A critical dose of doxorubicin is required to alter the gene expression profiles in MCF-7 cells acquiring multidrug resistance.
Cellular mechanisms of multidrug resistance (MDR) are related to ABC transporters, apoptosis, antioxidation, drug metabolism, DNA repair and cell proliferation. It remains unclear whether the process of resistance development is programmable. We aimed to study gene expression profiling circumstances in MCF-7 during MDR development. Eleven MCF-7 sublines with incremental doxorubicin resistance were established as a valued tool to study resistance progression. MDR marker P-gp was overexpressed only in cells termed MCF-7/ADR-1024 under the selection dose approaching 1024 nM. MCF-7/ADR-1024 and authentic MCF-7/ADR shared common features in cell morphology and DNA ploidy status. MCF-7/ADR-1024 and authentic MCF-7/ADR down regulated repair genes BRCA1/2 and wild type p53, apoptosis-related gene Bcl-2 and epithelial-mesenchymal transition (EMT) epithelial marker gene E-cadherin. While detoxifying enzymes glutathione-S transferase-π and protein kinase C-α were up-regulated. The genes involving in EMT mesenchymal formation were also overexpressed, including N-cadherin, vimentin and the E-cadherin transcription reppressors Slug, Twist and ZEB1/2. PI3K/AKT inhibitor wortmannin suppressed expression of Slug, Twist and mdr1. Mutant p53 with a deletion at codons 127-133 markedly appeared in MCF-7/ADR-1024 and authentic MCF-7/ADR as well. In addition, MCF-7/ADR-1024 cells exerted CSC-like cell surface marker CD44 high/CD24 low and form mammospheres. Overall, results suggest that resistance marker P-gp arises owing to turn on/off or mutation of the genes involved in DNA repair, apoptosis, detoxifying enzymes, EMT and ABC transporters at a turning point (1.024 μM doxorubicin challenge). Behind this point, no obvious alterations were found in most tested genes. Selection for CSC-like cells under this dose may importantly attribute to propagation of the population presenting invasive properties and drug resistance. We thereby suggest two models in the induction of drug resistance. Model 1: Selection for CSC-like cells. Model 2: Mutations for gain-of resistance. Either model 1 or model 2 requires doxorubicin dose approaching 1 μM to alter gene regulation.


Effect of Treatment of Premature Infants with Respiratory Distress Using Low-cost Bubble CPAP in a Rural African Hospital.
Kenya's neonatal mortality rate remains unacceptably high, at 22 deaths per 1000 live births, with a third of those attributable to prematurity. Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in the premature neonate. Continuous positive airway pressure (CPAP) is a proven modality of therapy but is rarely used in low-resource settings. We report on the introduction of bubble CPAP (BCPAP), a low-cost method of delivering CPAP appropriate to our setting, by comparing survival-to-discharge before and after the technology was introduced. The inpatient hospital records of all preterm infants (<37 weeks) diagnosed with RDS in the AIC Kijabe Hospital Nursery during two 18-month periods before and after the introduction of BCPAP (46 infants enrolled from 1 November 2007 to 30 April 2009 vs. 72 infants enrolled from 1 November 2009 to 30 April 2011) were reviewed. Differences in survival-to-discharge rates between the two time periods were analyzed. The survival-to-discharge rate was higher in Period 2 (after the introduction of BCPAP) than in Period 1 (pre-BCPAP) (85% vs. 61%, p = 0.007). Similarly, there were lower referral rates of preterm infants with RDS in Period 2 than Period 1 (4% vs. 17%, p = 0.037). BCPAP has contributed significantly to favorable outcomes for preterm infants with RDS at AIC Kijabe Hospital. The use of this simple technology should be considered and studied for expansion to all hospitals in Kenya that care for preterm infants.


Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p.
To test the hypothesis that the same genetic loci confer susceptibility to, or protection from, disease in different populations, and that a combined analysis would improve the map resolution of a common susceptibility locus, we analyzed data from three studies that had reported linkage to bipolar disorder in a small region on chromosome 4p. Data sets comprised phenotypic information and genetic marker data on Scottish, Danish, and USA extended pedigrees. Across the three data sets, 913 individuals appeared in the pedigrees, 462 were classified, either as unaffected (323) or affected (139) with unipolar or bipolar disorder. A consensus linkage map was created from 14 microsatellite markers in a 33 cM region. Phenotypic and genetic data were analyzed using a variance component (VC) and allele sharing method. All previously reported elevated test statistics in the region were confirmed with one or both analysis methods, indicating the presence of one or more susceptibility genes to bipolar disorder in the three populations in the studied chromosome segment. When the results from both the VC and allele sharing method were considered, there was strong evidence for a susceptibility locus in the data from Scotland, some evidence in the data from Denmark and relatively less evidence in the data from the USA. The test statistics from the Scottish data set dominated the test statistics from the other studies, and no improved map resolution for a putative genetic locus underlying susceptibility in all three studies was obtained. Studies reporting linkage to the same region require careful scrutiny and preferably joint or meta analysis on the same basis in order to ensure that the results are truly comparable.


PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis.
Developing erythrocytes take up exceptionally large amounts of iron, which must be transferred to mitochondria for incorporation into heme. This massive iron flux must be precisely controlled to permit the coordinated synthesis of heme and hemoglobin while avoiding the toxic effects of chemically reactive iron. In cultured animal cells, iron chaperones poly rC-binding protein 1 (PCBP1) and PCBP2 deliver iron to ferritin, the sole cytosolic iron storage protein, and nuclear receptor coactivator 4 (NCOA4) mediates the autophagic turnover of ferritin. The roles of PCBP, ferritin, and NCOA4 in erythroid development remain unclear. Here, we show that PCBP1, NCOA4, and ferritin are critical for murine red cell development. Using a cultured cell model of erythroid differentiation, depletion of PCBP1 or NCOA4 impaired iron trafficking through ferritin, which resulted in reduced heme synthesis, reduced hemoglobin formation, and perturbation of erythroid regulatory systems. Mice lacking Pcbp1 exhibited microcytic anemia and activation of compensatory erythropoiesis via the regulators erythropoietin and erythroferrone. Ex vivo differentiation of erythroid precursors from Pcbp1-deficient mice confirmed defects in ferritin iron flux and heme synthesis. These studies demonstrate the importance of ferritin for the vectorial transfer of imported iron to mitochondria in developing red cells and of PCBP1 and NCOA4 in mediating iron flux through ferritin.


Lossless compression of VQ index with search-order coding.
In memoryless vector quantization (VQ) for images, each block is quantized independently and its corresponding index is sent to the decoder. This paper presents a new lossless algorithm that exploits the interblock correlation in the index domain. We compare the current index with previous indices in a predefined search path, and then send the corresponding search order to the decoder. The new algorithm achieves significant reduction of bit rates without introducing extra coding distortion when compared to memoryless VQ. It is very simple and computationally efficient.


Diagnostic Accuracy of Random ECG in Primary Care for Early, Asymptomatic Cardiac Autonomic Neuropathy.
Cardiac autonomic reflex tests (CARTs) are time consuming and require patient cooperation for detecting cardiac autonomic neuropathy (CAN). Heart rate variability (HRV) analysis requires less patient cooperation and is quicker to complete. However the reliability of HRV results as a clinical tool, with respect to length of recording and accuracy of diagnosis is inconclusive. The current study investigated the reproducibility associated with varying length of recording for early CAN (eCAN) assessment. Participants were 68 males, 72 females with average age of 55 for controls and 63 for early CAN. Inclusion criteria were that participants were medication free and presented with no comorbidities. ECGs of control and eCAN were recorded and heart rate changes analyzed with the fast Fourier transform (FFT) and Lomb-Scargle periodogram (LSP). Ten-second to 5-minute recordings were extracted from a 15-minute lead-II ECG and accuracy in assessment of eCAN determined. The eCAN group was older ( P < .001) and systolic blood pressure was higher ( P < .01). HDL-cholesterol was also higher in the eCAN group ( P < .05). HRV analysis showed that both FFT and LSP results were significantly different between eCAN and control down to a 10-second ECG length for low frequency (LSP: P = .013, FFT: P = .024) and high frequency (HF-LSP: P = .002, FFT: P = .002) power. eCAN assessment was optimal down to 90-second recordings with a sensitivity of 100% and specificity of 29.49%. HRV is suitable for clinical practice from ECG recordings of more than 90 seconds with high accuracy and repeatability within a session for each participant.


Biotinylated indoles as probes for indole-binding proteins.
Biotinylated indoles were prepared for application as bifunctional probes for the detection of indole-binding proteins which participate in the life processes of humans, animals, plants, and bacteria. The indole nucleus was functionalized, at ring positions 3, 5, or 6, by attachment of a 2-aminoethyl group, which was then coupled to the carboxyl moiety of biotin, via a spacer composed of 3 or 4 concatenated beta-alanine residues. The constructs thus obtained were able to inhibit tryptophanase activity, similarly to indole in a concentration-dependent manner. They also bound strongly to lysozyme and weakly to bovine and human serum albumins, in accordance with the known affinities of these proteins for indole and 3-(2-aminoethyl)indole (tryptamine). The biotin end of the protein-bound bifunctional probes could then be detected by coupling to (strept)avidin conjugated to alkaline phosphatase or horseradish peroxidase, followed by incubation with substrates which are converted by these enzymes to intensely colored or chemiluminescent products.


Temperature and light induced bistability in a Co3[Os(CN)6]2 6 H2O Prussian blue analog.
To expand the field of new cyanide materials of the 5d elements, we incorporated the [Os(CN)(6)](3-) anion into PB architectures in combination with the Co(II) cation. Herein, we report the first example of a photomagnetic PB analog containing Os(III) ions. In a similar vein as the prototypical CoFe PB analogs, this compound exhibits a wide variety of properties including Charge Transfer Induced Spin Transition (CTIST), Temperature Induced Excited Spin State Trapping (TIESST), and magnetic ordering.


Adult dietary protein has age- and context-dependent effects on male post-copulatory performance.
The highly conserved effect of dietary protein restriction on lifespan and ageing is observed in both sexes and across a vast range of taxa. This extension of lifespan is frequently accompanied by a reduction in female fecundity, and it has been hypothesized that individuals may reallocate resources away from reproduction and into somatic maintenance. However, effects of dietary protein restriction on male reproduction are less consistent, suggesting that these effects may depend on other environmental parameters. Using the neriid fly, Telostylinus angusticollis, we examined age-specific effects of adult dietary protein restriction on male post-copulatory reproductive performance (fecundity and offspring viability). To explore the context dependence of these effects, we simultaneously manipulated male larval diet and adult mating history. We found that protein-restricted males sired less viable offspring at young ages, but offspring viability increased with paternal age and eventually exceeded that of fully fed males. The number of eggs laid by females was not affected by male dietary protein, whereas egg hatching success was subject to a complex interaction of male adult diet, age, larval diet and mating history. These findings suggest that effects of protein restriction on male reproduction are highly context dependent and cannot be explained by a simple reallocation of resources from reproduction to somatic maintenance. Rather, these effects appear to involve changes in the scheduling of male reproductive investment with age.


Combining serum biomarkers: the association of C-reactive protein, insulin sensitivity, and homocysteine with cardiovascular disease history in the general US population.
Elevated levels of serum biomarkers such as C-reactive protein (CRP) and homocysteine have been independently associated with cardiovascular risk. However, the prevalence of concurrent elevations of these biomarkers in the general population is unknown, as is their association with cardiovascular disease (CVD). Data from adults (n = 4900) in the National Health and Nutrition Examination Survey were used to investigate the relationship between combinations of serum biomarkers of inflammation (CRP), atherosclerosis (homocysteine), and insulin sensitivity [homeostatic model assessment (HOMA) fasting insulin] and CVD. Using SUDAAN, logistic regression models were constructed to examine the relationships between elevated serum biomarkers (CRP, homocysteine, HOMA, or insulin), singly or in combination, and having a history of heart failure, myocardial infarction (MI), stroke, or any CVD, while controlling for age, race, sex, obesity, smoking, cholesterol level, diabetes history, hypertension history, exercise level, and dietary fiber intake. After adjustment for covariates, there was a significant relationship between concomitant elevations of CRP plus homocysteine and a history of MI [odds ratio (OR) 2.21], heart failure (OR 2.14), and any CVD (OR 1.87) that was stronger than the relationship between individual biomarkers alone and a history of CVD. In addition, combinations of elevated CRP plus HOMA and CRP plus insulin, remained significantly related to having a history of any CVD. Recent scientific evidence and the present findings demonstrate the possibility for improving cardiovascular risk stratification through the concurrent evaluation of multiple biomarkers. In particular, these findings demonstrate the need to evaluate the combination of CRP and homocysteine prospectively as predictors of CVD.


Post menopausal hormone replacement therapy and risk of acute myocardial infarction--a case control study of women in the East Midlands, UK.
To examine the relationship between hormone replacement therapy (HRT) and acute myocardial infarction (AMI) adjusting for coronary risk factors and social and behavioural confounders that might indicate a healthy user effect and could account for the discrepancy between randomized and observational studies of HRT use. A case-control study of 864 women aged between 35-65 suffering an AMI with two age matched community controls from the same geographical area. Information was collected by interview and from general practitioner records. Conditional logistic regression was used to calculate odds ratios (OR) adjusted for diabetes, hypertension, smoking, alcohol, social class, family history and a health conscious behaviour score. HRT use was recorded for 34% of non-fatal AMI cases and 39% of controls with the adjusted OR for ever-use of HRT versus never-use being 0.74 (95% CI 0.55-0.99). The pattern of risk of AMI was similar for oestrogen only and combined HRT. During the first 12 months of HRT use there was a small increase in risk of AMI with the adjusted OR being 1.14 (0.72-1.80). HRT use for 13-60 months was associated with a small reduction in AMI risk (adjusted OR 0.85, 0.55-1.29). Only HRT used for >60 months was associated with a substantial risk reduction (adjusted OR 0.42, 0.24-0.73). Data for deceased cases and controls showed a similar pattern. HRT use whether as oestrogen only or combined hormones was only associated with a significant reduction in risk when used for greater than 60 months. These findings could reflect a dual effect of HRT on AMI risk by prothrombotic and anti-atherogenic mechanisms. Neither oestrogen only or combined HRT can be recommended for prevention of coronary artery disease.


Estrogen and peptide YY are associated with bone mineral density in premenopausal exercising women.
In women with anorexia nervosa, elevated fasting peptide YY (PYY) is associated with decreased bone mineral density (BMD). Prior research from our lab has demonstrated that fasting total PYY concentrations are elevated in exercising women with amenorrhea compared to ovulatory exercising women. The purpose of this study was to assess the association between fasting total PYY, average monthly estrogen exposure and BMD in non-obese premenopausal exercising women. Daily urine samples were collected and assessed for metabolites of estrone 1-glucuronide (E1G) and pregnandiol glucuronide (PdG) for at least one menstrual cycle if ovulatory or a 28-day monitoring period if amenorrheic. Fasting serum samples were pooled over the measurement period and analyzed for total PYY and leptin. BMD and body composition were assessed by dual-energy X-ray absorptiometry. Multiple regression analyses were performed to determine whether measures of body composition, estrogen status, exercise minutes, leptin and PYY explained a significant amount of the variance in BMD at multiple sites. Premenopausal exercising women aged 23.8±0.9years with a mean BMI of 21.2±0.4kg/m(2) exercised 346±48min/week and had a peak oxygen uptake of 49.1±1.8mL/kg/min. Thirty-nine percent (17/44) of the women had amenorrhea. Fasting total PYY concentrations were negatively associated with total body BMD (p=0.033) and total hip BMD (p=0.043). Mean E1G concentrations were positively associated with total body BMD (p=0.033) and lumbar spine (L2-L4) BMD (p=0.047). The proportion of variance in lumbar spine (L2-L4) BMD explained by body weight and E1G cycle mean was 16.4% (R(2)=0.204, p=0.012). The proportion of variance in hip BMD explained by PYY cycle mean was 8.6% (R(2)=0.109, p=0.033). The proportion of variance in total body BMD explained by body weight and E1G cycle mean was 21.9% (R(2)=0.257, p=0.003). PYY, mean E1G and body weight are associated with BMD in premenopausal exercising women. Thus, elevated PYY and suppressed estrogen concentrations are associated with, and could be directly contributing to, low BMD in exercising women with amenorrhea, despite regular physical activity.


Deep-learning-based image segmentation for image-based computational hemodynamic analysis of abdominal aortic aneurysms: a comparison study.
Computational hemodynamics is increasingly being used to quantify hemodynamic characteristics in and around abdominal aortic aneurysms (AAA) in a patient-specific fashion. However, the time-consuming manual annotation hinders the clinical translation of computational hemodynamic analysis. Thus, we investigate the feasibility of using deep-learning-based image segmentation methods to reduce the time required for manual segmentation. Two of the latest deep-learning-based image segmentation methods, ARU-Net and CACU-Net, were used to test the feasibility of automated computer model creation for computational hemodynamic analysis. Morphological features and hemodynamic metrics of 30 computed tomography angiography (CTA) scans were compared between pre-dictions and manual models. The DICE score for both networks was 0.916, and the correlation value was above 0.95, indicating their ability to generate models comparable to human segmentation. The Bland-Altman analysis shows a good agreement between deep learning and manual segmentation results. Compared with manual (computational hemodynamics) model recreation, the time for automated computer model generation was significantly reduced (from ∼2 h to ∼10 min). Automated image segmentation can significantly reduce time expenses on the recreation of patient-specific AAA models. Moreover, our study showed that both CACU-Net and ARU-Net could accomplish AAA segmentation, and CACU-Net outperformed ARU-Net in terms of accuracy and time-saving.


22-year survival following radical nephrectomy and several metastasectomies in a case of renal cell carcinoma.
Renal cell carcinoma (RCC) is a common malignancy. Metastases can be seen both synchronously, at the time of diagnosis, and metachronously during follow-up. At the time of diagnosis, 23% of the patients have metastatic disease. and 25% of patients will develop metastasis during follow-up period after nephrectomy. Nearly 80% of them develop within the first 5 years. However late metastasis of RCC have been also reported within the postoperative 10 years in the literature. For metastatic lesions, if surgically feasible, metastasectomy, and targeted pharmaceutical agents have been recommended. However any randomized controlled study which aimed to determine treatment protocol in patients who develop multiple metastases has not been cited in the literature. Herein, we are presenting a case with renal cell carcinoma in whom within 22 years of follow-up after 10 years of survival multiple metastases in different organs were detected which were managed with surgical, and medical treatments. As far as we know, this case is the first patient with the longest survival whose non-pulmonary metastases had been treated with more than one surgical interventions.


Reviewing consolidation guidelines for not-for-profit providers.
For many years, some not-for-profit providers of healthcare services have struggled with a decision whether to consolidate. Various accounting-related organizations have issued statements outlining their views on major issues related to consolidation policy. This article explains some of those statements, reviews their implications, and outlines the latest statements issued regarding consolidation guidelines and standards.


[Lipoprotein metabolism in the blood plasma and liver in alimentary dyslipoproteinemias in an experiment].
It has been shown in rats with experimental alimentary dyslipoproteinemias that the rate of metabolism of the basic apoproteins of blood plasma lipoproteins and lipid-transporting proteins of the liver experiences certain changes. It is postulated that variation in the rate of metabolism of the proteins under consideration influences the intensity of lipid (phospholipid, cholesterol) exchange between different classes of lipoproteins in blood plasma as well as between the latter lipoproteins and plasma membranes of liver cells.


Determinants of recent aflatoxin exposure among pregnant women in rural Zimbabwe.
Aflatoxins (AFs) are toxic secondary metabolites of Aspergillus species that contaminate staple foods such as maize and groundnuts. AF exposure during pregnancy has been associated with adverse birth outcomes in limited-scale surveys in sub-Saharan Africa. The objective of this study was to describe the determinants of AF exposure, using urinary aflatoxin M1 (AFM1) biomarkers and data generated by the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial for rural Zimbabwean women in early pregnancy. Sanitation Hygiene Infant Nutrition Efficacy is a large, cluster-randomized community-based trial in Zimbabwe designed to investigate the independent and combined effects of nutrition and hygiene interventions on early child growth. Urine samples collected from 1580 pregnant women in rural Zimbabwe at median gestational age of 13.9 wk were measured for AFM1. AFM1 was detected in 30% of samples (median of exposed, 162 pg AFM1/mg creatinine; range 30-6046 pg AFM1/mg). In multivariable ordinal logistic models, geographical location (p<0.001), seasonality (p < 0.001) and dietary practices (p = 0.011) were significant predictors of urinary AFM1. This is the largest AF biomarker survey conducted in Zimbabwe, and demonstrated frequent exposure in pregnant women with clear temporal and spatial variability in AF biomarker levels.


Psychological predictors of recovery from low back pain: a prospective study.
Recovery from low back pain (LBP) is an important outcome for patients and clinicians. Psychological factors are known to impact the course of LBP but have not been extensively investigated for predicting recovery. The purposes of this study were to: 1) describe LBP recovery rates at 6 months following 4 weeks of physical therapy; 2) identify psychological factors predictive of 6 month recovery status; and 3) identify psychological factors that co-occur with 6 month recovery status. This study was a secondary analysis of a prospective cohort of patients (n = 111) receiving outpatient physical therapy for LBP. Patients were administered the STarT Back Screening Tool (SBT), individual psychological measures, a numerical pain rating scale (NPRS) and Roland Morris Disability Questionnaire (RMDQ) at intake, 4-week, and 6-month assessments. LBP recovery was operationally defined based on meeting NPRS = 0/10 and RMDQ ≤ 2 criterion at 6-month follow-up assessment. Recovery groups were then compared for differences on all variables at intake and on individual psychological measures at 6-months. Discriminant function analysis (DFA) identified which descriptive variables were predictive of recovery status. The 6-month recovery rate was 14/111 (12.6%) for the combined NPRS and RMDQ criterion. Non-recovered patients were associated with SBT risk status (p = 0.004), higher intake pain intensity (p = .008) and higher depressive symptoms (p < .001) scores compared to recovered patients. The overall accuracy for intake classification using DFA was 87.2% with SBT risk status, pain intensity, and depressive symptoms all making unique contributions. At 6-months, non-recovered patients had higher fear-avoidance, kinesiophobia, and depressive symptoms (p's < .001) compared to recovered patients. The overall accuracy for 6-month classification using DFA was 86.4% with fear-avoidance, kinesiophobia, and depressive symptoms all making unique contributions. Our findings indicated that psychological risk status, depressive symptoms, and pain intensity were predictive of 6 month recovery status. Furthermore elevated fear-avoidance, kinesiophobia, and depressive symptoms co-occurred with non-recovery at 6 months. Future studies should investigate whether stratified psychologically informed treatment options have the potential to improve recovery rates for those most at risk for non-recovery.


Reconstruction of ENSO variability using the standardized growth index of a Tridacna shell from Yongshu Reef, South China Sea.
El Niño-Southern Oscillation (ENSO) is the strongest signal of global interannual climate anomaly and reconstructing past ENSO variations using high-resolution paleoclimate archives can improve our understanding of ENSO variability, as well as improve our ability to predict future climate changes. Here, a daily resolution standardized growth index (SGI) was established using a giant clam (Tridacna spp.) shell specimen MD2 (life span: 1994-2013 CE), collected from the Yongshu Reef, southern South China Sea (SCS). The cross-spectral and correlation analysis indicated that the SGI variation of MD2 was strongly influenced by ENSO variability on an interannual timescale. Tridacna spp. is in symbiosis with zooxanthellae, and its growth index is usually modulated by the photosynthetic efficiency of zooxanthellae. During the El Niño (La Niña) period, the convective anomalies stimulated in western Pacific would increase (decrease) the effective solar radiation on Yongshu Reef, and in turn influence the photosynthesis rate of zooxanthellae and enzyme activity for the calcification site and thus the SGI of giant clam MD2. The SGI can explain 54.7 % of ENSO variance, demonstrating the potential for Tridacna SGI in ENSO reconstruction. Compared with conventional ENSO reconstruction using high-resolution geochemical proxies, the method of giant clam SGI is rapid and economical.


Trifluridine/Tipiracil and Regorafenib in Patients with Metastatic Colorectal Cancer: A Retrospective Study at a Tertiary Oncology Center.
Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist. A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, real-world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second- or third-line were performed. One hundred twenty-six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value <.05; rwDCR 64.2% vs. 46.1%; adjusted OR = 2.5; all p value <.05). Similar findings were observed for FTD/TPI versus regorafenib as second- or third-line therapy (rwORR 54.8% vs. 25.9%; adjusted OR = 4.1; all p value <.05; rwDCR 69.0% vs. 37.0%; adjusted OR = 4.9; all p value <.05). A greater proportion of patients treated with FTD/TPI versus regorafenib survived at 3 months (86.2% vs. 73.4%; p value = .016) and 4 months (79.6% vs. 65.8%; p value = .017). Adjusted OS hazard ratio for FTD/TPI versus regorafenib was 0.80, p value = .157. Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second- or third-line suggests that early use of FTD/TPI may have clinical benefits. In this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. This study offers insight into patients' treatment experience in real-world clinical settings.


Antimicrotubule effects of estramustine, an antiprostatic tumor drug.
Estramustine [17 beta-estradiol 3 N bis(2-chloroethyl)carbamate; EM] is a stable conjugate of estradiol and nor-nitrogen mustard that is used for the treatment of human prostatic carcinoma. We have studied the cytotoxic effects of EM on the cytoskeletal organization of squirrelfish pigment cells (erythrophores) and human prostatic tumor cells (DU 145) in culture. Light and whole-mount electron microscopy studies reveal that, at microM levels (60 to 120 microM), EM has a dose-dependent disruptive effect on cell shape, cytoskeletal organization, and intracellular transport. Upon removal of the drug, the cytological effects of EM are rapidly reversible in fish cells but not DU 145s. Immunofluorescent studies reveal that EM produces microtubule disassembly in fish erythrophores and DU 145 cells. A concomitant disruption of actin-microfilament arrays also occurs in DU 145 cells. These morphological data suggest that EM, in contradistinction to its constituent estradiol: nitrogen mustard species, induces cytotoxicity as an antimicrotubule drug. The observed disruption of the microtubules and cytomatrix of interphase cells is not reversible in the prostatic carcinoma cells. The disruptive action of EM on the cytoskeleton could ultimately produce a cytotoxic antimitotic effect in dividing cells.


Flexible, rapid and automatic neocortical word form acquisition mechanism in children as revealed by neuromagnetic brain response dynamics.
Children learn new words and word forms with ease, often acquiring a new word after very few repetitions. Recent neurophysiological research on word form acquisition in adults indicates that novel words can be acquired within minutes of repetitive exposure to them, regardless of the individual's focused attention on the speech input. Although it is well-known that children surpass adults in language acquisition, the developmental aspects of such rapid and automatic neural acquisition mechanisms remain unexplored. To address this open question, we used magnetoencephalography (MEG) to scrutinise brain dynamics elicited by spoken words and word-like sounds in healthy monolingual (Danish) children throughout a 20-min repetitive passive exposure session. We found rapid neural dynamics manifested as an enhancement of early (~100ms) brain activity over the short exposure session, with distinct spatiotemporal patterns for different novel sounds. For novel Danish word forms, signs of such enhancement were seen in the left temporal regions only, suggesting reliance on pre-existing language circuits for acquisition of novel word forms with native phonology. In contrast, exposure both to novel word forms with non-native phonology and to novel non-speech sounds led to activity enhancement in both left and right hemispheres, suggesting that more wide-spread cortical networks contribute to the build-up of memory traces for non-native and non-speech sounds. Similar studies in adults have previously reported more sluggish (~15-25min, as opposed to 4min in the present study) or non-existent neural dynamics for non-native sound acquisition, which might be indicative of a higher degree of plasticity in the children's brain. Overall, the results indicate a rapid and highly plastic mechanism for a dynamic build-up of memory traces for novel acoustic information in the children's brain that operates automatically and recruits bilateral temporal cortical circuits.


Ni vs. Pd in Suzuki-Miyaura sp2-sp2 cross-coupling: a head-to-head study in a comparable precatalyst/ligand system.
The Suzuki-Miyaura reaction is a cornerstone method for sp2-sp2 cross-coupling in industry. There has been a concerted effort to enable the use of Ni catalysis as an alternative to Pd in order to mitigate cost and improve sustainability. Despite significant advances, ligand development for Ni-catalyzed Suzuki-Miyaura cross-coupling remains underdeveloped when compared to Pd and, as a consequence, ligands for Ni-catalyzed processes are typically taken from the Pd arena. In this study we evaluate the effect of using a similar Ni and Pd precatalyst based on a common bidentate ligand (dppf) in a head-to-head format for the most common type of biaryl couplings, establishing the practical implications of direct replacement of Pd with Ni, and identifying the potential origins of these observations in a mechanistic context.


Fewer and older patients with rheumatoid arthritis need total knee replacement.
Recent studies have suggested a decreased need for orthopaedic surgery in patients with rheumatoid arthritis (RA). We analysed trends in total knee replacement (TKR) in RA using TKR in osteoarthritis (OA) as a point of reference. Data on TKRs from the Finnish Arthroplasty Register and population data from Statistics Finland were used to analyse the trends in TKRs among patients aged ≥ 40 years with primary osteoarthritis (OA) or RA in Finland for the period from 1980 to 2010. During 1980-2010, the overall incidence of TKRs increased 20-fold from 14.2 to 305.3 operations per 10(5) person-years. After peaking in 1992, the annual incidence of TKRs for RA decreased gradually from 19.6 to 10.8 per 10(5) [incidence rate ratio (IRR) 0.97, p < 0.001]. The decrease was more pronounced in women and the older (≥ 60 years) age group. The mean age at the time of TKR among patients with RA increased over time, converging with that of patients with OA. There is a clear decrease in the annual incidence of TKRs in RA, while among OA patients the incidence is increasing steadily. Furthermore, patients with RA seem to receive their TKRs at an older age. Both of these findings suggest improving long-term outcome in RA.


Why vitamin D in Alzheimer's disease? The hypothesis.
Scientists have worked for over a century to uncover the basis of Alzheimer's disease (AD) with the ultimate goal of discovering a treatment. However, none of the approaches utilized have defined the exact cause of the disease or an ultimate treatment for AD. In this review, we aim to define the role of vitamin D in AD from a novel and fundamental perspective and attempt to answer the following question: Why should we seriously consider "simple" vitamin D as a "fundamental factor" in AD? To answer this question, we explain the protective effects of vitamin D in the central nervous system and how the action of vitamin D and AD-type pathology overlap. Furthermore, we suggest that the role of vitamin D in AD includes not only vitamin D deficiency and vitamin D-related genes but also the disruption of vitamin D metabolism and action. This suggestion is supported by evidence that the disruption of vitamin D pathways mimic amyloid pathology. We define the term "inefficient utilization of vitamin D" as any alteration in vitamin D-related genes, including receptors, the enzymes related to vitamin D metabolism or the transporters of vitamin D, and we discuss the potential correlation of vitamin D status with the vulnerability of neurons to aging and neurodegeneration. Finally, in addition to the current knowledge that defines AD, we suggest that AD could be the result of a long-term hormonal imbalance in which the critical hormone is vitamin D, a secosteroid that has long been misnamed.


Database for the ampC alleles in Acinetobacter baumannii.
Acinetobacter baumannii is a troublesome opportunistic pathogen with a high capacity for clonal dissemination. We announce the establishment of a database for the ampC locus in A. baumannii, in which novel ampC alleles are differentiated based on the occurrence of ≥ 1 nucleotide change, regardless of whether it is silent or missense. The database is openly accessible at the pubmlst platform for A. baumannii (http://pubmlst.org/abaumannii/). Forty-eight distinctive alleles of the ampC locus have so far been identified and deposited in the database. Isolates from clonal complex 1 (CC1), according to the Pasteur multilocus sequence typing scheme, had a variety of the ampC locus alleles, including alleles 1, 3, 4, 5, 6, 7, 8, 13, 14, 17, and 18. On the other hand, isolates from CC2 had the ampC alleles 2, 3, 19, 20, 21, 22, 23, 24, 26, 27, 28, and 46. Allele 3 was characteristic for sequence types ST3 or ST32. The ampC alleles 10, 16, and 25 were characteristic for CC10, ST16, and CC25, respectively. Our study points out that novel gene databases, in which alleles are numbered based on differences in their nucleotide identities, should replace traditional records that use amino acid substitutions to define new alleles.


Escherichia coli in patients with renal scarring: genotype and phenotype of Gal alpha 1-4Gal beta-, Forssman- and mannose-specific adhesins.
The frequency of Escherichia coli with Gal alpha 1-4Gal beta-specific adhesins is reduced among children who develop renal scars. The adhesion-negative phenotype may be due to the absence of the pap DNA sequences which encode these adhesins or to a phase variation event induced by in vitro culture. In the present study the frequency of pap and pil homologous DNA was determined by dot blot analysis with probes specific for the respective sequence using E. coli strains from children with recurrent pyelonephritis with and without renal scarring. The frequency of pap was 79% in the strains isolated from the nonscarring group compared with 39% in the strains from the scarring group (P less than 0.001). The Gal alpha 1-4Gal beta phenotype was expressed by 89% of the pap-positive strains from the nonscarring group compared with 71% in the scarring group (P less than 0.05). In addition 13 of 77 of the pap-positive E. coli strains agglutinated sheep erythrocytes but not the Gal alpha 1-4Gal beta latex beads; a reaction attributed to reactivity with the Forssman glycolipid. DNA sequences homologous with pil were found in 95% of all strains and there was no significant difference between the nonscarring and the scarring groups. The low frequency of Gal alpha 1-4Gal beta specific strains in the scarring group was therefore due to the absence of pap-homologous DNA sequences and to a reduced rate of phenotypic expression among pap-positive scarring strains. There was no support for a relationship between type 1 fimbriae and renal scarring.


Resistance exercise biology: manipulation of resistance exercise programme variables determines the responses of cellular and molecular signalling pathways.
Recent advances in molecular biology have elucidated some of the mechanisms that regulate skeletal muscle growth. Logically, muscle physiologists have applied these innovations to the study of resistance exercise (RE), as RE represents the most potent natural stimulus for growth in adult skeletal muscle. However, as this molecular-based line of research progresses to investigations in humans, scientists must appreciate the fundamental principles of RE to effectively design such experiments. Therefore, we present herein an updated paradigm of RE biology that integrates fundamental RE principles with the current knowledge of muscle cellular and molecular signalling. RE invokes a sequential cascade consisting of: (i) muscle activation; (ii) signalling events arising from mechanical deformation of muscle fibres, hormones, and immune/inflammatory responses; (iii) protein synthesis due to increased transcription and translation; and (iv) muscle fibre hypertrophy. In this paradigm, RE is considered an 'upstream' signal that determines specific downstream events. Therefore, manipulation of the acute RE programme variables (i.e. exercise choice, load, volume, rest period lengths, and exercise order) alters the unique 'fingerprint' of the RE stimulus and subsequently modifies the downstream cellular and molecular responses.


Contemporary gene flow between wild An. gambiae s.s. and An. arabiensis.
In areas where the morphologically indistinguishable malaria mosquitoes Anopheles gambiae Giles and An. arabiensis Patton are sympatric, hybrids are detected occasionally via species-diagnostic molecular assays. An. gambiae and An. arabiensis exhibit both pre- and post-reproductive mating barriers, with swarms largely species-specific and male F1 (first-generation) hybrids sterile. Consequently advanced-stage hybrids (back-crosses to parental species), which would represent a route for potentially-adaptive introgression, are expected to be very rare in natural populations. Yet the use of one or two physically linked single-locus diagnostic assays renders them indistinguishable from F1 hybrids and levels of interspecific gene flow are unknown. We used data from over 350 polymorphic autosomal SNPs to investigate post F1 gene flow via patterns of genomic admixture between An. gambiae and An. arabiensis from eastern Uganda. Simulations were used to investigate the statistical power to detect hybrids with different levels of crossing and to identify the hybrid category significantly admixed genotypes could represent. A range of admixture proportions were detected for 11 field-collected hybrids identified via single-locus species-diagnostic PCRs. Comparison of admixture data with simulations indicated that at least seven of these hybrids were advanced generation crosses, with backcrosses to each species identified. In addition, of 36 individuals typing as An. gambiae or An. arabiensis that exhibited outlying admixture proportions, ten were identified as significantly mixed backcrosses, and at least four of these were second or third generation crosses. Our results show that hybrids detected using standard diagnostics will often be hybrid generations beyond F1, and that in our study area around 5% (95% confidence intervals 3%-9%) of apparently 'pure' species samples may also be backcrosses. This is likely an underestimate because of rapidly-declining detection power beyond the first two backcross generations. Post-F1 gene flow occurs at a far from inconsequential rate between An. gambiae and An. arabiensis, and, especially for traits under strong selection, could readily lead to adaptive introgression of genetic variants relevant for vector control.


[Hepatopulmonary syndrome and pulmonary perfusion scan].
We introduce you a case report of a female patient who has got a chronic liver disease and who entered our hospital with clinical suspicion of pulmonary embolism. The radionuclide lung perfusion scan using 99m Technetium-labelled with macroaggregated albumin, showed an abnormal uptake out of the lungs in liver, spleen, and kidneys. Once all possible etiologies of extrapulmonary uptake were excluded and confirming that the hepatopulmonary syndrome clinical criteria were coincident with our case, we attribute that the abnormal extrapulmonary uptake was explainable due to this syndrome. This is an hepatopulmonary syndrome case in which nuclear medicine techniques were decisive for the diagnosis in front of other diagnostic tests (radiography, echography and CT) that gave valuable but non conclusive information.


Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome.
This study sought to evaluate the ability of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to successfully identify functional cortical areas in patients with primary brain tumors, to evaluate the use of the fMRI results in presurgical planning, and to assess the functional outcome of the patients with respect to the functional maps obtained with fMRI. The study included 25 consecutive preoperative fMRI sessions in patients with primary brain tumors in or near sensorimotor and/or language cortices. All fMRI paradigms were analyzed and rated according to the degree of success. Several distances between tumor and functional cortex as delineated with BOLD fMRI were measured to assess the topographic relationship between these two structures. Pre- and postoperative neurological statuses were obtained from the patients' journals. Acquisition of BOLD fMRI images was successful in 80% of the cases. The primary cause of unsuccessful fMRI was echo-planar imaging signal voids that were the result of previous craniotomy; the secondary cause was excessive motion. The neurosurgeons used the fMRI results for preoperative planning in 75% of the cases in which fMRI was successful. The risk of postoperative loss of function tested with fMRI was significantly lower when the distance between tumor periphery and BOLD activity was 10 mm or more. The majority of patients with primary brain tumors were capable of satisfactorily performing the fMRI paradigms, and the information obtained was used in the preoperative planning. A distance of 10 mm or more between the functional cortex, as delineated with fMRI, and the tumor significantly reduced the risk of postoperative loss of function.


Pyrophosphate hydrolysis is an intrinsic and critical step of the DNA synthesis reaction.
DNA synthesis by DNA polymerases (dPols) is central to duplication and maintenance of the genome in all living organisms. dPols catalyze the formation of a phosphodiester bond between the incoming deoxynucleoside triphosphate and the terminal primer nucleotide with the release of a pyrophosphate (PPi) group. It is believed that formation of the phosphodiester bond is an endergonic reaction and PPi has to be hydrolyzed by accompanying pyrophosphatase enzymes to ensure that the free energy change of the DNA synthesis reaction is negative and it can proceed in the forward direction. The fact that DNA synthesis proceeds in vitro in the absence of pyrophosphatases represents a long-standing conundrum regarding the thermodynamics of the DNA synthesis reaction. Using time-resolved crystallography, we show that hydrolysis of PPi is an intrinsic and critical step of the DNA synthesis reaction catalyzed by dPols. The hydrolysis of PPi occurs after the formation of the phosphodiester bond and ensures that the DNA synthesis reaction is energetically favorable without the need for additional enzymes. Also, we observe that DNA synthesis is a two Mg2+ ion assisted stepwise associative SN2 reaction. Overall, this study provides deep temporal insight regarding the primary enzymatic reaction responsible for genome duplication.


Regional variation in lateral and medial gastrocnemius muscle fibre lengths obtained from diffusion tensor imaging.
Assessment of regional muscle architecture is primarily done through the study of animals, human cadavers, or using b-mode ultrasound imaging. However, there remain several limitations to how well such measurements represent in vivo human whole muscle architecture. In this study, we developed an approach using diffusion tensor imaging and magnetic resonance imaging to quantify muscle fibre lengths in different muscle regions along a muscle's length and width. We first tested the between-day reliability of regional measurements of fibre lengths in the medial (MG) and lateral gastrocnemius (LG) and found good reliability for these measurements (intraclass correlation coefficient [ICC] = 0.79 and ICC = 0.84, respectively). We then applied this approach to a group of 32 participants including males (n = 18), females (n = 14), young (24 ± 4 years) and older (70 ± 2 years) adults. We assessed the differences in regional muscle fibre lengths between different muscle regions and between individuals. Additionally, we compared regional muscle fibre lengths between sexes, age groups, and muscles. We found substantial variability in fibre lengths between different regions within the same muscle and between the MG and the LG across individuals. At the group level, we found no difference in mean muscle fibre length between males and females, nor between young and older adults, or between the MG and the LG. The high variability in muscle fibre lengths between different regions within the same muscle, possibly expands the functional versatility of the muscle for different task requirements. The high variability between individuals supports the use of subject-specific measurements of muscle fibre lengths when evaluating muscle function.


The Veterans Affairs medical care system: hospital and clinic utilization statistics for 1994.
The authors describe the role the Veterans Affairs (VA) medical system plays as a provider of clinic and hospital services by examining utilization levels and users' characteristics. The Veterans Affairs hospital discharge database, the Veterans Affairs outpatient clinic files, and the veteran population files were used to estimate the number of persons using the Veterans Affairs medical care system in 1994 and the intensity of their clinic and hospital use. Demographic and clinical characteristics of users were tabulated. In 1994, 2.7 million veterans, 10.3% of all US veterans, and approximately 23% of veterans who would have met the statutory eligibility requirements for Veterans Affairs care, used the hospital and/or clinic components of the Veterans Affairs medical system. Sixty-three percent of the system's users were younger than age 65, and 10.5% were women. These 2.7 million veterans had 901,665 Veterans Affairs hospital stays, 15.5 million bed-days, and 31.2 million outpatient visits in fiscal year 1994. The average number of hospitalizations per hospital user was 1.71; the average number of visits per clinic user was 11.7. Medical, surgical, and psychiatric diagnosis-related groups (DRGs) accounted for 56%, 21%, and 23%, respectively, of hospitalizations, but psychiatric diagnosis-related groups accounted for 43% of all inpatient days. Principal medicine clinic visits and psychiatry clinic visits accounted for 21% and 16% of Veterans Affairs ambulatory care. Because the patient population served by the Veterans Affairs system is skewed in a number of ways, its contribution as a provider of health services in the United States varies by gender, age, socioeconomic status, and diagnosis.


Cellular recombination pathways and viral terminal repeat hairpin structures are sufficient for adeno-associated virus integration in vivo and in vitro.
The human parvovirus adeno-associated virus (AAV) is unique in its ability to target viral integration to a specific site on chromosome 19 (ch-19). Recombinant AAV (rAAV) vectors retain the ability to integrate but have apparently lost this ability to target. In this report, we characterize the terminal-repeat-mediated integration for wild-type (wt), rAAV, and in vitro systems to gain a better understanding of these differences. Cell lines latent for either wt or rAAV were characterized by a variety of techniques, including PCR, Southern hybridization, and fluorescence in situ hybridization analysis. More than 40 AAV-rAAV integration junctions were cloned, sequenced, and then subjected to comparison and analysis. In both immortalized and normal diploid human cells, wt AAV targeted integration to ch-19. Integrated provirus structures consisted of head-to-tail tandem arrays with the majority of the junction sequences involving the AAV inverted terminal repeats (ITRs). No complete viral ITRs were directly observed. In some examples, the AAV p5 promoter sequence was found to be fused at the virus-cell junction. Data from dot blot analysis of PCR products were consistent with the occurrence of inversions of genomic and/or viral DNA sequences at the wt integration site. Unlike wt provirus junctions, rAAV provirus junctions mapped to a subset of non-ch-19 sequences. Southern analysis supported the integration of proviruses from two independent cell lines at the same locus on ch-2. In addition, provirus terminal repeat sequences existed in both the flip and flop orientations, with microhomology evident at the junctions. In all cases with the exception of the ITRs, the vector integrated intact. rAAV junction sequence data were consistent with the occurrence of genomic rearrangement by deletion and/or rearrangement-translocation at the integration locus. Finally, junctions formed in an in vitro system between several AAV substrates and the ch-19 target site were isolated and characterized. Linear AAV substrates typically utilized the end of the virus DNA substrate as the point of integration, whereas products derived from AAV terminal repeat hairpin structures in the presence or absence of Rep protein resembled AAV-ch-19 junctions generated in vivo. These results describing wt AAV, rAAV, and in vitro integration junctions suggest that the viral integration event itself is mediated by terminal repeat hairpin structures via nonviral cellular recombination pathways, with specificity for ch-19 in vivo requiring additional viral components. These studies should have an important impact on the use of rAAV vectors in human gene therapy.


Work-unit measures of organisational justice and risk of depression--a 2-year cohort study.
The aim of this study is to analyse if low justice at work, analysed as aggregated workplace means, increases the risk of depression. A total of 4237 non-depressed Danish public employees within 378 different work units were enrolled in 2007. Mean levels of procedural and relational justice were computed for each work unit to obtain exposure measures that were robust to reporting bias related to depression. Two years later in 2009, 3047 (72%) participated at follow-up. Those reporting high levels of depressive, burn-out or stress symptoms were assigned to a psychiatric diagnostic interview. In the interview 58 cases of new onset depression were identified. Depression ORs by work unit level of procedural and relational justice were estimated by multivariable logistic regression accounting for established risk factors for depression. Working in a work unit with low procedural justice (adjusted ORs of 2.50, 95% CI 1.06 to 5.88) and low relational justice (3.14, 95% CI 1.37 to 7.19) predicted onset of depression. Our results indicate that a work environment characterised by low levels of justice is a risk factor for depression.


Joint cortical registration of geometry and function using semi-supervised learning.
Brain surface-based image registration, an important component of brain image analysis, establishes spatial correspondence between cortical surfaces. Existing iterative and learning-based approaches focus on accurate registration of folding patterns of the cerebral cortex, and assume that geometry predicts function and thus functional areas will also be well aligned. However, structure/functional variability of anatomically corresponding areas across subjects has been widely reported. In this work, we introduce a learning-based cortical registration framework, JOSA, which jointly aligns folding patterns and functional maps while simultaneously learning an optimal atlas. We demonstrate that JOSA can substantially improve registration performance in both anatomical and functional domains over existing methods. By employing a semi-supervised training strategy, the proposed framework obviates the need for functional data during inference, enabling its use in broad neuroscientific domains where functional data may not be observed. The source code of JOSA will be released to the public at https://voxelmorph.net.


Orally active alpha-tocopheryloxyacetic acid suppresses tumor growth and multiplicity of spontaneous murine breast cancer.
We recently demonstrated the antitumor efficacy of orally administered alpha-tocopheryloxyacetic acid (alpha-TEA), a redox silent and nonhydrolyzable derivative of naturally occurring vitamin E. In order to move alpha-TEA closer to the clinic to benefit patients with breast cancer, the present study had two goals. First, to determine the minimal effective treatment dose; and second, to test the efficacy of dietary administration of alpha-TEA in the clinically relevant MMTV-PyMT mouse model of spontaneous breast cancer that more closely resembles human disease. The minimal effective dose of alpha-TEA was evaluated in the transplantable 4T1 tumor model and we show a dose-dependent decrease of primary tumor growth and reduction of metastatic spread to the lung. Six-week-old MMTV-PyMT mice were treated with oral alpha-TEA for 9 weeks, with no apparent signs of drug toxicity. The alpha-TEA treatment delayed tumor development and significantly slowed tumor progression, resulting in a 6-fold reduction of the average cumulative tumor size. In addition, oral alpha-TEA caused an 80% reduction in spontaneous metastases. In situ analysis of tumor tissue identified apoptosis as an important mechanism of alpha-TEA-mediated tumor suppression in addition to inhibition of tumor cell proliferation. This study shows, for the first time, the ability of orally administered alpha-TEA to delay tumor onset and to inhibit the progression and metastatic spread of a clinically relevant model of spontaneous breast cancer. Our finding of the high efficacy in this tumor model highlights the translational potential of oral alpha-TEA therapy.


Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma.
The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ≥1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan-Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.


Direct Oxidative Damage of Naked DNA Generated upon Absorption of UV Radiation by Nucleobases.
It has been shown that in addition to formation of pyrimidine dimers, UV irradiation of DNA in the absence of photosensitizer also induces formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, but the mechanism of formation of that oxidized base has not been clearly established. In the present study, we provide an unambiguous demonstration that absorption of UVC and UVB radiation by the nucleobases induces DNA oxidation via a direct process (one-electron oxidation) and not singlet oxygen. Evidence arose from the fact that polyamine-guanine adducts that are specifically produced through the transient formation of guanine radical cation are generated following UV irradiation of DNA in the presence of a polyamine even in the absence of any photosensitizer.


Physical stabilization of low-molecular-weight amorphous drugs in the solid state: a material science approach.
Use of the amorphous state is considered to be one of the most effective approaches for improving the dissolution and subsequent oral bioavailability of poorly water-soluble drugs. However as the amorphous state has much higher physical instability in comparison with its crystalline counterpart, stabilization of amorphous drugs in a solid-dosage form presents a major challenge to formulators. The currently used approaches for stabilizing amorphous drug are discussed in this article with respect to their preparation, mechanism of stabilization and limitations. In order to realize the potential of amorphous formulations, significant efforts are required to enable the prediction of formulation performance. This will facilitate the development of computational tools that can inform a rapid and rational formulation development process for amorphous drugs.


Immunological studies of the human placenta. Characterization of immunoglobulins on trophoblastic basement membranes.
Immunohistological and elution studies of the human placenta revealed the presence of IgG on the trophoblastic basement membrane (TBM) which demonstrated specificity for placental but not lung, thyroid, or kidney basement membranes, suggesting the presence of a placenta-specific antigen in TBM. IgG comprised the bulk of immunoglobulin in eluates, and small amounts of IgA, trace amounts of IgM, but no IgE or IgD were identified in eluates. The distribution of IgG subclasses in eluate was not unusual as compared to maternal and neonatal sera, and Gm and Inv typing of eluates indicated that it was of maternal origin. Small amounts of eluate-IgG effectively inhibited the blastogenic response of unrelated lymphocytes to old tuberculin, phytohemagglutinin, and in one- or two-way mixed lymphocyte culture reactions. The inhibition was distinct from nonspecific inhibitors, and dose-response analysis indicated that eluate was very much more potent as an inhibitor than were the nonspecific inhibitors. Inhibition was shown to not be due to anti-HL-A activity, and was probably not due to aggregated IgG or immune complexes. Binding of eluate to lymphocytes was very loose as shown by washing experiments, and no binding could be shown by immunofluorescence. The capacity of eluate IgG to inhibit MLC was retained after pepsin digestion to F(ab')(2), suggesting that the inhibition reactions were immunological. It is suggested that eluate-IgG is maternal blocking antibody to a hitherto uncharacterized trophoblast antigen, and it is speculated that either abnormal antigen or aberrant responses to antigen could result in fetal wastage.


Plasticity in leader-follower roles in human teams.
In humans, emergence of leaders and followers is key to group performance, but little is known about the whys and hows of leadership. A particularly elusive question entails behavioral plasticity in leadership across social contexts. Addressing this question requires to eliminate social feedback between focal individuals and their partners in experiments that could illuminate the spontaneous emergence of social roles. We investigated plasticity in leader-follower roles in cooperation, where members choose the task toward a shared goal, and coordination, where members adjust their actions in real time based on social responsiveness. Through a computer-programmed virtual partner, we demonstrate adaptive plasticity in leader-follower roles. Humans increased their followership to cooperate when the partner led more in the choice of the task, whereas they showed only weak leadership when the partner followed more. We leveraged the information-theoretic notion of transfer entropy to quantify leadership and followership in coordination from their movements. When exhibiting stronger followership in task cooperation, humans coordinated more with the partner's movement, with greater information being transferred from the partner to humans. The evidence of behavioral plasticity suggests that humans are capable of adapting their leader-follower roles to their social environments, in both cooperation and coordination.


Electrophysiological properties of automatic fibers in rabbit atrioventricular valves.
Subsidiary atrial automaticity generated by cardiac fibers of the rabbit tricuspid valve was studied in vitro with the use of standard microelectrode techniques. The time course of diastolic depolarization of leading pacemaker fibers was characteristically biphasic over a potential range of -80 to -55 mV, with a brief primary phase of relatively steep slope and a longer secondary phase of lesser slope. The regenerative upstroke of pacemaker potentials was suppressed by cobalt ions and varied with changes in extracellular Ca2+ concentration in a manner suggesting a slow channel process. The time course of each diastolic phase, estimated by measuring slope, varied in a reproducible manner with changes in membrane potential elicited with long duration current pulses. Cesium ions reduced the slope of both diastolic phases at all potentials with greater effects on the primary diastolic phase, but spontaneous activity in the absence of current pulses was not significantly altered. Furthermore, pacemaker activity varied with changes in extracellular K+ concentration and in response to barium ions in manners suggesting the presence of a decaying K+ conductance. These experiments demonstrate the utility of valve tissue as a model of subsidiary atrial pacemaker activity and suggest the presence of current systems qualitatively similar to those observed in the sinoatrial node.


The Migration of Arizona's Post-Insanity Defense Procedures to a Modified GBMI Model.
Arizona's insanity defense and post-insanity procedures have evolved over the last 30 years into a unique system. Arizona moved from a typical M'Naughten-based insanity defense to an adaptation of the Oregon Psychiatric Security Review Board (PSRB) model and then to its current form, in which the PSRB is cast in a correctional framework. These changes have resulted in a correctional statute, with outcomes that may subject the guilty except insane (GEI) offender to a disposition similar to that of someone found guilty but mentally ill (GBMI). We review the literature on the GBMI defense first developed in Michigan in the 1970s and compare Arizona's current system to the earlier GBMI models. We conclude with a discussion of Arizona's GEI verdict and implications of managing these offenders in a correctional framework, resulting in a modified GBMI statute.


Functionally redundant isoforms of a yeast Hsp70 chaperone subfamily have different antiprion effects.
Why eukaryotes encode multiple Hsp70 isoforms is unclear. Saccharomyces cerevisiae Ssa1p and Ssa2p are constitutive 98% identical Hsp70's. Stress-inducible Ssa3p and Ssa4p are 80% identical to Ssa1/2p. We show Ssa1p-4p have distinct functions affecting [PSI(+)] and [URE3] prions. When expressed as the only Ssa, Ssa1p antagonized [URE3] and Ssa2p antagonized [PSI(+)]. Ssa3p and Ssa4p influenced [URE3] and [PSI(+)] somewhat differently but overall their effects paralleled those of Ssa1p and Ssa2p, respectively. Additionally, Ssa3p suppressed a prion-inhibitory effect of elevated temperature. Our previously described Ssa1-21p mutant weakens [PSI(+)] in SSA1-21 SSA2 cells and abolishes it in SSA1-21 ssa2Delta cells. To test if the same mutation affected other prions or altered Ssa2p similarly, we compared effects of a constructed Ssa2-21p mutant and Ssa1-21p on both prions. Surprisingly, [URE3] was unaffected in SSA1-21 SSA2 cells and could propagate in SSA1-21 ssa2Delta cells. Ssa2-21p impaired [URE3] considerably and weakened [PSI(+)] strongly but in a manner distinct from Ssa1-21p, highlighting functional differences between these nearly identical Hsp70's. Our data uncover exquisite functional differences among isoforms of a highly homologous cytosolic Hsp70 subfamily and point to a possibility that variations in Hsp70 function that might improve fitness under optimal conditions are also important during stress.


Impairment of psychological functions in children environmentally exposed to lead.
The major objective of the study was to determine whether environmental exposure to lead exerts a negative impact upon psychological functions in children. The examined group consisted fo school age children (6-15 years old, x = 9.5, SD = 1.4) living close to copper works. Out of 4548 children with measured blood lead concentrations, two groups were selected one with the highest exposure levels (12.0-27.2 micrograms/dl) and the other drawn from the remaining children, with low blood lead levels. The mean exposure level for the whole examined group equalled 10.18 mu/dl PbB (SD-4.73 micrograms/dl). To assess effects of the exposure, the following variables were measured in the examined children: intelligence, hand-eye coordination, perception, memory, reaction time and accuracy, and behaviour disorders. The moderator variables of sociodemographic character, i.e. parents' education, income, etc., were also controlled. A significant impact of lead upon psychological functions and behaviour was revealed for two variables only: intelligence and attention concentration. An increase in the exposure level by 10 micrograms/dl PbB was associated with deterioration of general IQ by 5.3 points and growth of the number of mistakes in the Simple Reaction Time test by 3.3. It was also revealed that the short-term memory deteriorates with growing level of exposure, the strength of this relationship was close to the level of statistical significance (p < 0.07).


Acute poisoning of friesian heifers by Solanum macrocarpon L. ssp dasyphyllum.
Solanum macrocarpon (African eggplant) is a tropical plant widely cultivated as a delicious vegetable; the non-edible wild variety called Solanum macrocarpon L. ssp dasyphyllum (the wild African eggplant) bears thorns or spikes on the stem and leaves. Thirteen yearling heifers on a dairy farm in Uganda suffered acute poisoning after eating berries of S. macrocarpon L. ssp dasyphyllum. There was sudden onset of anorexia, copious salivation, severe dysentery and passage of red urine. The animals also had central nervous derangement (incordination, walking blindly) and exudative dermatitis. Four heifers died. Necropsy lesions were icterus, hemorrhages, gastroenteritis, lympadenomegally, and friable and bronze colored livers and kidneys. The rumen and reticulum contained masses of the plant seeds. This is the first report of cattle poisoning by this plant.


Maltreatment and trauma symptoms: Does type of maltreatment matter?
Children frequently report a heightened experience of psychological problems such as depression, anxiety, aggression, and posttraumatic stress disorder in response to maltreatment. However, in recent years, scholars have suggested that different types of maltreatment may be associated with different symptomatology in children. In the present study, we employ the Trauma Symptom Checklist for Young Children (TSCYC) to investigate whether children who have experienced different types of maltreatment reveal different profiles of symptomatology. Nonmaltreated (n = 101) and maltreated (n = 52) children between 3 and 12 years of age were included in the present study. Maltreatment was further categorized into the subgroups abuse and neglect. Findings proved the TSCYC to be successful in distinguishing nonmaltreated from maltreated children in terms of symptomatology. Furthermore, abused children showed a broader spectrum of symptoms, whereas neglected children differed on fewer symptom scales compared with their nonmaltreated peers. Lastly, abused children evinced more externalizing symptoms than the neglected children. In line with previous research, maltreated children do have more psychological symptoms, and, abused children showed enhanced psychological problems and more externalizing symptoms in particular. (PsycINFO Database Record


Test characteristics of electrocardiography for detection of left ventricular hypertrophy in asymptomatic emergency department patients with hypertension.
The objective was to evaluate the diagnostic test characteristics of three validated electrocardiographic (ECG) criteria for the diagnosis of left ventricular hypertrophy (LVH) in undifferentiated, asymptomatic emergency department (ED) patients with hypertension (HTN). This was a prospective cohort study of ED patients with asymptomatic HTN at a single tertiary care facility. Patients 35 years of age or older with systolic blood pressure (sBP) ≥ 140 mm Hg or diastolic blood pressure (dBP) ≥ 90 mm Hg on two separate readings (at least 1 hour apart) were eligible for inclusion. At enrollment, ECGs were obtained for all patients. Presence of LVH on ECG was defined using Cornell voltage, Cornell product, and Minnesota Code 3.1/3.2 criteria. Echocardiography was then performed, with LVH defined by the presence of one or more of the following validated criteria: interventricular septal or posterior wall thickness ≥ 1.3 cm, LV mass ≥ 225 g (male) or ≥ 163 g (female), or LV mass indexed to height raised to the power of 2.7 ≥ 48 g/m(2.7) (male) or ≥ 45 g/m(2.7) (female). Descriptive statistics and diagnostic characteristics (i.e., sensitivity and specificity) with corresponding 95% confidence intervals (CIs) for each of the three ECG criteria were derived for both the composite and the individual echocardiographic determinants of LVH. Logistic regression was also used to model LVH before and after subsequent inclusion of clinically relevant variables. A total of 161 patients (93.8% African American; mean [±SD] age = 49.8 [±8.3] years) were enrolled, and LVH was present in 89 patients (55.2%, 95% CI = 47.6% to 62.8%). On ECG analysis, mean Cornell voltage (21.5 mV vs. 28.7 mV; difference = -7.2 mV, 95% CI = -3.8 to -10.7 mV) and Cornell product (1868.4 msec × mV vs. 2616.4 msec × mV; difference = -748.0 msec × mV, 95% CI = -401.2 to -1094.8 msec × mV) were significantly lower among those without LVH on echocardiography. Subjects without LVH on echocardiography were less likely to meet Cornell voltage (30.5% vs. 48.3%; difference = -17.8%, 95% CI = -2.5% to -31.7%) or Cornell product (26.4% vs. 49.4%; difference = -23.0%, 95% CI = -8.0% to -36.5%) criteria for LVH. The diagnosis of LVH by Minnesota Code was less common (18.1% vs. 25.8%; difference = -7.7%, 95% CI = -20.1% to 5.3%) with no difference by group. Sensitivity and specificity were as follows: for the Cornell voltage, sensitivity 25.4% (95% CI = 15.3% to 37.9%), specificity 50.0% (95% CI = 67.6% to 93.2%); for the Cornell product, sensitivity 25.4% (95% CI = 15.3% to 37.9%), specificity 75.0% (95% CI = 19.4% to 99.4%); and for the Minnesota code, sensitivity 26.9% (95% CI = 16.6% to 39.7%), specificity 75.0% (95% CI = 19.4% to 99.4%). On logistic regression, the c-statistics for Cornell voltage and Cornell product were equivalent (0.67), with only marginal improvement after the addition of body mass index (BMI; 0.69 and 0.70, respectively), B-type natriuretic peptide (BNP; 0.68 and 0.69, respectively), or both (0.71 and 0.72, respectively) to the models. In this cohort of predominately African American ED patients with asymptomatic HTN, sensitivity and specificity of standard ECG criteria were relatively poor for the diagnosis of LVH on echocardiography. Thus, ECG is of limited use for LVH risk stratification in asymptomatic ED patients with elevated blood pressure, with additional clinical information only modestly strengthening its predictive value.


Bulk-boundary correspondence in soft matter.
Bulk-boundary correspondence is the emergence of features at the boundary of a material that are dependent on and yet distinct from the properties of the bulk of the material. The diverse applications of this idea in topological insulators as well as high energy physics prove its universality. However, whether a form of bulk-boundary correspondence holds also in soft matter such as gels, polymers, lipids, and other biomaterials is thus far unknown. Aerosil-dispersed liquid crystal gels provide a good testing ground to explore the relation between the controlled variations of the aerosil density within the liquid crystal bulk and the surface topography of the sample. Here we report on a direct observation of such a correspondence where the controlled strength of random disorder created by aerosil dispersion in the bulk liquid crystal is correlated with the fractal dimension of the surface. We obtained the surface topography of our gel samples with different quenched random disorder strengths by using atomic force microscope techniques, and computed the fractal dimension for each sample. We found that an increase of the aerosil gel density in the bulk corresponds to an increase in the fractal dimension at the surface. From our results emerges a method to acquire the bulk properties of soft matter such as density, randomness, and phase merely from the fractal dimension of the surface.


Hypophosphatemia in a patient with lymphoma in leukemic phase.
A patient with histiocytic lymphoma had abdominal masses, hypophosphatemia, normocalcemia, and a normal serum parathyroid hormone value. After chemotherapy, transient hyperphosphatemia ensued, the abdominal masses resolved, and other manifestations of the disease were suppressed. One week after discontinuation of the chemotherapy, the abdominal masses and other signs indicative of reactivation of the malignant disease reappeared. During the relapse, the serum phosphorus level fell to 0.7 mg/dL, and urinary excretion of phosphorus became negligible. After resumption of chemotherapy, serum concentration and urinary excretion of phosphorus increased. These observation suggest that severe hypophosphatemia may be a complication of hematologic neoplasia. It is proposed that this abnormally may be caused by a shift of excessive amounts of extracellular phosphorus into the rapidly replicating malignant cells.


Power and sample size calculations for comparison of two regression lines with heterogeneous variances.
The existence of interactive effects of a dichotomous treatment variable on the relationship between the continuous predictor and response variables is an essential issue in biological and medical sciences. Also, considerable attention has been devoted to raising awareness of the often-untenable assumption of homogeneous error variance among treatment groups. Although the procedures for detecting interactions between treatment and predictor variables are well documented in the literature, the corresponding problem of power and sample size calculations has received relatively little attention. In order to facilitate interaction design planning, this article describes power and sample size procedures for the extended Welch test of difference between two regression slopes under heterogeneity of variance. Two different formulations are presented to explicate the implications of appropriate reliance on the predictor variables. The simplified method only utilizes the partial information of predictor variances and has the advantages of statistical and computational simplifications. However, extensive numerical investigations showed that it is relatively less accurate than the more profound procedure that accommodates the full distributional features of the predictors. According to the analytic justification and empirical performance, the proposed approach gives reliable solutions to power assessment and sample size determination in the detection of interaction effects. A numerical example involving kidney weigh and body weigh of crossbred diabetic and normal mice is used to illustrate the suggested procedures with flexible allocation schemes. Moreover, the organ and body weights data is incorporated in the accompany SAS and R software programs to illustrate the ease and convenience of the proposed techniques for design planning in interactive research.


Immediate and Long-Term Therapy of Patients with Acute Coronary Syndromes with Thienopyridines. Current Status According to the Latest European Society of Cardiology (ESC) Guidelines.
For patients with acute coronary syndrome (ACS), the first priority is to alert emergency services. In addition to an ECG (ideally taken during the first medical contact at the patient's home), the key of life saving is the immediate antithrombotic therapy with acetylsalicylic acid (ASA) and (unless contraindicated) an injection of unfractionated heparin or bivalirudin as an alternative anticoagulant. Dual anti-platelet therapy (ASA combined with other antiplatelet drugs, like thienopyridines) should be started as soon as possible in the ambulance or at the latest in the hospital. For clopidogrel, a loading dose of 600 mg is the standard. To avoid the risk of an unknown low or missing clopidogrel response, prasugrel is recommended instead, with administration of a loading dose of 60 mg, if no contraindication (s/p stroke or TIA) exists. When PCI is planned, the ambulance must head directly to the nearest hospital with continuous (24/7) PCI service within 90 (to 120) minutes. The maintenance dose for clopidogrel is 75 mg/d; a daily double-dose has not proven to be superior, even in "low responders". For prasugrel, the maintenance dose is usually 10 mg/d. To avoid bleeding complications in patients ≥ 75 y and/or < 60 kg, a prasugrel maintenance dose of 5 mg/d is recommended. The ESC guidelines recommend DAPT for 1 year after ACS in all patients - independent of the type of ACS and independent of whether any or which coronary stent has been implanted. With DAPT, the patient - and not the stent - is treated.


Choice of second-line systemic therapy in stage IV small cell lung cancer (SCLC) - A decision-making analysis amongst European lung cancer experts.
Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3-6 months since the end of first-line therapy. Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in.


Expression of cell cycle regulator genes in KB, a human squamous cell carcinoma cell line, after irradiation.
DNA damage induced by irradiation causes overexpression of the p53 gene, and subsequently the upregulation of p53 downstream genes involved in cell cycle modification. Irradiated malignant cells which possess wild-type p53 have been known to undergo G1 arrest due to p21/Cip1/Waf1 upregulation. Other p53 downstream genes related to the modification of the cell cycle such as gadd45 may cause G2 arrest. Many of the genes which regulate the cell cycle progression have been identified, including the G1 phase specific ink4 family of cyclin-dependent kinase inhibitors (CDK-I), another group of CDK-Is, which affect the cyclin-CDK complexes ubiquitously, and S/G2 accelerator genes. The sequential changes in these cell cycle regulator genes after irradiation has not been clarified. We analyzed the appearance of the apoptotic fraction and cell cycle perturbation after irradiation using KB, a human squamous cell carcinoma line derived from oral floor, and examined the alteration of gene expression for cell cycle regulator genes. The KB cells proceeded to undergo apoptosis in a time and dose dependent manner after irradiation and showed G2 arrest accompanied by upregulation of p53, ubiquitous CDK-Is, and S and G2 accelerator genes.


Characterization of insulin and insulin-like growth factor I receptors of purified Leydig cells and their role in steroidogenesis in primary culture: a comparative study.
Characterization of insulin and type I insulin-like growth factor (IGF-I) receptors and the effects of insulin and IGF-I on steroidogenesis were evaluated by using purified adult Leydig cells from Sprague-Dawley rats. Purified Leydig cells were found to contain both high and low affinity binding sites for insulin, with Ka values of 1.08 X 10(9) and 1.1 X 10(7) M-1, respectively. Using affinity cross-linking of [125I]iodoinsulin to plasma membrane insulin receptor, several bands were identified by autoradiography under nonreduced conditions with mol wt of 230,000, 280,000, and 300,000. After reduction with 50 mM dithiothreitol, only one band was identified with a mol wt of 130,000, consistent with the alpha-subunit of insulin receptor. Purified Leydig cells also contain specific type I IGF receptors with estimated binding affinity of 0.6 X 10(9) M-1. Multiple high mol wt bands (greater than 250,000) were identified under nonreduced conditions by affinity cross-linking. Under reduced conditions, one band with an approximate mol wt of 135,000 was identified. Purified Leydig cells (10(5) cells/ml) were cultured in Dulbecco's Modified Eagle's Medium-Ham's F-12 Nutrient Mixture (1:1) containing 0.1% fetal calf serum at 37 C in a humidified atmosphere of 5% CO2-95% air. Insulin and IGF-I stimulated testosterone formation as early as 3 h after administration, and their effects were completely blocked by the addition of a protein synthesis inhibitor, cycloheximide (1 microgram/ml). Insulin and IGF-I also significantly potentiated hCG-and 8-bromo-cAMP-induced testosterone formation. Furthermore, insulin and IGF-I potentiated hCG-stimulated cAMP formation. This suggests that insulin and IGF-I have effects at both the LH receptor sites and the steps beyond adenylate cyclase. The ED50 values of insulin and IGF-I-stimulated testosterone formation were comparable (25 ng/ml). In conclusion, we found that Leydig cells contain specific insulin and type I IGF receptors, and both insulin and IGF-I are capable of modulating Leydig cell steroidogenesis.


Health care disparities in emergency medicine.
The Institute of Medicine's landmark report, "Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care," documents the pervasiveness of racial and ethnic disparities in the U.S. health care delivery system, and provides several recommendations to address them. It is clear from research data, such as those demonstrating racial and ethnic disparities in emergency department (ED) pain management, that emergency medicine (EM) is not immune to this problem. The IOM authors describe two strategies that can reduce disparities in EM. First, workforce diversity is likely to result in a community of emergency physicians who are better prepared to understand, learn from, and collaborate with persons from other racial, ethnic, and cultural backgrounds, whether these be patients, fellow clinicians, or the larger medical and scientific community. Given the ethical and practical advantages of a more diverse EM workforce, continued and expanded initiatives to increase diversity within EM should be undertaken. Second, the specialty's educational programs should produce emergency physicians with the skills and knowledge needed to serve an increasingly diverse population. This cultural competence should include an awareness of existing racial and ethnic health disparities, recognition of the risks of stereotyping and biased treatment, and knowledge of the incidence and prevalence of health conditions among diverse populations. Culturally competent emergency care providers also possess the skills to identify and manage racial and ethnic differences in health values, beliefs, and behaviors with the ultimate goal of delivering quality health services to all patients cared for in EDs.


Innovative strategies for a successful SLMTA country programme: The Rwanda story.
In 2009, to improve the performance of laboratories and strengthen healthcare systems, the World Health Organization Regional Office for Africa (WHO AFRO) and partners launched two initiatives: a laboratory quality improvement programme called Strengthening Laboratory Management Toward Accreditation (SLMTA), and what is now called the Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA). This study describes the achievements of Rwandan laboratories four years after the introduction of SLMTA in the country, using the SLIPTA scoring system to measure laboratory progress. Three cohorts of five laboratories each were enrolled in the SLMTA programme in 2010, 2011 and 2013. The cohorts used SLMTA workshops, improvement projects, mentorship and quarterly performance-based financing incentives to accelerate laboratory quality improvement. Baseline, exit and follow-up audits were conducted over a two-year period from the time of enrolment. Audit scores were used to categorise laboratory quality on a scale of zero (< 55%) to five (95% - 100%) stars. At baseline, 14 of the 15 laboratories received zero stars with the remaining laboratory receiving a two-star rating. At exit, five laboratories received one star, six received two stars and four received three stars. At the follow-up audit conducted in the first two cohorts approximately one year after exit, one laboratory scored two stars, five laboratories earned three stars and four laboratories, including the National Reference Laboratory, achieved four stars. Rwandan laboratories enrolled in SLMTA showed improvement in quality management systems. Sustaining the gains and further expansion of the SLMTA programme to meet country targets will require continued programme strengthening.


Multiple Joint Osteonecrosis in a Patient on Long-term Intranasal Corticosteroids.
We present the first report of bilateral knee and left ankle osteonecrosis in a 58-year-old female patient on long-term intranasal corticosteroids. Initially, our patient presented with progressive disabling knee pain with normal radiographs. The patient was presumed to have mild degenerative joint disease; therefore, she was treated conservatively. Then, the patient developed severe left ankle pain, and she was thought to have L5/S1 radiculopathy; therefore, she underwent epidural steroid injection that did not provide any benefit. However, extensive bilateral osteonecrosis of the medial tibial plateau in addition to osteonecrosis of the talus bone of left ankle were later diagnosed by MRI. The patient underwent staged bilateral total knee arthroplasty. In conclusion, the diagnosis of osteonecrosis might be challenging because of overlapping clinical presentation with other disorders particularly in the early stage of the disease with normal radiographs. Therefore, a high index of suspicion and thorough history with supplemental MRI imaging are essential for the assessment of patients presented with atypical refractory joint pain particularly in the presence of risk factors.


Rheology and dispensing of real and vegan mayo: the chickpea or egg problem.
The rheology, stability, texture, and taste of mayonnaise, a dense oil-in-water (O/W) emulsion, are determined by interfacially active egg lipids and proteins. Often mayonnaise is presented as a challenging example of an egg-based food material that is hard to emulate using plant-based or vegan ingredients. In this contribution, we characterize the flow behavior of animal-based and plant-based mayo emulsions, seeking to decipher the signatures that make the real mayonnaise into such an appetizing complex fluid. We find that commercially available vegan mayos can emulate the apparent yield stress and shear thinning of yolk-based mayonnaise by the combined influence of plant-based proteins (like those extracted from chickpeas) and polysaccharide thickeners. However, we show that the dispensing and dipping behavior of egg-based and vegan mayos display striking differences in neck shape, sharpness, and length. The ratio of apparent extensional to shear yield stress value is found to be larger than the theoretically predicted square root of three for all mayo emulsions. The analysis of neck radius evolution of these extension thinning yield stress fluids reveals that even when the power law exponent governing the intermediate pinching dynamics is similar to the exponent obtained from the shear flow curve, the terminal pinching dynamics show strong local effects, possibly influenced by interstitial fluid properties, finite drop size and deformations, and capillarity.


[Physician workforce and population aging in Greece].
In 1996, there were 41,511 medical doctors in Greece i.e. 340 doctors per 100,000 population. Recent forecasts showed that in 2001, there would be 46,558 doctors in the country i.e. 422 doctors per 100,000 population. There is currently no numerous clauses at the start of medical training. Medical workforce growth is fueling increase in health expenditures and the underground activities of doctors. In the upcoming decades, population aging will accelerate the growth of health expenditures. All these moves will no doubt impose upon a restructuring of all the health care system.


ANCA-positive and ANCA-negative phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA): outcome and long-term follow-up of 50 patients from a single Polish center.
The aim of the study was to compare the course of the disease and treatment outcomes in ANCA-positive and ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) patients from one Polish tertiary referral centre. Retrospective and prospective cohort study carried out on 50 patients treated in our department between 1998 and 2012. EGPA diagnosis was based on the American College of Rheumatology (ACR) criteria. Treatment protocol was based primarily on the predictive Five Factor Score (FFS) scale. Clinical characteristics of the patients, general symptoms, organ involvement, treatment regimen, and follow-up outcomes were evaluated according to ANCA status. Fifteen ANCA-positive patients and 35 ANCA-negative patients were enrolled. At the time of diagnosis ANCA-positive patients had a higher incidence of renal involvement (53% vs. 7.7%; p<0.001), skin involvement (93.3% vs. 57.1%; p=0.03), and peripheral neuropathy in the form of mononeuritis multiplex (60% vs. 25.7%; p=0.021). ANCA-negative patients had significantly more frequent cardiac manifestations, but only with regard to the entire period of follow-up (68.6% vs. 33.3%; p=0.021). Patients in both groups were under the same treatment regimens, however steroid dose necessary to maintain remission of the disease was significantly higher in the group of ANCA-positive patients (9±2.5 vs. 7.4±1.9 mg/day of methylprednisolone; p=0.023). The presence of ANCA did not affect the frequency of relapses. Our results confirm the differences in clinical disease presentation based on ANCA status and indicate that ANCA-positive patients should be treated more aggressively.