlogged forest surprisingly coincided with an increase in group density. Finally, while red colobus food availability and quality increased over time in the heavily logged area, their group density was stable in all areas. We suggest that these populations are in nonequilibrium states. If such states occur frequently, it suggests that large protected areas will be required to protect species so that declines in some areas can be compensated for by increases in adjacent areas with different histories.


Innovative human resource practices in U.S. hospitals: an empirical study.
Contemporary organizations increasingly recognize human resource (HR) capabilities as a source of sustained competitive advantage; about 80% of an organization's value is attributable to intangible assets, including human assets and capital. Some scholars consider effective human resource management (HRM) the single most important factor affecting organizational performance. This study examined (1) the extent to which HRM strategies were included in organizational strategic planning and (2) the association between the involvement of senior HR professionals in strategic planning and the use of innovative HR practices in U.S. hospitals employing strategic HRM theory. A survey was administered to 168 chief executive officers and HR executives from 85 hospitals during spring 2005. Binary logistic regression was conducted to determine whether HRM involvement was associated with the use of innovative HRM strategies in the hospitals. We found significant associations between HRM strategy inclusion in the strategic planning process and senior HR professionals' involvement in organizational strategic planning and in three innovative HR activities: finding talent in advance for key job openings (odds ratio [OR] = 4.61, 95% confidence interval [CI]: 1.10-7.38), stressing organizational culture and values in the selection process (OR = 3.97, 95% CI: 1.01-3.97), and basing individual or team compensation on goal-oriented results (OR = 6.17, 95% CI: 1.17-3.37). Our data indicate that innovative HR practices were underused in some U.S. hospitals despite their potential to improve overall hospital performance. Hospitals that emphasized effective HRM were more likely to use some of the innovative HR approaches. In this article, we discuss this research and the practical implications of the findings.


Clinical utility of head and neck aspiration cytology.
Over the past 3.5 yr, we have examined 195 head and neck fine-needle aspiration (FNA) specimens from three diverse medical settings. Specimens were collected in saline solution or Saccomanno fixative and processed using cytocentrifugation or membrane filtration. This allowed us simultaneously to perform cytologic evaluations, special stains, and immunologic marker studies from a single specimen. Good correlation between clinical experience with FNA and obtaining satisfactory specimens was demonstrated. Our sensitivity (89%) and specificity (94%) reflect problems associated with specimen collection in a training environment where clinician experience with the procedure is low. A definitive diagnosis was possible in most cases, and the treatment plan was often based on the FNA results. In patients without a history of a primary malignancy, a FNA done early in the clinical course helped direct the initial workup of the patient, saving time and expense.


The association of personality and the likelihood of serious unintentional injury during childhood.
In this study a survival analysis was conducted to examine whether childhood personality was associated with the likelihood and the timing of an unintentional injury requiring hospitalization or medical attention before the age of 13. Maternal ratings of childhood personality (at 5 or 6 years of age) were used to derive resiliency, undercontrol, and overcontrol prototypical profile scores for a diverse sample of 1,013 child participants from the child sample of the National Longitudinal Survey of Youth. A significant inverse association was found between likelihood of childhood unintentional injury and the overcontrolled prototype score. The findings are interpreted in light of their implications for researchers and health care practitioners interested in improving the health and well-being of children and adolescents.


Zellweger syndrome - a lethal peroxisome biogenesis disorder.
Zellweger syndrome (ZS) is the severest variety of peroxisomal biogenesis disorder (PBD). This is a fatal hereditary, autosomal recessive disorder. It is characterized by the absence of peroxisomes in the cells which are essential for many metabolic functions especially beta oxidation of very long chain fatty acids (VLCFAs). We report the case of a female Saudi toddler. She presented with dysmorphism, profound hypotonia, psychomotor retardation, seizures, and loss of hearing and vision with findings of optic atrophy. Biochemical study revealed significantly elevated level of VLCFAs, cerotic acid and phytanic acid. She also had periventricular leukomalacia and abnormal electroencephalography results and a PEX 1 gene mutation. The clinical data and investigations were consistent with ZS. As it is fatal in early life, genetic counseling and prenatal diagnosis are thus crucial.


Compensating the distortion of micro-speakers in a closed box with consideration of nonlinear mechanical resistance.
For micro-speakers in a closed box, commonly used nonlinear compensation methods only compensate the distortion caused by the force factor and the stiffness. In this letter, a method to compensate the distortion with consideration of the nonlinear mechanical resistance is proposed based on the feedback linearization criterion. The proposed method is further improved by minimizing the variation of the output power spectrum after compensation. The simulations and experiments show that the total harmonic distortion and the intermodulation distortion of the sound pressure can be reduced significantly with little influence on the sound pressure level.


An online home-based exercise program improves autonomic dysfunction in breast cancer survivors.
Introduction: Exercise interventions for breast cancer survivors have proved their potential to improve clinical, physical, and psychosocial outcomes. However, limited studies have explored exercise effects on autonomic dysfunction and the measurement of exercise tolerance and progression through daily heart rate variability (HRV). Purpose: To analyze the effects of a 16-wk exercise intervention on the autonomic modulation of breast cancer survivors, as well as to examine the evolution of daily measured HRV and its interaction with exercise sessions in this population. Methods: A total of 29 patients who had undergone chemotherapy and radiotherapy were randomly assigned to the exercise group or to the control group. The exercise intervention was delivered remotely through online meetings and consisted of supervised training resistance and cardiovascular exercise 3 times per week. During the intervention all patients measured their HRV daily obtaining the napierian logarithm of the root mean square of successive differences between normal heartbeats (lnrMSSD) and the napierian logarithm of the standard deviation of the interbeat interval of normal sinus beats (lnSDNN) values at four moments: day 0 (the morning of the training sessions), 24, 48, and 72 h after exercise. Results: The results revealed a significant interaction between group and months during the intervention period for lnrMSSD and lnSDNN (p < 0.001). Additionally, there were significant differences in lnSDNN recovery time between months (p < 0.05), while differences in lnrMSSD become apparent only 24 h after exercise (p = 0.019). The control group experienced a significant decrease in both variables monthly (p < 0.05) while exercise group experienced a significant increment (p < 0.05). Conclusion: HRV is daily affected by exercise training sessions in cancer patients. Although results strongly support the role of exercise as a post-chemotherapy and radiotherapy rehabilitation strategy for breast cancer survivors to improve autonomic imbalance, further research is necessary to validate these initial findings.


Successful Intrathecal Chemotherapy Combined with Radiotherapy Followed by Pomalidomide and Low-Dose Dexamethasone Maintenance Therapy for a Primary Plasma Cell Leukemia Patient.
Primary plasma cell leukemia (PPCL) is a rare aggressive variant of plasma cell disorder and frequently presents with extramedullary disease. Central nervous system (CNS) involvement with PPCL has an extremely poor prognosis. We describe a 46-year-old man with PPCL treated with a combination of lenalidomide, bortezomib, and dexamethasone as induction therapy following upfront allogeneic stem cell transplantation (allo-SCT). Despite achieving a very good partial response, the patient suffered from an isolated CNS relapse 12 months after allo-SCT. He was immediately started on concurrent intrathecal chemotherapy (IT) and cranial irradiation (RT). Subsequently, pomalidomide and low-dose dexamethasone (Pd) were given as maintenance therapy. He has been without CNS recurrence for more than 18 months. Our case suggests that concurrent IT and RT followed by Pd maintenance therapy may be an effective option to control CNS relapse of PPCL after allo-SCT.


The Use of Non-verbal Displays in Framing COVID-19 Disinformation in Europe: An Exploratory Account.
While online disinformation practices have grown exponentially over the past decade, the COVID-19 pandemic provides arguably the best opportunity to date to study such communications at a cross-national level. Using the data provided by the International Fact-Checking Network (IFCN), we examine the strategic uses of non-verbal and verbal arguments to push disinformation through social media and websites during the first wave of lockdowns in 2020 across 16 European countries. Our paper extends the work by Brennen et al. (2021) on the use of visuals in COVID-19 misinformation claims by investigating the use of facial emotional expressions and body pose depictions in conjunction with framing elements such as problems identified and attribution of responsibility in the construction of disinformation messages. Our European-wide comparative analysis of 174 messages indexed by the IFCN during the months of April and May 2020 helps provide a rounder understanding of the use of non-verbal devices in advancing COVID-19 disinformation across the continent, and can provide the basis for a framework for further study of the strategic use of non-verbal devices in COVID-19 disinformation world-wide.


The emergence of socioeconomic inequalities in smoking during adolescence and early adulthood.
While it is known that educational inequalities in smoking start during early and middle adolescence, it is unknown how they further develop until adulthood. The aim of this article is to map, in the Portuguese context, how educational inequalities in smoking emerge from pre-adolescence until young adulthood. This study used longitudinal data from the EPITeen Cohort, which recruited adolescents enrolled in schools in Porto, Portugal. We included the 1,038 participants followed at ages 13 (2003/2004), 17, 21, and 24 years. We computed the odds ratio (OR) for the prevalence of smoking states (never smoking, experimenter, less-than-daily, daily and former smoker) and the incidence of transitions between these states, as function of age and education, stratified by sex. We also added interaction terms between age and education. Educational inequalities in daily smoking prevalence, with higher prevalence among those with lower educational level, emerged at 17 years old and persisted until higher ages. They were formed in a cumulative way by the increased risk of experimenting between 13 and 17 years, and increased risk of becoming daily smoker between 17 and 21 years. The incidence of smoking cessation was higher among the higher educated. Inequalities were formed similarly for women and men, but with lower level and showed no significance among women. These results highlight that actions to prevent smoking should also take in account the potential impact in smoking inequalities, and should focus not only on middle adolescence but also on late adolescence and early adulthood.


Asymmetric energy flow in liquid alkylbenzenes: A computational study.
Ultrafast IR-Raman experiments on substituted benzenes [B. C. Pein et al., J. Phys. Chem. B 117, 10898-10904 (2013)] reveal that energy can flow more efficiently in one direction along a molecule than in others. We carry out a computational study of energy flow in the three alkyl benzenes, toluene, isopropylbenzene, and t-butylbenzene, studied in these experiments, and find an asymmetry in the flow of vibrational energy between the two chemical groups of the molecule due to quantum mechanical vibrational relaxation bottlenecks, which give rise to a preferred direction of energy flow. We compare energy flow computed for all modes of the three alkylbenzenes over the relaxation time into the liquid with energy flow through the subset of modes monitored in the time-resolved Raman experiments and find qualitatively similar results when using the subset compared to all the modes.


A hypervariable N-terminal region of Yersinia LcrV determines Toll-like receptor 2-mediated IL-10 induction and mouse virulence.
The virulence antigen LcrV of Yersinia enterocolitica O:8 induces IL-10 in macrophages via Toll-like receptor 2 (TLR2). The TLR2-active region of LcrV is localized within its N-terminal amino acids (aa) 31-57. Sequencing of codons 25-92 of the lcrV gene from 59 strains of the three pathogenic Yersinia species revealed a hypervariable hotspot within aa 40-61. According to these sequence differences, seven LcrV groups were identified, with Y. pestis and Y. pseudotuberculosis represented in group I and the other six distributed within Y. enterocolitica. By testing LcrV sequence-derived synthetic oligopeptides of all seven LcrV groups in CD14/TLR2-transfected human embryonic kidney 293 cells, we found the highest TLR2 activity with a peptide derived from group IV comprising exclusively Y. enterocolitica O:8 strains. These findings were verified in murine peritoneal macrophages by using recombinant LcrV truncates representing aa 1-130 from different Yersinia spp. By systematically replacing charged aa residues by glutamine in synthetic oligopeptides, we show that the K42Q substitution leads to abrogation of TLR2 activity in both in vitro cell systems. This K42Q substitution was introduced in the lcrV gene from Y. enterocolitica O:8 WA-C(pYV), resulting in WA-C(pYVLcrV(K42Q)), which turned out to be less virulent for C57BL/6 mice than the parental strain. This difference in virulence was not observed in TLR2(-/-) or IL-10(-/-) mice, proving that LcrV contributes to virulence by TLR2-mediated IL-10 induction. LcrV is a defined bacterial virulence factor shown to target the TLR system for evasion of the host's immune response.


Management of digestive bleeding related to portal hypertension in cirrhotic patients: A French multicenter cross-sectional practice survey.
To investigate the conformity of management practices of gastrointestinal hemorrhage in cirrhotic patients with relevant guidelines. A questionnaire on the management of digestive bleeding was completed for all consecutive cirrhotic patients admitted to 31 French hospitals. One hundred and twenty-six bleeding events were recorded. It was the first bleeding episode in 79 patients (63%), of whom 40 (51%) had a prior diagnosis of cirrhosis and 25 (32%) had previously undergone an endoscopy. The bleeding episode was a recurrence in 46 patients (37%). The median time between onset and admission was 4 h, but exceeded 12 h in 42% of cases. There was an agreement between centers for early vasoactive drug administration (87% of cases), association with ligation (42%) more often than sclerosis (21%) at initial endoscopy, and antibiotic prophylaxis (64%). By contrast, prescription of beta-blockade alone or in combination (0 to 100%, P = 0.003) for secondary prophylaxis and lactulose (26% to 86%, P = 0.04), differed among centers. In French hospitals, management of bleeding related to portal hypertension in cirrhotic patients is generally in keeping with the consensus. Broad variability still remains concerning beta-blockade use for secondary prophylaxis. Screening for esophageal varices, the use of antibiotic prophylaxis and patients information need to be improved.


Sociocultural Influence on Obesity and Lifestyle in Children: A Study of Daily Activities, Leisure Time Behavior, Motor Skills, and Weight Status.
Juvenile overweight is increasing, and effective preventive measures are needed. After years of arbitrarily assigning these measures disregarding socioeconomic and/or cultural differences, it has become necessary to tailor interventions more specific to these target groups. Providing data for such an intervention is the objective of this study. Influencing variables on children's weight status, motor skills and lifestyle have been analyzed among 997 first graders (53.2% male) involved in the Children's Health InterventionaL Trial (CHILT). Median age was 6.9 years; 7.3% were obese, 8.8% were overweight. Children with low socioeconomic status (SES) were more likely to be obese (p = 0.029). Low SES (p ˂ 0.001), migration background (p = 0.001) and low sports activity levels (p = 0.007) contributed most to an increased consumption of television. Migration background (p = 0.003) and male gender (p < 0.001) were the strongest factors in predicting a greater consumption of computer/video games. Children with higher SES (p = 0.02), lower BMI (p = 0.035), and males (p = 0.001) performed better in motor tests. Children with a low SES and migration background were more likely to exhibit unfavorable health behavior patterns, higher BMI scores, and poorer motor skills. Interventions should integrate motivational and targeting strategies and consider cultural and educational differences to address these vulnerable groups.


Cost-Savings From an Antipsychotic Tablet-Splitting Program.
Newer atypical antipsychotics such as aripiprazole (Abilify, Otsuka) and lurasidone (Latuda, Sunovion) have favorable safety and efficacy profiles, but their use is limited by high cost. University Hospitals Richmond Medical Center initiated an antipsychotic tablet-splitting program in August 2015 to counter the costs based on the identical pricing structure of aripiprazole and lurasidone doses. A retrospective chart review was completed for all patients dispensed aripiprazole or lurasidone oral tablets from May 1, 2015, through December 31, 2015, to evaluate the potential cost-savings for our facility. Findings were extrapolated to 12 months to estimate an annual cost-savings from tablet splitting. Two-hundred thirty-five charts were reviewed during this eight-month period. Estimated annual savings ranged from $3,617 for lurasidone 20-mg tablets to $6,637 for aripiprazole 5-mg tablets. The antipsychotic tablet-splitting program for lurasidone and aripiprazole resulted in 30% to 50% annual savings for each individual medication strength. Previous literature suggests variable percentage of weight deviation in tablet-splitting studies; however, small deviations in weight may not be clinically relevant for antipsychotic agents based on their mechanism of action. Aripiprazole and lurasidone are optimal agents for tablet splitting. Initiation of a tablet-splitting program has the potential to save up to 50% of drug costs for an inpatient hospital. Splitting of aripiprazole and lurasidone tablets may decrease drug cost and waste while ensuring patient accessibility to treatment.


Limiting Vancomycin Exposure in Pediatric Oncology Patients With Febrile Neutropenia May Be Associated With Decreased Vancomycin-Resistant Enterococcus Incidence.
Limited data exists regarding the effects of empiric antibiotic use in pediatric oncology patients with febrile neutropenia (FN) on the development of antibiotic resistance. We evaluated the impact of a change in our empiric FN guideline limiting vancomycin exposure on the development of vancomycin-resistant Enterococcus in pediatric oncology patients. Retrospective, quasi-experimental, single-center study using interrupted timeseries analysis in oncology patients aged ≤18 years with at least 1 admission for FN between 2009 and 2015. Risk strata incorporated diagnosis, chemotherapy phase, Down syndrome, septic shock, and typhlitis. Microbiologic data and inpatient antibiotic use were obtained by chart review. Segmented Poisson regression was used to compare VRE incidence and antibiotic days of therapy (DOT) before and after the intervention. We identified 285 patients with 697 FN episodes pre-intervention and 309 patients with 691 FN episodes postintervention. The proportion of high-risk episodes was similar in both periods (49% vs 48%). Empiric vancomycin DOT/1000 FN days decreased from 315 pre-intervention to 164 post-intervention (P < .01) in high-risk episodes and from 199 to 115 in standard risk episodes (P < .01). Incidence of VRE/1000 patient-days decreased significantly from 2.53 pre-intervention to 0.90 post-intervention (incidence rate ratio, 0.14; 95% confidence interval, 0.04-0.47; P = .002). A FN guideline limiting empiric vancomycin exposure was associated with a decreased incidence of VRE among pediatric oncology patients. Antimicrobial stewardship interventions are feasible in immunocompromised patients and can impact antibiotic resistance.


The optimal time window of ischemic preconditioning (IPC) on the reperfusion injury in moderate to severe hepatocirrhosis in rats.
To evaluate the effects of different-time ischemic preconditioning (IPC) schemes on the ischemia-reperfusion (I/R) injury in moderate to severe hepatocirrhosis in rats and to identify the optimal time window of IPC. A total of 90 male SD rats with moderate to severe hepatocirrhosis were randomly divided into 5 groups (IR group, 5-10 min-IPC group, 8-10 min-IPC group, 10-10 min-IPC group and 15-10 min-IPC group), in which the liver was preconditioned by IPC of various durations, and then subjected to I/R injury in the last four groups. Thirty-six normal (non-cirrhotic) SD rats were divided into 2 groups (IR group and 10-10 min-IPC group). Ischemia-reperfusion injury was induced by clamping of the portal triad for 30 min followed by reperfusion for 30 min. Hepatocellular viability was assessed by measuring the concentration of ALT and AST in serum. The concentration of NO in serum and those of MDA, MPO, and SOD in the liver tissue were also assessed at 1h, 4h, and 24h after the operation respectively. After 30-30min of I/R, the levels of ALT and AST were significantly elevated in the IR group and the groups under IPC, but the elevations were significantly lower in the 5-10 min-IPC group and the 8-10 min-IPC group, especially at 4h after I/R (P<0.05). The levels of MDA and MPO in liver tissue were lower in the 5-10 min-IPC and 8-10min-IPC groups than in the rest of the IPC groups and IR group in the cirrhotic rats, and the level of SOD was higher (P <0.05). The level of serum NO was significantly higher in the 5-10 min-IPC and 8-10min-IPC groups than in the rest of the cirrhotic groups (P <0.05). The 5-10 min through 8-10 min-IPC achieves the highest protective effect on the I/R injury of moderate to severe hepatocirrhosis. With the aggravation of liver cirrhosis, the pre-implementation time has been shortened. Thus, IPC of 5-10min may be effective for severe liver cirrhosis.


[Transthyretin amyloid cardiomyopathy. Features of histological diagnosis: study design].
To compare efficiency and specific features of transthyretin amyloid staining by different histological dyes and thus to assess their suitability for diagnostic purposes. Samples of left and right heart ventricles were taken from patients over 70 years-old of both genders (n=10) with immunohistochemically verified transthyretin amyloidosis (ATTR). All samples were stained with Congo red, Alcian blue, toluidine blue and methylene violet. Specificity and sensitivity of Congo red staining was comparable to those of immunohistochemical staining. For verification of amyloid presence after Congo red staining one could use fluorescent microscopy instead of polarization microscopy. It allows a more accurate diagnosis of amyloidosis. Confocal microscopy with spectral unmixing improves detection sensitivity of amyloid by elimination of background fluorescence of muscle tissue and autofluorescence of lipofuscin. Alcian blue staining gives the same result as Congo red. In addition, its less labor-intensive and free of false-positive and false-negative results caused by final processing of slide preparation. Toluidine blue and methylene violet develop metachromatic staining upon binding to transthyretin fibrils, likely due to specific biochemical features of these fibrils. The most reliable method for histochemical diagnosis of ATTR is the Congo red staining with subsequent analysis using fluorescence or confocal microscopy. For diagnostic screening, the use of Sodium sulphate-Alcian blue staining method is highly promising. Metachromatic stains are less effective for ATTR diagnosis.


Stable isotope ratios of marijuana. I. Carbon and nitrogen stable isotopes describe growth conditions.
There remains significant uncertainty in illicit marijuana cultivation. We analyzed the delta(13)C and delta(15)N of 508 domestic samples from known U.S.A. counties, 31 seized from a single location, 5 samples grown in Mexico and Colombia, and 10 northwest border seizures. For a subset, inflorescences and leaves were analyzed separately. These data revealed a strong correspondence, with inflorescences having slightly higher delta(13)C and delta(15)N values than leaves. A framework for interpreting these results is introduced and evaluated. Samples identified as outdoor-grown by delta(13)C were generally recorded as such by the Drug Enforcement Administration (DEA). DEA-classified indoor-grown samples had the most negative delta(13)C values, consistent with indoor cultivation, although many were also in the outdoor-grown domain. Delta(15)N indicated a wide range of fertilizers across the dataset. Samples seized at the single location suggested multiple sources. Northwest border delta(13)C values suggested indoor growth, whereas for the Mexican and Colombian samples they indicated outdoor growth.


Moderate Amounts of Epistasis are Not Evolutionarily Stable in Small Populations.
High mutation rates select for the evolution of mutational robustness where populations inhabit flat fitness peaks with little epistasis, protecting them from lethal mutagenesis. Recent evidence suggests that a different effect protects small populations from extinction via the accumulation of deleterious mutations. In drift robustness, populations tend to occupy peaks with steep flanks and positive epistasis between mutations. However, it is not known what happens when mutation rates are high and population sizes are small at the same time. Using a simple fitness model with variable epistasis, we show that the equilibrium fitness has a minimum as a function of the parameter that tunes epistasis, implying that this critical point is an unstable fixed point for evolutionary trajectories. In agent-based simulations of evolution at finite mutation rate, we demonstrate that when mutations can change epistasis, trajectories with a subcritical value of epistasis evolve to decrease epistasis, while those with supercritical initial points evolve towards higher epistasis. These two fixed points can be identified with mutational and drift robustness, respectively.


Laser in situ keratomileusis for simple myopic, mixed, and simple hyperopic astigmatism.
To summarize initial results of astigmatic laser in situ keratomileusis (LASIK) for 41 eyes of 26 patients using the EC-5000 Nidek system and assess its safety, efficacy and predictability. The EC-5000 Nidek excimer laser was used to correct simple myopic, mixed, and simple hyperopic astigmatism with manifest cylinder from 2.00 to 6.50 D. Ablation zone diameters were 6.5 mm (steep meridian ablation) to 7.5 mm (flat meridian ablation) with a repetition rate of 40-41 Hz. In eyes with simple myopic and mixed astigmatism, ablation was performed in both meridians; in eyes with simple hyperopic astigmatism, ablation was performed in the flat meridian alone. Follow-up was 3 months in all eyes. Uncorrected visual acuity was 20/40 or better in 85% of the eyes. Uncorrected visual acuity was equal to the preoperative spectacle-corrected visual acuity in 63% of the eyes. Intended cylinder correction was within 1.00 D in 95% of eyes. No eyes lost lines of spectacle-corrected visual acuity. LASIK using the EC-5000 excimer laser appears to effective in the treatment of simple myopic, mixed, and simple hyperopic astigmatism, with favorable results as compared to those previously described for astigmatic keratotomy.


Association of HLA and autoantibody in transfused sickle cell disease patients.
This study evaluates autoantibody production in sickle cell disease patients and determines whether genes in the major histocompatibility complex are associated with autoantibody responses. Rheumatoid factor was significantly increased for both male and female patients and was less prevalent in highly transfused patients. Significant increases were also detected in the incidences of antinuclear antibody for females and antismooth muscle antibody for males. Low incidence of antinuclear antibody was significantly associated with HLA-DR3. Significant associations were also found between the incidence of antinuclear antibody and both HLA-A28 and B15.


A Case of a Child With Several Anaphylactic Reactions to Drugs.
Adverse drug reaction is defined as any harmful, unintended, and undesired effect of a drug that occurs at doses used for treatment, prevention, or diagnoses. Most of these reactions are classified as type A reactions, which by definition are predictable, common, dose-dependent, and caused by known pharmacological actions of the drug, drug toxicity, and side effects. Allergic reactions are qualified as type B reactions independent of dose, affecting a small population, suggesting that individual patient host factors are important. In pediatric population, β-lactam antibiotics are the most common reason for adverse drug reactions, followed by nonsteroidal anti-inflammatory drugs. In this article, we report the case of a child with several anaphylactic reactions to several drugs, including cefuroxime, amoxicillin/clavulanate, clarithromycin, ibuprofen, and budesonide, in a context of suspected Helicobacter pylori infection.


Ecdysteroid synthesis and imaginal disc development in the midge Chironomus riparius as biomarkers for endocrine effects of tributyltin.
Acute effects of the endocrine disruptor bis(tri-n-butyltin) oxide (TBTO) on molting-hormone biosynthesis and imaginal-disc development were investigated in larvae of the midge Chironomus riparius (Meigen). Ecdysteroid synthesis was measured by 24-h incubation of molting-hormone-synthesizing tissues (prothoracic glands) in vitro with or without the addition of TBTO. The amount of ecdysteroids produced was analyzed by radioimmunoassay. Developmental effects in vivo were investigated by determining the developmental phase of the genital imaginal discs before and after a 48-h exposure to TBTO in water. Sex-specific effects were found with both endpoints. Ecdysteroid synthesis was significantly reduced (analysis of variance [ANOVA], p < or = 0.005) in female larvae at all concentrations (TBTO-Sn at 50, 500, and 5,000 ng/L), whereas a significant elevation of the biosynthesis rate occurred in male larvae in the 500-ng/L treatment (ANOVA, p < or = 0.05). In vivo experiments with development of the genital imaginal disc within a 48-h exposure period revealed a significantly slower development in female larvae and a significantly faster development in male larvae (contingency tables, p < or = 0.001) at all concentrations tested (TBTO-Sn at 10, 50, 200, and 1,000 ng/L). These results partly coincided with the in vitro effects on molting-hormone synthesis. The 48-h median lethal concentration (LC50) was 25 microg/L (20-30 microg/L 95% confidence intervals). The combination of in vitro and in vivo methods has proven to be a useful approach for the detection of endocrine effects of TBTO in C. riparius at levels 2,000-fold below the LC50 value. High sensitivity and short test duration suggest that chironomids may have potential as freshwater sentinel organisms for endocrine-disrupting chemicals.


Azygos vein cannulation after catheterisation of the left internal jugular vein in a toddler.
Central venous catheterisation is routinely performed in paediatric patients to facilitate therapeutic management when long-term vascular access is needed. Misplacement of the catheter tip in thoracic vessels other than the superior vena cava has been described, along with related complications. Hereby, a case of a 15-month-old child is presented with a fully functional Hickman catheter introduced via the left internal jugular vein. The tip of the catheter was misplaced into the azygos vein. Intraoperative spot fluoroscopic images and anatomical explanations for the course of the catheter are presented. An understanding of the aetiology of the radiological appearance may help to increase recognition of such cases and avoid complications.


Phospho PTEN mediated dephosphorylation of mitotic kinase PLK1 and Aurora Kinase A prevents aneuploidy and preserves genomic stability.
PTEN, dual phosphatase tumor suppressor protein, is found to be frequently mutated in various cancers. Post-translational modification of PTEN is important for its sub-cellular localization and catalytic functions. But how these modifications affect cytological damage and aneuploidy is not studied in detail. We focus on the role of phosphatase activity along with C-terminal phosphorylation of PTEN in perspective of cytological damage like micronucleus, nuclear bud, and nuclear bridge formation. Our data suggest that wild-type PTEN, but not phospho-mutant PTEN significantly reduces cytological damage in PTEN null PC3 cells. In case of phosphatase-dead PTEN, cytological damage markers are increased during 24 h recovery after DNA damage. When we use phosphorylation and phosphatase-dead dual mutant PTEN, the extent of different cytological DNA damage parameters are similar to phosphatase-dead PTEN. We also find that both of those activities are essential for maintaining chromosome numbers. PTEN null cells exhibit significantly aberrant γ-tubulin pole formation during metaphase. Interestingly, we observed that p-PTEN localized to spindle poles along with PLK1 and Aurora Kinase A. Further depletion of phosphorylation and phosphatase activity of PTEN increases the expression of p-Aurora Kinase A (T288) and p-PLK1 (T210), compared to cells expressing wild-type PTEN. Again, wild-type PTEN but not phosphorylation-dead mutant is able to physically interact with PLK1 and Aurora Kinase A. Thus, our study suggests that the phosphorylation-dependent interaction of PTEN with PLK1 and Aurora Kinase A causes dephosphorylation of those mitotic kinases and by lowering their hyperphosphorylation status, PTEN prevents aberrant chromosome segregation in metaphase.


Multi-voxel pattern analysis (MVPA) reveals abnormal fMRI activity in both the "core" and "extended" face network in congenital prosopagnosia.
The ability to identify faces is mediated by a network of cortical and subcortical brain regions in humans. It is still a matter of debate which regions represent the functional substrate of congenital prosopagnosia (CP), a condition characterized by a lifelong impairment in face recognition, and affecting around 2.5% of the general population. Here, we used functional Magnetic Resonance Imaging (fMRI) to measure neural responses to faces, objects, bodies, and body-parts in a group of seven CPs and ten healthy control participants. Using multi-voxel pattern analysis (MVPA) of the fMRI data we demonstrate that neural activity within the "core" (i.e., occipital face area and fusiform face area) and "extended" (i.e., anterior temporal cortex) face regions in CPs showed reduced discriminability between faces and objects. Reduced differentiation between faces and objects in CP was also seen in the right parahippocampal cortex. In contrast, discriminability between faces and bodies/body-parts and objects and bodies/body-parts across the ventral visual system was typical in CPs. In addition to MVPA analysis, we also ran traditional mass-univariate analysis, which failed to show any group differences in face and object discriminability. In sum, these findings demonstrate (i) face-object representations impairments in CP which encompass both the "core" and "extended" face regions, and (ii) superior power of MVPA in detecting group differences.


Production of bioactive recombinant human fibroblast growth factor 12 using a new transient expression vector in E. coli and its neuroprotective effects.
In recent years, an increasing number of studies have shown that fibroblast growth factor 12 (FGF12) plays important roles in regulating neural development and function. Importantly, changes of FGF12 expression are thought to be related to the pathophysiology of many neurological diseases. However, little research has been performed to explore the protective effect of FGF12 on nerve damage. This study aims to explore its neuroprotective effects using our recombinant humanized FGF12 (rhFGF12). The hFGF12 gene was cloned and ligated into an expression vector to construct a recombinant plasmid pET-3a-hFGF12. Single colonies were screened to obtain high expression engineering strains, and fermentation and purification protocols for rhFGF12 were designed and optimized. The biological activities and related mechanisms of rhFGF12 were investigated by MTT assay using NIH3T3 and PC12 cell lines. The in vitro neurotoxicity model of H2O2-induced oxidative injury in PC12 cells was established to explore the protective effects of rhFGF12. The results indicate that the beneficial effects of rhFGF12 were most likely achieved by promoting cell proliferation and reducing apoptosis. Moreover, a transgenic zebrafish (islet) with strong GFP fluorescence in the motor neurons of the hindbrain was used to establish a central injury model caused by mycophenolate mofetil (MMF). The results suggested that rhFGF12 could ameliorate central injury induced by MMF in zebrafish. In conclusion, we have established an efficient method to express and purify active rhFGF12 using an Escherichia coli expression system. Besides, rhFGF12 plays a protective effect of on nerve damage, and it provides a promising therapeutic approach for nerve injury. KEY POINTS: • Effective expression and purification of bioactive rhFGF12 protein in E. coli. • ERK/MAPK pathway is involved in rhFGF12-stimulated proliferation on PC12 cells. • The rhFGF12 has the neuroprotective effects by inhibiting apoptosis.


Mechanism of inactivation of S-adenosylhomocysteine hydrolase by (Z)-4',5'-didehydro-5'-deoxy-5'-fluoroadenosine.
S-Adenosyl-L-homocysteine (AdoHcy) hydrolase, an enzyme important in the regulation of biological methylation reactions, was shown by McCarthy et al. (McCarthy, J.R., Jarvi, E.T., Matthews, D.P., Edwards, M.L., Prakash, N.J., Bowlin, T.L., Mehdi, S., and Bey, P. (1989) J. Am. Chem. Soc. 111, 1127-1128) to be inactivated by (Z)-4',5'-didehydro-5'-deoxy-5'-fluoroadenosine (ZDDFA). In this study we have shown that the mechanism of this inactivation of AdoHcy hydrolase (NAD+ form) includes a rapid addition of water to the 5'-position of ZDDFA and elimination of fluoride ion, resulting in the formation of the 5'-carboxaldehydes 3 and 4. The 5'-carboxaldehydes 3 and 4 are then oxidized in a slower step to the 3'-keto-5'-carboxaldehydes 5 and 6 by reduction of the enzyme-bound NAD+ to NADH. Evidence in support of this mechanism includes the observation that the first step in this mechanism (i.e. elimination of fluoride ion and formation of the 5'-carboxaldehydes 3 and 4) can be catalyzed by apo-AdoHcy hydrolase and the NADH form of AdoHcy hydrolase. Incubation of ZDDFA with either the apo or NADH form of AdoHcy hydrolase resulted in rapid release of fluoride ion (determined by 19F NMR) and formation of the 5'-carboxyaldehydes 3 and 4 (determined by high performance liquid chromatography). The carboxaldehydes 3 and 4 were synthesized independently and were shown to be potent inhibitors of the NAD+ form of the enzyme. When the relative first-order rates of fluoride ion release (determined by 19F NMR) from ZDDFA, NAD+ reduction to NADH, and inactivation of the NAD+ form of the enzyme were compared, the release of fluoride ion was found to be approximately 20 times faster than NAD+ reduction or enzyme inactivation. Incubation of ZDDFA with the NAD+ form of AdoHcy hydrolase was shown to afford the 3'-keto-5'-carboxaldehydes 5 and 6, which were also formed upon incubation of the enzyme with the 5'-carboxaldehydes 3 and 4. The 3'-keto-5'-carboxaldehydes 5 and 6 were shown to be tightly (but not covalently) bound to the enzyme, since these products could be released by treatment of the ZDDFA-inactivated enzyme with HClO4 or other denaturing agents.


Androstane alkaloids from musk of Moschus moschiferus.
Two androstane alkaloids were isolated from the musk of Moschus moschiferus. The structures were elucidated to be 3alpha-ureido-androst-4-en-17-one (1) and 3alpha-ureido-androst-4-en-17beta-ol (2) by two-dimensional NMR analysis (HMQC, 1H-1H COSY, HMBC, and NOESY).


Tandem resection of multiple spinal schwannomas.
This video depicts the resection of three separate intradural extramedullary spinal tumors performed under the same anesthetic. Neuromonitoring was used to identify motor nerve roots, and laminoplasty was performed at the thoracolumbar junction to preserve alignment and minimize the risk of postoperative CSF leak.


Exploring molecular targets in diabetic kidney disease.
Diabetic kidney disease is the leading cause of end-stage kidney disease, and it remains a major challenge. Many factors, such as glomerular hyperfiltration, oxidative stress, inflammation, hypoxia, and epigenetics, are associated with the progression of diabetic kidney disease; however, the whole mechanism is not yet completely understood. No specific treatment for diabetic kidney disease has been established, so new approaches are being explored extensively. Sodium-glucose cotransporter 2 inhibitors have shown renoprotective effects in several human clinical trials. Glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists have been reported to be effective in diabetic kidney disease, and novel therapeutic candidates are also being examined. In the TSUBAKI trial, a nuclear factor erythroid 2-related factor 2 activator, bardoxolone methyl, improved the glomerular filtration rate of diabetic kidney disease patients. Similarly, new agents that act in the oxidative stress and inflammation pathways are of major interest, such as pentoxifylline, apoptosis signal-regulating kinase-1 inhibitors, C-C chemokine receptor 2 inhibitors, and Janus kinase-1/2 inhibitors. Endothelin-1 receptor A antagonists and soluble guanylate cyclase stimulators are also expected to affect renal hemodynamics. Some preclinical studies suggest that hypoxia-inducible factor prolyl hydroxylase inhibitors, which influence multiple inflammations and oxidative stress pathways, reduce albuminuria in diabetic kidney disease. Advanced glycation end-product inhibitors and treatments related to epigenetics have also shown promise as potential diabetic kidney disease treatments in preclinical studies. The discovery of new targets could provide new therapeutic options for overcoming diabetic kidney disease.


Colon Cancer and Specific Ways to Deliver Drugs to the Large Intestine.
It has been postulated that colon cancer is the third cause of cancer death worldwide. Recently, colon-targeted drug delivery systems have been developed for improving systemic drug delivery and treatment of local colon associated diseases. Using such drug delivery systems increases the drug's effectiveness and results in reduced systemic side effects. Drug delivery systems formulated for the colon requires that the triggering of drug release mechanism is designed based on the colon's physiological conditions. However, improving the site specificity and drug release kinetics of colon-targeted drug delivery systems is desired and is currently under active research. This review discusses colon cancer along with various colon-targeted drug delivery systems such as pro-drug formation, pH-sensitive polymers, hydrogels, time-dependent release systems, bio-adhesive and nanoparticle systems. The aim is to understand the effect of using colon-targeted drug delivery systems on therapeutic effectiveness of the drug by improving its degradation and bioavailability. Colon targeting holds a great promise as a therapeutic approach but it still requires more innovation. The distribution of the drugs in the colon suffers from problems related to the pH, retention time, micro-flora, and degrading enzymes of gastrointestinal tract. Moreover, these drug delivery systems are capable of overcoming some of the limitations in common targeting approaches. A precise assessment of such systems needs the use of various assaying protocols in order to characterize their traits and clarify their design rationales.


Melting of superheated molecular crystals.
Melting dynamics of micrometer scale, polycrystalline samples of isobutane, dimethyl ether, methyl benzene, and 2-propanol were investigated by fast scanning calorimetry. When films are superheated with rates in excess of 105 K s-1, the melting process follows zero-order, Arrhenius-like kinetics until approximately half of the sample has transformed. Such kinetics strongly imply that melting progresses into the bulk via a rapidly moving solid-liquid interface that is likely to originate at the sample's surface. Remarkably, the apparent activation energies for the phase transformation are large; all exceed the enthalpy of vaporization of each compound and some exceed it by an order of magnitude. In fact, we find that the crystalline melting kinetics are comparable to the kinetics of dielectric α-relaxation in deeply supercooled liquids. Based on these observations, we conclude that the rate of non-isothermal melting for superheated, low-molecular-weight crystals is limited by constituent diffusion into an abnormally dense, glass-like, non-crystalline phase.


Authoritarian dynamics and unethical decision making: high social dominance orientation leaders and high right-wing authoritarianism followers.
When dilemmas require trade-offs between profits and ethics, do leaders high in social dominance orientation (SDO) and followers high in right-wing authoritarianism (RWA) make decisions that are more unethical than those made by others? This issue was explored in 4 studies with female participants performing managerial role-playing tasks. First, dyads comprising a person who was either low or high in SDO and a person who was either low or high in RWA negotiated for a leadership position. People high in SDO were more likely to obtain leader positions than to obtain follower positions. No other effects were significant. Second, leaders high in SDO partnered with an agreeable (confederate) follower made decisions that were more unethical than those of leaders low in SDO. Third, followers high in RWA were more acquiescent to and supportive of an unethical (confederate) leader than were followers low in RWA. Fourth, high SDO leader-high RWA follower dyads made decisions that were more unethical than those made in role-reversed dyads because leaders had more influence. Implications of these results for conceptualizing SDO, RWA, and authoritarian dynamics are discussed.


Clinical Features of Human Metapneumovirus Infection in Ambulatory Children Aged 5-13 Years.
We detected human metapneumovirus (HMPV) in 54 (5%) of 1055 children aged 5 to 13 years with acute respiratory illness (ARI) identified by outpatient and emergency department surveillance between November and May 2003-2009. Its clinical features were similar to those of HMPV-negative ARI, except a diagnosis of pneumonia was more likely (13% vs 4%, respectively; P = .005) and a diagnosis of pharyngitis (7% vs 24%, respectively; P = .005) was less likely in patients with HMPV- positive ARI than those with HMPV-negative ARI.


Effects of coil design on delivery of focal magnetic stimulation. Technical considerations.
The localization of effects from magnetic coil stimulation is not immediately obvious. We measured the magnetic fields produced by several different coils and compared the results with theoretical calculations. Magnetic stimuli were delivered from a Cadwell MES-10 magnetic stimulator using 3 circular coils (one 9 cm in diameter; two with an angulated extension, 5 and 9 cm in diameter) and twin oval coils arranged in a butterfly shape (each coil approximately 4 cm in diameter) and from a Novametrix Magstim 200 using two circular flat-spiral coils (6.7 and 14 cm in diameter). Peak-induced strength of the magnetic field was recorded with a measuring loop (1 cm in diameter) at different distances from the center of the coil. When the measuring loop was moved in the same plane laterally from the center of the coil, for all coils except the butterfly-shaped coil, the field was highest in the center and fell off near the circumference of the coil. The field dropped progressively when measurements were made more distant from the plane of the coils. The electric field induced from the magnetic coil could be calculated from the coil geometry. For all coils except the butterfly-shaped coil, the largest electric field was at the circumference of the coils. The 6.7 cm flat-spiral coil induced currents similar to those induced by the larger coils but more focally. The butterfly-shaped coil induced the largest currents under its center, where the circumferences of the two component coils come together. The component of the electric field parallel to the wire in the center of this coil was the largest and most localized.


Yeast RNA polymerase II lacking the Rpb9 subunit is impaired for interaction with transcription factor IIF.
Previous studies have shown that transcription factors IIB (TFIIB), IIF (TFIIF), and RNA polymerase II (RNAPII) play important roles in determining the position of mRNA 5'-ends in the yeast Saccharomyces cerevisiae. Yeast strains containing a deletion of the small, nonessential Rpb9 subunit of RNAPII exhibit an upstream shift in the positions of mRNA 5'-ends, whereas mutation of the large subunit of yeast TFIIF (Tfg1) can suppress downstream shifts that are conferred by mutations in TFIIB. In this study, we report an approach for the production of functional recombinant yeast holo-TFIIF (Tfg1-Tfg2 complex) and use of the recombinant protein in both reconstituted transcription assays and gel mobility shifts in order to investigate the biochemical alterations associated with the deltaRpb9 polymerase. The results demonstrated that upstream shifts in the positions of mRNA 5'-ends could be conferred by the deltaRpb9 RNAPII in transcription reactions reconstituted with highly purified yeast general transcription factors and, importantly, that these shifts are associated with an impaired interaction between the DeltaRpb9 polymerase and TFIIF. Potential mechanisms by which an altered interaction between the DeltaRpb9 RNAPII and TFIIF confers an upstream shift in the positions of mRNA 5'-ends are discussed.


Characterization of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat.
1. Single-unit activity was recorded from S1 sacral dorsal root afferent fibers in the anesthetized rat. A total of 364 afferent fibers were identified by electrical stimulation of the pelvic nerve and subsequently tested for response to colorectal distension (CRD) and urinary bladder distension (UBD). Sixty-seven percent (n = 244) of the fibers were unmyelinated C-fibers and 33% (n = 120) were thinly myelinated A delta-fibers. 2. In three initial experiments, 35 fibers were identified by pelvic nerve stimulation and tested for response only to CRD; none of these fibers responded to CRD. In 20 subsequent experiments, 329 pelvic nerve afferent fibers were tested for response to CRD and UBD. Thirty-four percent (n = 112) of the 329 fibers were unresponsive to noxious CRD (80 mmHg) or to UBD (slow filling < or = 100 mmHg), 44% (n = 146) responded to UBD, 16% (n = 53) responded to CRD, and 6% (n = 18) responded to mechanical stimulation of the anal mucosa. 3. Of the total of 53 pelvic nerve afferent fibers that responded to CRD, 43 (81%) were C-fibers (mean: 1.5 m/s) and 10 (19%) were A delta-fibers (mean: 4.7 m/s). Fifteen of the CRD-sensitive fibers had no resting activity, whereas 38 fibers exhibited some resting activity (mean: 2.6 imp/s). 4. Reproducibility of responses to repeated CRD (80 mmHg, 30s, 10 trials at 4-min intervals) was tested in 17 fibers. In 16, responses to repeated distension were reproducible without evidence of facilitation or inhibition of subsequent responses. One fiber gave greater responses during the 9th and 10th trials. 5. Responses to graded CRD were studied in 44 fibers. All fibers exhibited monotonic, increasing stimulus-response functions < or = 80 mmHg of distension. Thresholds for response of the 44 fibers were determined after extrapolation of the least-squares linear-regression line to the ordinate and varied between 0 and 40 mmHg. Two populations of pelvic nerve afferent fibers in the colon were apparent: low threshold (LT) afferent fibers had a mean threshold of 2.9 mmHg (range: 0-10 mmHg; n = 34) and high threshold (HT) afferent fibers had a mean threshold of 32.6 mmHg (range: 28.0-40.0 mmHg; n = 10). 6. Chemosensitivity to bradykinin (BK) was tested in nine LT fibers. Seven fibers responded to BK (0.1 to 100 micrograms/kg ia) and two fibers did not respond up to 100 micrograms/kg of BK. Responses to BK tested in three fibers were dose dependent.(ABSTRACT TRUNCATED AT 400 WORDS)


Nordic Crops as Alternatives to Soy-An Overview of Nutritional, Sensory, and Functional Properties.
Soy (Glycine max) is used in a wide range of products and plays a major role in replacing animal-based products. Since the cultivation of soy is limited by cold climates, this review assessed the nutritional, sensory, and functional properties of three alternative cold-tolerant crops (faba bean (Vicia faba), yellow pea (Pisum sativum), and oat (Avena sativa)). Lower protein quality compared with soy and the presence of anti-nutrients are nutritional problems with all three crops, but different methods to adjust for these problems are available. Off-flavors in all pulses, including soy, and in cereals impair the sensory properties of the resulting food products, and few mitigation methods are successful. The functional properties of faba bean, pea, and oat are comparable to those of soy, which makes them usable for 3D printing, gelation, emulsification, and extrusion. Enzymatic treatment, fermentation, and fibrillation can be applied to improve the nutritional value, sensory attributes, and functional properties of all the three crops assessed, making them suitable for replacing soy in a broad range of products, although more research is needed on all attributes.


The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences.
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.


Nausea and vomiting of pregnancy: an obstetric syndrome.
Although the cause of nausea and vomiting of pregnancy is not known, there is strong evidence linking human chorionic gonadoptropin or estrogens. Evidence is presented to show that the incidence and severity of nausea and vomiting of pregnancy is linked to temporal and pathologic alterations in these hormones during pregnancy. The way in which the pregnant woman responds to the primary stimulus to nausea and vomiting of pregnancy appears to depend on her susceptibility mediated by vestibular, gastrointestinal, olfactory, and behavioral pathways. Conceiving of nausea and vomiting of pregnancy as a syndrome suggests new pathways of investigation and possible therapies.


Testicular trauma resulting in shock and systemic inflammatory response syndrome: a case report.
Acute painful scrotum in children may be associated with torsion of the testis, hematocele, epididymitis and direct testicular injury with hematoma formation. More frequently, however, acute scrotum occurs without a precipitating factor. While most traumatic testicular injuries resolve with conservative management, many require surgical exploration and some are life-threatening. A 13-year-old boy with a history of testicular trauma presented with severe scrotal swelling and shock. This case study examines the presentation and possible role of cytokines in the development of systemic inflammatory response syndrome in a child with acute traumatic epididymitis. Post-traumatic epididymitis presenting as shock in boys is rarely reported. We advocate early recognition of the chain of events leading to clinical presentation of shock and prompt treatment to preserve testicular viability.


Compression of the tibial nerve by the tendinous arch of origin of the soleus muscle.
Details of 5 cases of surgically confirmed entrapment of the tibial nerve in the popliteal fossa are presented. In 4 cases the nerve was compressed beneath the tendinous arch of the origin of the soleus muscle. In 1 of these cases, thrombosis of a tributary of the popliteal vein with oedema of structures in the popliteal fossa and secondary compression of the nerve was found. In the fifth case the popliteal vein was compressed by the soleus arch with secondary compression of the nerve. The clinical presentation in these cases was characterised by severe pain and tenderness in the popliteal fossa, aggravated by active and passive dorsiflexion of the foot, inability to weight bear, and numbness and pain in the sole of the foot and heel. In each case, surgical exploration and division of the soleus arch led to prompt relief of symptoms.


Objective measurement of occupational stress factors--an example with San Francisco urban transit operators.
Eighty-one observational work analyses were conducted to measure stressors independently of worker appraisal in the San Francisco transit system. On the basis of action regulation theory, stress factors were defined as hindrances for task performance due to poor work organization or technological design. Stressors included (a) work barriers, defined as obstacles that cause extra work or unsafe behavior; (b) time pressure; (c) monotonous conditions; and (d) time binding, defined as control over timing. Reliability, measured as interrater agreement, ranged between 80 and 97%, with kappas of .46-.70. Validity analyses were done with 71 transit operators who participated in the observations and 177 operators who were assigned mean line-specific observational stressor measures. High odds ratios (ORs) were found for barriers and psychosomatic complaints (OR = 3.8, p = .00), time pressure and relaxation time needed after work (OR = 3.1, p = .05), and barriers and smoking to cope (OR = 3.8, p = .02). Using observational data in conjunction with self-report data can reduce confounding and improve interpretability of stress and health studies.


["Meet the AIX-PERTs." Emergency medical care at the beginning of the medical reform curriculum in Aachen].
Extensive knowledge and skills in the basics of emergency medical care are of paramount importance for every physician and should therefore be an integral part of medical education. Regulations for medical licensure in Germany were revised by the administrative authorities in 2002 and as a consequence the Medical Faculty of the University of Aachen (Germany) decided to start the Medical Reform Curriculum Aachen. A multidisciplinary, problem-oriented and organ-related approach to medical education replaces the classical discrimination between basic and clinical sciences. With AIX-PERT (AIX-la-Chapelle Program for Emergency medical care and Resuscitation Training), a program consisting of problem-based learning sessions was developed for introduction to the first year students. Defined teaching objectives in emergency medicine are now incorporated in undergraduate medical education. The extremely positive evaluation of the new approach encouraged us to promote AIX-PERT further. In the future the effects of success of this approach will be assessed by longitudinal studies of skills and knowledge during the continuing curriculum.


Occupational complexity and lifetime cognitive abilities.
To examine associations between complexity of main lifetime occupation and cognitive performance in later life. Occupational complexity ratings for data, people, and things were collected from the Dictionary of Occupational Titles for 1,066 individuals (men = 534, women = 532) in the Lothian Birth Cohort 1936. IQ data were available from mean age 11 years. Cognitive ability data across the domains of general ability, processing speed, and memory were available at mean age 70 years. General linear model analyses indicated that complexity of work with people and data were associated with better cognitive performance at age 70, after including age 11 IQ, years of education, and social deprivation. The current findings are supportive of the differential preservation hypotheses that more stimulating environments preserve cognitive ability in later life, although the continued effects into old age are still debated. Studies that have early-life cognitive ability measures are rare, and the current study offers interesting prospects for future research that may further the understanding of successful aging.


Values, preferences and burden of treatment for the initiation of GLP-1 receptor agonists and SGLT-2 inhibitors in adult patients with type 2 diabetes: a systematic review.
Assess values, preferences and burden of treatment that patients with type 2 diabetes consider when initiating glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with other glucose-lowering options. Paired reviewers independently included studies reporting quantitative or qualitative methods to assess values, preferences and burden of treatment reported by patients with type 2 diabetes regarding the initiation of GLP-1 RA or SGLT-2i over other alternatives. A systematic search in MEDLINE, Scopus, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials from inception until May 2020 was performed by an experienced librarian. Risk of bias was assessed with a specifically designed tool for values and preferences studies. 17 studies (7296 patients) proved eligible. Studies fulfilling criteria for SGLT-2i were not identified. Five studies (2662 patients) evaluated preferences for GLP-1 RA compared with other glucose-lowering medications. 12 studies (4634 patients) evaluated preferences between, at least, two kinds of GLP-1 RA or their injection devices based on the following attributes: efficacy, dose, application frequency, device characteristics. Among studies comparing GLP-1 RA to other glucose-lowering medications, some preferences were observed for dypeptil peptidase-4 inhibitors compared with once daily liraglutide. Comparing different attributes of GLP-1 RA drugs and devices, cardiovascular risk reduction, glucose lowering potential, once weekly and simple administered regimens were the most preferred. As no evidence for preferences on SGLT-2i was available, only preferences for GLP-1 RA were assessed; however, evidence is still limited for the latter. Studies comparing preferences for GLP1-RA to other glucose-lowering alternatives only included twice daily or once daily injection regimens of GLP-1 RA drugs. According to our findings, once weekly alternatives are widely preferred than the formers. The extent to which patients with type 2 diabetes value reduced adverse cardiovascular and kidney outcomes, weighed benefits against harms and burden of treatment is limited and with very low certainty. CRD42020159284.


Talbot interferometry with curved quasi-periodic gratings: towards large field of view X-ray phase-contrast imaging.
X-ray phase-contrast imaging based on grating interferometry has become a common method due to its superior contrast in biological soft tissue imaging. The high sensitivity relies on the high-aspect ratio structures of the planar gratings, which prohibit the large field of view applications with a diverging X-ray source. Curved gratings allow a high X-ray flux for a wider angular range, but the interference fringes are only visible within ~10° range due to the geometrical mismatch with the commonly used flat array detectors. In this paper, we propose a design using a curved quasi-periodic grating for large field of view imaging with a flat detector array. Our scheme is numerically verified in the X-ray regime and experimentally verified in the visible optical regime. The interference fringe pattern is observed over 25°, with less than 10% of decrease in visibility in our experiments.


Prevalence and Toxin Characteristics of Bacillus thuringiensis Isolated from Organic Vegetables.
The prevalence and toxin characteristics of Bacillus thuringiensis isolated from 39 organic vegetables were investigated. B. thuringiensis was detected in 30 out of the 39 organic vegetables (76.9%) with a mean value of 2.60 log CFU/g. Twenty-five out of the 30 B. thuringiensis isolates (83.3%) showed insecticidal toxicity against Spodoptera exigua. The hblCDA, nheABC, and entFM genes were found to be the major toxin genes, but the ces gene was not detected in any of the tested B. thuringiensis isolates. The hemolysin BL enterotoxin was detected in all 30 B. thuringiensis isolates (100%). The non-hemolytic enterotoxin complex was found in 27 out of 30 B. thuringiensis isolates (90.0%). The B. thuringiensis tested in this study had similar toxin gene characteristics to B. cereus, which possessed more than one toxin gene. B. thuringiensis could have the potential risk of foodborne illness based on the toxin genes and toxin-producing ability.


[Diagnostic techniques described in the study of Duchenne/Becker muscular dystrophy].
Duchenne/Becker muscular dystrophy (DMD/B) is one of the commonest myopathies, with an incidence of 1/3,500 male live births. It is characterized by the slow degeneration of muscle fibres, so that the patient has become an invalid by the age of 10 years, followed by death from respiratory or cardiac failure. It has a sex linked recessive mode of inheritance. The gene causing this disorder is the DMD gene and is found on the short arm of the X chromosome. The commonest mutations of this gene are deletions. Many molecular techniques for study of the disorder have been developed over the years. These include the Southern Blot, polymerase chain reaction (PCR), use of the Short Tandem Repeat (STR), polymorphic length restriction fragments (RFLP), Western Blot for the study of the protein and others. In this paper we review the diagnostic tests most widely used in this disease. These have permitted improved study of the various families affected and thus improved the quality of life of the families at risk.


Pacemaker current (I(f)) in the human sinoatrial node.
Animal studies revealed that the hyperpolarization-activated pacemaker current, I(f), contributes to action potential (AP) generation in sinoatrial node (SAN) and significantly determines heart rate. I(f) is becoming a novel therapy target to modulate heart rate. Yet, no studies have demonstrated that I(f) is functionally present and contributes to pacemaking in human SAN. We aimed to study I(f) properties in human SAN. In a patient undergoing SAN excision, we identified SAN using epicardial activation mapping. From here, we isolated myocytes and recorded APs and I(f) using patch-clamp techniques. Pacemaker cells generated spontaneous APs (cycle length 828 +/- 15 ms) following slow diastolic depolarization, maximal diastolic potential - 61.7 +/- 4.3 mV, and maximal AP upstroke velocity 4.6 +/- 1.2 V/s. They exhibited an hyperpolarization-activated inward current, blocked by external Cs(+) (2 mmol/L), characterizing it as I(f). Fully-activated conductance was 75.2 +/- 3.8 pS/pF, reversal potential - 22.1 +/- 2.4 mV, and half-maximal activation voltage and slope factor of steady-state activation - 96.9 +/- 2.7 and - 8.8 +/- 0.5 mV. Activation time constant ranged from approximately 350 ms (-130 mV) to approximately 1 s (-100 mV), deactivation time constant 156 +/- 45 ms (-40 mV). The role of I(f) in pacemaker activity was demonstrated by slowing of pacemaker cell diastolic depolarization and beating rate by Cs(+). I(f) is functionally expressed in human SAN and probably contributes to pacemaking in human SAN.


Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects.
Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.


The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis.
Recent health technology assessments have given us the go-ahead to use cholinesterase inhibitors, which, in combination with community services, are currently the most appropriate treatment for patients with Alzheimer's disease (AD). Initial research focused upon acetylcholinesterase (AChE)-selective agents, but it is now thought that dual inhibitors of AChE and butyrylcholinesterase (BuChE) may provide more sustained efficacy over the course of AD and may help to slow disease progression. Rivastigmine is a potent inhibitor of AChE and BuChE and has demonstrated broad benefits across the severity of AD and across the cognitive, functional and behavioural domains of AD. In addition, rivastigmine has shown cognitive and behavioural benefits in patients with dementia with the Lewy body variant of AD. These benefits may reflect the inhibition of both AChE and BuChE, as demonstrated by significant correlations between cognitive improvements and cholinesterase inhibition in rivastigmine-treated patients with AD. Rivastigmine shows a clear dose-response relationship, and physicians should aim to maintain patients on doses of 6 mg/day or higher, to a maximum of 12 mg/day. As with all cholinesterase inhibitors, rapid forced dose escalation may increase the incidence of typical cholinergic side-effects, resulting in lower maintenance doses. In a chronic disease such as AD, there is time to implement slow dose escalation and higher final maintenance doses. If used appropriately, the benefits of rivastigmine seen in clinical practice may prove to be even greater than those reported in clinical trials.


Transmembrane fluxes of potassium in dog kidney slices. A quantitation of the effect of warm ischemia.
The effect of warm ischemia on the transmembrane transport of potassium in dog kidney slices was studied by measurement of the uptake of 42K. The requirement for steady-state conditions concerning the intracellular potassium concentration was thereby studied. The total potassium content in the slices was found to be constant between 120 and 180 min incubation at both 25 and 37 degrees C. The cell water calculated from the total tissue water and 14C-inulin space in the dog kidney slices amounted to 38 ml-100 g wet weight-1 at 37 degrees C and 45 ml-100 g wet weight-1 at 25 degrees C and was found to remain constant for the incubation interval 120--180 min. The major part of the tissue uptake of 42K could be described by one single mono-exponential function under these conditions. The transmembrane influx at 37 degrees C calculated by using a modified Keynes formula amounted to 1.70 mmol K+-kg wet weight-1-min-1 after no warm ischemia and to 0.89 mmol K+-kg wet weight-1-min-1 after 2 h warm ischemia. The corresponding values for incubation at 25 degrees C were 1.26 and 0.77 mmol K+-kg wet weight-1-min-1, respectively. In the slices incubated at 25 degrees C, the potassium content was higher and the sodium content lower than in slices incubated at 37 degrees C.


Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression.
The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (DeltaCH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of approximately 35-50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA(S)) accounts for approximately 70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF-responsive transcription.


Evaluation of tissue shrinkage after CT-guided microwave ablation in patients with liver malignancies using Jacobian determinant.
To assess short-term tissue shrinkage in patients with liver malignancies undergoing computed tomography (CT)-guided microwave ablation (MWA) using Jacobian determinant (JD). Twenty-nine patients with 29 hepatic malignancies (primary n = 24; metastases n = 5; median tumor diameter 18 mm) referred to CT-guided MWA (single position; 10 min, 100 W) were included in this retrospective IRB-approved study, after exclusion of five patients. Following segmentation of livers and tumors on pre-interventional images, segmentations were registered on post-interventional images. JD mapping was applied to quantify voxelwise tissue volume changes after MWA. Percentual volume changes were evaluated in the ablated tumor, a 5-cm tumor perimeter and in the whole liver and compared in different clinical conditions (tumor entity: primary vs. secondary; tumor location: subcapsular vs. non-subcapsular; tumor volume: >/<6 ml: cirrhosis: yes vs. no; prior chemotherapy: yes vs. no using Shapiro-Wilk, χ2 and Wilcoxon rank sum tests, respectively (with p < 0.05 deemed significant). Tissue volume change was 0.6% in the ablated tumor, 1.6% in the 5-cm perimeter and 0.3% in the whole liver. Shrinkage in the ablated tumor was pronounced in non-subcapsular located tumors, whereas tissue expansion was noted in subcapsular tumors (median -3.5 vs. 1.1%; p = 0.0195). Shrinkage in the whole liver was higher in tumor volumes >6ml, compared with smaller tumors, in which tissue expansion was noted (median -1.0 vs. 2.5%; p = 0.002). Other clinical conditions had no significant influence on the extent of tissue shrinkage (p > 0.05). 3D Jacobian analysis shows that hepatic tissue deformation following MWA is most pronounced in a 5-cm area surrounding the treated tumor. Tumor location and tumor volume may have an impact on the extent of tissue shrinkage which may affect estimation of the safety margin.


Ions in water: the microscopic structure of concentrated hydroxide solutions.
Neutron-diffraction data on aqueous solutions of hydroxides, at solute concentrations ranging from 1 solute per 12 water molecules to 1 solute per 3 water molecules, are analyzed by means of a Monte Carlo simulation (empirical potential structure refinement), in order to determine the hydration shell of the OH- in the presence of the smaller alkali metal ions. It is demonstrated that the symmetry argument between H+ and OH- cannot be used, at least in the liquid phase at such high concentrations, for determining the hydroxide hydration shell. Water molecules in the hydration shell of K+ orient their dipole moment at about 45 degrees from the K+-water oxygen director, instead of radially as in the case of the Li+ and Na+ hydration shells. The K+-water oxygen radial distribution function shows a shallower first minimum compared to the other cation-water oxygen functions. The influence of the solutes on the water-water radial distribution functions is shown to have an effect on the water structure equivalent to an increase in the pressure of the water, depending on both ion concentration and ionic radius. The changes of the water structure in the presence of charged solutes and the differences among the hydration shells of the different cations are used to present a qualitative explanation of the observed cation mobility.


Association between anti-Mullerian hormone and insulin resistance in non-obese adolescent females with polycystic ovary syndrome.
The present study was designed to evaluate the association between anti-Mullerian hormone (AMH) and insulin resistance (IR) in non-obese adolescent females with polycystic ovary syndrome (PCOS) with and without IR. Seventy-seven consecutive non-obese patients were recruited and distributed into three groups according to diagnoses of PCOS and IR. Group I included 27 females diagnosed with PCOS and IR, group II included 18 females diagnosed with PCOS but without IR, and group III included 32 controls without PCOS. Group I had significantly higher AMH levels compared to group II and group III (p < 0.012 and p < 0.000, respectively). ROC curve analyses demonstrated that the AUC, indicative of the AMH value for discriminating PCOS with IR, was 0.763, with a confidence interval of 0.607-0.920 (p = 0.004). There was a significant positive correlation between serum AMH and HOMA-IR levels in adolescent females with PCOS (p = 0.003). We found that serum AMH levels were higher in non-obese adolescent females with PCOS and IR than in PCOS patients without IR and the healthy controls. There was a significant positive correlation between AMH levels and IR in non-obese adolescent females with PCOS.