A model calculation of coherence effects in the elastic backscattering of very low energy electrons (1-20 eV) from amorphous ice.
Backscattering of very low energy electrons in thin layers of amorphous ice is known to provide experimental data for the elastic and inelastic cross sections and indicates values to be expected in liquid water. The extraction of cross sections was based on a transport analysis consistent with Monte Carlo simulation of electron trajectories. However, at electron energies below 20 eV, quantum coherence effects may be important and trajectory-based methods may be in significant error. This possibility is here investigated by calculating quantum multiple elastic scattering of electrons in a simple model of a very small, thin foil of amorphous ice. The average quantum multiple elastic scattering of electrons is calculated for a large number of simulated foils, using a point-scatterer model for the water molecule and taking inelastic absorption into account. The calculation is compared with a corresponding trajectory simulation. The difference between average quantum scattering and trajectory simulation at energies below about 20 eV is large, in particular in the forward scattering direction, and is found to be almost entirely due to coherence effects associated with the short-range order in the amorphous ice. For electrons backscattered at the experimental detection angle (45° relative to the surface normal) the difference is however small except at electron energies below about 10 eV. Although coherence effects are in general found to be strong, the mean free path values derived by trajectory-based analysis may actually be in fair agreement with the result of an analysis based on quantum scattering, at least for electron energies larger than about 10 eV.


Mediterranean Diet and Red Yeast Rice Supplementation for the Management of Hyperlipidemia in Statin-Intolerant Patients with or without Type 2 Diabetes.
Lipid profile could be modified by Mediterranean diet (MD) and by red yeast rice (RYR). We assessed the lipid-lowering effects of MD alone or in combination with RYR on dyslipidemic statin-intolerant subjects, with or without type 2 diabetes, for 24 weeks. We evaluated the low-density lipoprotein (LDL) cholesterol level, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride, liver enzyme, and creatinine phosphokinase (CPK) levels. We studied 171 patients: 46 type 2 diabetic patients treated with MD alone (Group 1), 44 type 2 diabetic patients treated with MD associated with RYR (Group 2), 38 dyslipidemic patients treated with MD alone (Group 3), and 43 dyslipidemic patients treated with MD plus RYR (Group 4). The mean percentage changes in LDL cholesterol from the baseline were -7.34 ± 3.14% (P < 0.05) for Group 1; -21.02 ± 1.63% (P < 0.001) for Group 2; -12.47 ± 1.75% (P < 0.001) for Group 3; and -22 ± 2.19% (P < 0.001) for Group 4 with significant intergroup difference (Group 1 versus Group 2, P < 0.001; Group 3 versus Group 4, P > 0.05). No significant increase in AST, ALT, and CPK levels was observed in all groups. Our results indicate that MD alone is effective in reducing LDL cholesterol levels in statin-intolerant patients with a presumably low cardiovascular risk, but associating MD with the administration of RYR improves patients' LDL cholesterol levels more, and in patients with type 2 diabetes.


Regulation of hematogenous tumor metastasis by acid sphingomyelinase.
Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis.


Improving short-term sun safety practices among adolescent survivors of childhood cancer: a randomized controlled efficacy trial.
Skin cancer is one of the most common secondary neoplasms among childhood cancer survivors. However, little evidence exists for effective interventions to promote sun safety behaviors within this population. This small-scale randomized controlled trial examined the efficacy of the Survivor Health and Resilience Education (SHARE) Program intervention, a multiple health behavior change intervention designed to increase sun safety practices among adolescent survivors of childhood cancer. Adolescent survivors of childhood cancer (11-21 years) were randomly allocated to a group-based behavioral intervention (n = 38) or wait-list control (n = 37). Self-reported sun safety behaviors were assessed using a valid, 8-item scale at baseline and 1-month post-intervention. Controlling for baseline sun safety, gender, and seasonal influences, intervention participants reported significantly more sun safety practices (e.g., using sunscreen, reapplying sunscreen regularly) at 1-month post-intervention than control participants (B = 2.64, 95% CI = 1.02, 4.27, p = 0.002). The results suggest that SHARE was efficacious in producing improvements in short-term self-reported sun safety practices among adolescent survivors of childhood cancer. Future research is needed to build upon this work by incorporating objective measures of sun safety behaviors and examining intervention durability. Behavioral interventions addressing lifestyle factors, including sun safety behaviors, among adolescent survivors of childhood cancer should be integrated into long-term care to reduce the risk for secondary malignancies and diseases.


Multiple exciton generation in colloidal silicon nanocrystals.
Multiple exciton generation (MEG) is a process whereby multiple electron-hole pairs, or excitons, are produced upon absorption of a single photon in semiconductor nanocrystals (NCs) and represents a promising route to increased solar conversion efficiencies in single-junction photovoltaic cells. We report for the first time MEG yields in colloidal Si NCs using ultrafast transient absorption spectroscopy. We find the threshold photon energy for MEG in 9.5 nm diameter Si NCs (effective band gap identical with Eg = 1.20 eV) to be 2.4 +/- 0.1Eg and find an exciton-production quantum yield of 2.6 +/- 0.2 excitons per absorbed photon at 3.4Eg. While MEG has been previously reported in direct-gap semiconductor NCs of PbSe, PbS, PbTe, CdSe, and InAs, this represents the first report of MEG within indirect-gap semiconductor NCs. Furthermore, MEG is found in relatively large Si NCs (diameter equal to about twice the Bohr radius) such that the confinement energy is not large enough to produce a large blue-shift of the band gap (only 80 meV), but the Coulomb interaction is sufficiently enhanced to produce efficient MEG. Our findings are of particular importance because Si dominates the photovoltaic solar cell industry, presents no problems regarding abundance and accessibility within the Earth's crust, and poses no significant environmental problems regarding toxicity.


The Alzheimer's Disease Assessment Scale: patterns and predictors of baseline cognitive performance in multicenter Alzheimer's disease trials.
The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is used as an efficacy measure in clinical drug trials of Alzheimer's disease (AD). We used data from 1,648 AD participants in two identical 26-week multicenter drug trials to examine the distribution of baseline ADAS-Cog scores in relation to selected demographic and clinical variables, Mini-Mental State Exam (MMSE), Global Deterioration Scale (GDS), and Geriatric Evaluation by Relative's Rating Instrument (GERRI) scores. At baseline, the mean (+/-SD) MMSE score was 18 +/- 4, the ADAS-Cog score was 28 +/- 11, and most subjects were in GDS stage 4 or 5. The ADAS-Cog score was statistically significantly correlated with MMSE (R = -0.76, p < 0.0001) and GERRI (R = 0.40, p < 0.0001) total scores. Correlations among the ADAS-Cog items ranged from 0.19 to 0.59 and all were statistically significant (p < 0.0001). In a multiple regression model, younger age, male gender, older age at onset of dementia, use of concurrent estrogen, and use of concurrent anti-inflammatory agents were statistically significantly associated with superior cognitive performance. We also present data on the distribution of ADAS-Cog scores in relation to subjects' age, level of education, MMSE score, and GDS stage. Because age, MMSE score, and GDS stage (and not the ADAS-Cog) are commonly used to select subjects for AD clinical trials, our data should improve the ability of sponsors to predict ADAS-Cog scores of the subjects in their trials on the basis of the inclusion criteria used. Our data also suggest that age, gender, age at onset of dementia, level of education, and use of estrogen (in women) or anti-inflammatory drugs are related to cognitive abilities in AD. Further studies are needed to assess how and when cognitive differences related to these variables arise.


Limitations and opportunities of transcutaneous bilirubin measurements.
Although transcutaneous bilirubinometers have existed for over 30 years, the clinical utility of the technique is limited to a screening method for hyperbilirubinemia, rather than a replacement for invasive blood sampling. In this study, we investigate the reason for this limited clinical value and address possibilities for improvement. To obtain better insight into the physiology of bilirubin measurements, we evaluated a transcutaneous bilirubinometer that determines not only the cutaneous bilirubin concentration (TcB) but also the blood volume fraction (BVF) in the investigated skin volume. For 49 neonates (gestational age 30 ± 3.1 weeks, postnatal age 6 [4-10] days) at our NICU, we performed 124 TcB and 55 BVF measurements. The TcB correlated well with the total serum bilirubin concentration (TSB) (r = 0.88) with an uncertainty of 55 µmol/L. The BVF in the measured skin volume ranged between 0.1% and 0.75%. The performance of our bilirubinometer is comparable to existing transcutaneous devices. The limited clinical value of current bilirubinometers can be explained by the low BVF in the skin volume that is probed by these devices. Because the TcB depends for over 99% on the contribution of extravascular bilirubin, it is a physiologically different parameter from the TSB. Hence, the standard method of evaluation that compares the TcB to the TSB is insufficient to fully investigate the clinical value of transcutaneous bilirubinometers, ie, their predictive value for kernicterus. We suggest that the clinical value may be improved considerably by changing either the method of evaluation or the technological design of transcutaneous bilirubinometers.


Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury.
This series of 113 sequential biopsies of full facial transplants provides findings of potential translational significance as well as biological insights that could prompt reexamination of conventional paradigms of effector pathways in skin allograft rejection. Serial biopsies before, during, and after rejection episodes were evaluated for clinicopathological assessment that in selected cases included specific biomarkers for donor-versus-recipient T cells. Histologic evidence of rejection included lymphocyte-associated injury to epidermal rete ridges, follicular infundibula, and dermal microvessels. Surprisingly, during active rejection, immune cells spatially associated with target cell injury consisted abundantly or predominantly of lymphocytes of donor origin with an immunophenotype typical of the resident memory T-cell subset. Current dogma assumes that skin allograft rejection is mediated by recipient T cells that attack epidermal targets, and the association of donor T cells with sites of target cell injury raises questions regarding the potential complexity of immune cell interactions in the rejection process. A more histopathologically refined and immune-based biomarker approach to assessment of rejection of facial transplants is now indicated.


Isolation and characterization of two pathogen- and salicylic acid-induced genes encoding WRKY DNA-binding proteins from tobacco.
A pathogen- and salicylic acid (SA)-induced DNA-binding activity has been recently identified in tobacco that is related to a previously identified class of WRKY DNA-binding proteins. To identify members of the WRKY gene family associated with this DNA-binding activity, we have attempted to isolate those WRKY genes that are induced by pathogen infection. Using a domain-specific differential display procedure, we have isolated two tobacco WRKY genes, tWRKY3 and tWRKY4, that are rapidly induced in resistant tobacco plants after infection by tobacco mosaic virus (TMV). Both tWRK3 and tWRKY4 encode proteins with a single WRKY domain that contain the conserved WRKYGQK sequence. Unlike other isolated WRKY proteins that contain the Cys2His2 zinc motif, tWRKY3 and tWRKY4 appear to contain the Cys2HisCys zinc motif. Nonetheless, both tWRKY3 and tWRKY4 are capable of binding DNA molecules with the W-box (TTGAC) element recognized by other WRKY proteins. Expression of the tWRKY3 and tWRKY4 genes could be rapidly induced not only by TMV infection but also by SA or its biologically active analogues that are capable of inducing pathogenesis-related genes and enhanced resistance. Interestingly, induction of both genes by TMV infection was still observed in resistant tobacco plants expressing the bacterial salicylate hydroxylase gene (nahG), although the levels of induction appeared to be reduced. Identification of pathogen- and SA-induced genes encoding WRKY DNA-binding proteins should facilitate future studies on the regulation and functions of this novel group of DNA-binding proteins.


The intellectual disability protein Oligophrenin-1 controls astrocyte morphology and migration.
Astrocytes are involved in several aspects of neuronal development and properties which are altered in intellectual disability (ID). Oligophrenin-1 is a RhoGAP protein implicated in actin cytoskeleton regulation, and whose mutations are associated with X-linked ID. Oligophrenin-1 is expressed in neurons, where its functions have been widely reported at the synapse, as well as in glial cells. However, its roles in astrocytes are still largely unexplored. Using in vitro and in vivo models of oligophrenin1 disruption in astrocytes, we found that oligophrenin1 regulates at the molecular level the RhoA/ROCK/MLC2 pathway in astroglial cells. We also showed at the cellular level that oligophrenin1 modulates astrocyte morphology and migration both in vitro and in vivo, and is involved in glial scar formation. Altogether, these data suggest that oligophrenin1 deficiency alters not only neuronal but also astrocytic functions, which might contribute to the development of ID.


ADHD and the avoidance of mental effort: the role of response inhibition and avoidance motivation.
The tendency of people with ADHD to avoid tasks that require mental effort impacts their academic achievement. Findings in the literature suggest that children with ADHD find cognitive tasks more effortful and uncomfortable than their typically developing peers. However, neuropsychological processes contributing to this remain unclear. The present study investigated whether the relationship between prepotent motor response inhibition and avoiding mental effort is mediated by the ability to resist avoidance motivation and whether this proposed mediation mechanism is contingent on ADHD diagnosis. 40 children with ADHD and 40 gender and age-matched typically developing peers participated in the study. They completed the Cognitive Effort Avoidance Measure, the Go/No-go Task, and the Reinforcement Sensitivity Theory-Personality Questionnaire-Children. Mediation and moderated mediation analyses were employed to test the hypotheses. Children with ADHD scored lower in response inhibition and resisting avoidance motivation. Poorer scores in these variables were associated with a higher avoidance rate. Moreover, the ability to resist avoidance motivation completely mediated the relationship between response inhibition and avoidance rate only among children with ADHD. Findings imply that poorer response inhibition led to an increase in avoidance motivation among children with ADHD, which becomes challenging to regulate effectively due to an impairment in the ability to resist avoidance motivation. Theoretical and clinical implications are discussed.


Summary of CDC consultation to address social determinants of health for prevention of disparities in HIV/AIDS, viral hepatitis, sexually transmitted diseases, and tuberculosis. December 9-10, 2008.
In December 2008, the Centers for Disease Control and Prevention (CDC) convened a meeting of national public health partners to identify priorities for addressing social determinants of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), viral hepatitis, sexually transmitted diseases (STDs), and tuberculosis (TB). The consultants were divided into four working groups: (1) public health policy, (2) data systems, (3) agency partnerships and prevention capacity building, and (4) prevention research and evaluation. Groups focused on identifying top priorities; describing activities, methods, and metrics to implement priorities; and identifying partnerships and resources required to implement priorities. The meeting resulted in priorities for public health policy, improving data collection methods, enhancing existing and expanding future partnerships, and improving selection criteria and evaluation of evidence-based interventions. CDC is developing a national communications plan to guide and inspire action for keeping social determinants of HIV/AIDS, viral hepatitis, STDs, and TB in the forefront of public health activities.


The free and cued selective reminding test distinguishes frontotemporal dementia from Alzheimer's disease.
Memory impairment is often present in frontotemporal dementia (FTD) as a result of an inefficient use of learning strategies, sometimes leading to a misdiagnosis of Alzheimer's disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is a memory test that controls attention and acquisition, by providing category cues in the learning process. The main goal of this study was to show the usefulness of the FCSRT in the distinction between behavioral (bv-) FTD and AD. Three matched subgroups of participants were considered: bv-FTD (n = 32), AD (n = 32), and a control group of healthy adults (n = 32). Results proved that while AD patients exhibited an overall impairment in FCSRT, bv-FTD subjects showed to benefit more from the controlled learning through category cues. AD patients were 25 times more likely to have an impaired FCSRT. The FCSRT has shown its utility in the distinction between bv-FTD and AD, therefore increasing the diagnostic accuracy.


The Effect of Different Dosing Schedules of Intravitreal Sirolimus, a Mammalian Target of Rapamycin (mTOR) Inhibitor, in the Treatment of Non-Infectious Uveitis (An American Ophthalmological Society Thesis).
To determine if two different doses of intravitreal sirolimus, an mTOR inhibitor, can decrease inflammation and is safe in eyes with non-infectious posterior, intermediate, or panuveitis in the Sirolimus as a Therapeutic Approach UVEitis: Protocol-2 (SAVE-2) Study. SAVE-2 is a prospective randomized, phase II, open-label interventional clinical trial conducted at 4 clinical centers in the United States. Eligible subjects were randomized into one of two treatments. Group 1 received 440µg of intravitreal sirolimus in study eyes on days 0, 30, 60, 90, 120, and 150; group 2 received 880µg of intravitreal sirolimus on days 0, 60, and 120. Fellow eyes were also eligible to receive sirolimus (of opposite dose to that of study eye). Primary endpoint of the study was at month 6 (M6). 24 subjects have been randomized in SAVE-2 and are included in the analysis. Vitreous haze decreased by ≥2 steps in 63.6% and 50% of patients in groups 1 and 2, respectively at M6 (p=0.695). Mean change in best-corrected visual acuity for subjects was +3.66 and -2.91 ETDRS letters in group 1 and 2, respectively. Among subjects with macular edema at baseline (n=13), the mean change in foveal thickness was -89.42µm in group 1 and +81.5µm in group 2 at M6. Both low and high doses of intravitreal sirolimus were found to decrease vitreous haze in eyes with non-infectious uveitis. Low dose (440µg) sirolimus administered monthly may be more efficacious in reducing uveitic macular edema than high dose (880µg) administered every 2 months.


EDI experts realistic and optimistic.
Recently, Healthcare Financial Management contacted five EDI experts to discuss a variety of issues related to EDI and the healthcare industry. Their answers to our questions, presented below, are both optimistic and realistic. Our experts feel that EDI can transform the healthcare industry into a model of efficiency, but their enthusiasm is tempered by the realization that politics, bureaucracy, budgets, and resistance to change can take a toll on even the most ardent of EDI supporters. Nevertheless, they believe that EDI can and will work. In the pages that follow, they discuss why, how, and when.


Activation of estrogen receptor induces differential proteomic responses mainly involving migration, invasion, and tumor development pathways in human testicular embryonal carcinoma NT2/D1 cells.
The aims of the present study were to investigate the global changes on proteome of human testicular embryonal carcinoma NT2/D1 cells treated with 17β-estradiol (E2), and the effects of this hormone on migration, invasion, and colony formation of these cells. A quantitative proteomic analysis identified the presence of 1230 proteins in both E2-treated and control cells. The analysis revealed 75 differentially abundant proteins (DAPs), out of which 43 proteins displayed a higher abundance and, 30 proteins showed a lower abundance in E2-treated NT2/D1 cancer cells. Functional analysis using IPA highlighted some activation processes such as migration, invasion, metastasis, and tumor growth. Interestingly, the treatment with E2 and ERβ-selective agonist DPN increased the migration of NT2/D1 cells. On the other hand, ERα-selective agonist PPT did not modify cell migration, indicating that ERβ is the upstream receptor involved in this process. The activation of ERβ increased the invasion and anchorage‑independent growth of NT2/D1 cells more intensely than ERα. ERα and ERβ may play overlapping roles on invasion and colony formation of these cells. Further studies are required to clarify the mechanism underlying these effects. The molecular mechanisms revealed by proteomic and functional studies might also guide the development of potential targets for a better understanding of the biology of these cells and novel treatments for non-seminoma in the future.


Characteristics of Immune Memory and Effector Activity to Cancer-Expressed MHC Class I Phosphopeptides Differ in Healthy Donors and Ovarian Cancer Patients.
Elevated immunity to cancer-expressed antigens can be detected in people with no history of cancer and may contribute to cancer prevention. We have previously reported that MHC-restricted phosphopeptides are cancer-expressed antigens and targets of immune recognition. However, the extent to which this immunity reflects prior or ongoing phosphopeptide exposures was not investigated. In this study, we found that preexisting immune memory to cancer-expressed phosphopeptides was evident in most healthy donors, but the breadth among donors was highly variable. Although three phosphopeptides were recognized by most donors, suggesting exposures to common microbial/infectious agents, most of the 205 tested phosphopeptides were not recognized by peripheral blood mononuclear cells (PBMC) from any donor and the remainder were recognized by only 1 to 3 donors. In longitudinal analyses of 2 donors, effector immune response profiles suggested active reexposures to a subset of phosphopeptides. These findings suggest that the immunogens generating most phosphopeptide-specific immune memory are rare infectious agents or incipient cancer cells with distinct phosphoproteome dysregulations, and that repetitive immunogenic exposures occur in individual donors. Phosphopeptide-specific immunity in PBMCs and tumor-infiltrating lymphocytes from ovarian cancer patients was limited, regardless of whether the phosphopeptide was expressed on the tumor. However, 4 of 10 patients responded to 1 to 2 immunodominant phosphopeptides, and 1 showed an elevated effector response to a tumor-expressed phosphopeptide. As the tumors from these patients displayed many phosphopeptides, these data are consistent with lack of prior exposure or impaired ability to respond to some phosphopeptides and suggest that enhancing phosphopeptide-specific T-cell responses could be a useful approach to improve tumor immunotherapy.


Out-of-pocket medical expenses in severe CHD.
IntroductionFamilies of children born with CHD face added stress owing to uncertainty about the magnitude of the financial burden for medical costs they will face. This study seeks to assess the family responsibility for healthcare bills during the first 12 months of life for commercially insured children undergoing surgery for severe CHD. The MarketScan ® database from Truven was used to identify commercially insured infants in 39 states from 2010 to 2012 with an ICD-9 diagnosis code for transposition of the great arteries, tetralogy of Fallot, or truncus arteriosus, as well as the corresponding procedure code for complete repair. Data extraction identified payment responsibilities of the patients' families in the form of co-payments, deductibles, and co-insurance during the 1st year of life. There were 481 infants identified who met the criteria. Average family responsibility for healthcare bills during the 1st year of life was $2928, with no difference between the three groups. The range of out-of-pocket costs was $50-$18,167. Initial hospitalisation and outpatient care accounted for the majority of these responsibilities. Families of commercially insured children with severe CHD requiring corrective surgery face an average of ~$3000 in out-of-pocket costs for healthcare bills during the first 12 months of their child's life, although the amount varied considerably. This information provides a framework to alleviate some of the uncertainty surrounding healthcare financial responsibilities, and further examination of the origination of these expenditures may be useful in informing future healthcare policy discussion.


Future challenges for the economic evaluation of healthcare: patient preferences, risk attitudes and beyond.
The continued growth in the economic evaluation of healthcare over the past 25 years has led to a shortage of trained health economists globally, leading to a number of universities and/or national governments developing specialised health economics programmes to train more health economists. One of the common problems with many of these training programmes is that they only educate new health economists to the Masters level, and as such they are unable to cover the many skills needed by a successful health economist. Furthermore, government and industry interests have ensured that economic evaluation is a heavily regulated environment that gives little incentive to seek further education. These two related factors (under-education and over-regulation) have lead to a situation where economic evaluation methods may adversely limit innovation of therapeutics and devices in clinical areas that perform badly when evaluated on the cost per QALY scale. The good news, however, is that the tide is turning and theoretically sound adjustments (such as risk adjustments and stated preferences) to the current paradigm are now being considered. This, of cause, is just the tip of the iceberg with other important issues such as time preference and the endogeneity of preference remaining very much under-researched areas in health. This paper concludes that many of these real-world issues, such as patient preferences, can be avoided by using artificial objective functions such as cost per QALY, but this comes at the cost of irrelevance and the misallocation of resources. If we are to meet all of the future challenges in economic evaluation in healthcare then we must focus more on advanced education and far less on the regulation of health economists.


Utility of Distal Forearm DXA as a Screening Tool for Primary Osteoporotic Fragility Fractures of the Distal Radius: A Case-Control Study.
Osteoporotic fragility fractures frequently occur at the distal part of the radius. This suggests that initial osteoporosis evaluation at this site may inform screening and treatment to prevent additional fractures. The purpose of this study was to investigate the utility of distal forearm dual x-ray absorptiometry (DXA) as a screening tool to assess the risk of fragility fractures at the distal part of the radius. This retrospective, case-control study included postmenopausal women who had sustained a distal radial fracture (fracture group, n = 110) and postmenopausal women with no history of fracture (control group, n = 95). DXA measurements at the spine, hip, and distal part of the forearm (ultra-distal, mid-distal, and one-third distal sections) were compared between the groups on the basis of bone mineral density (BMD), T-score, and the proportion of patients with a T-score of ≤-2.5 standard deviations (SD). We also investigated the regional differences on the basis of T-score among the skeletal sites. Furthermore, the reliability of distal forearm DXA measurements was validated by assessing the statistical correlation (r) with volumetric BMD by computed tomography (CT). Compared with the control group, the fracture group showed significantly lower BMD and T-scores and higher proportions of patients with a T-score of ≤-2.5 SD at the ultra-distal, mid-distal, and one-third distal forearm; however, the spine and hip measurements did not differ significantly between the 2 groups. With respect to regional differences, in the fracture group, T-scores were significantly lower and the proportions of patients with a T-score of ≤-2.5 SD were significantly higher for the 3 distal forearm sites compared with the spine and hip. DXA measurements at all 3 of the distal forearm regions exhibited high correlation with volumetric BMD by CT (r = 0.83 to 0.92). Some postmenopausal women were found to exhibit bone loss preferentially at the distal part of the radius, which may render them vulnerable to fragility fractures. Forearm DXA for the assessment of local bone loss may demonstrate benefit in screening for those at risk for distal radial fractures and facilitate the early identification of patients who require intervention for osteoporosis. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Modeling Incoherent Discourse in Non-Affective Psychosis.
Computational linguistic methodology allows quantification of speech abnormalities in non-affective psychosis. For this patient group, incoherent speech has long been described as a symptom of formal thought disorder. Our study is an interdisciplinary attempt at developing a model of incoherence in non-affective psychosis, informed by computational linguistic methodology as well as psychiatric research, which both conceptualize incoherence as associative loosening. The primary aim of this pilot study was methodological: to validate the model against clinical data and reduce bias in automated coherence analysis. Speech samples were obtained from patients with a diagnosis of schizophrenia or schizoaffective disorder, who were divided into two groups of n = 20 subjects each, based on different clinical ratings of positive formal thought disorder, and n = 20 healthy control subjects. Coherence metrics that were automatically derived from interview transcripts significantly predicted clinical ratings of thought disorder. Significant results from multinomial regression analysis revealed that group membership (controls vs. patients with vs. without formal thought disorder) could be predicted based on automated coherence analysis when bias was considered. Further improvement of the regression model was reached by including variables that psychiatric research has shown to inform clinical diagnostics of positive formal thought disorder. Automated coherence analysis may capture different features of incoherent speech than clinical ratings of formal thought disorder. Models of incoherence in non-affective psychosis should include automatically derived coherence metrics as well as lexical and syntactic features that influence the comprehensibility of speech.


Alkaline Hydrothermal Synthesis, Characterization, and Photocatalytic Activity of TiO₂ Nanostructures: The Effect of Initial TiO₂ Phase.
One-dimensional (1D) titanate nanostructures were synthesized by hydrothermal route, using commercially available TiO₂ (P25) and anatase powders as precursor materials and strong NaOH solution as catalyzer. The prepared titanates were calcined, followed by protonation to produce TiO₂ nanostructures having enhanced photocatalytic and photovoltaic properties. The synthesized TiO₂ 1D nanostructures were characterized using field-emission scanning electron microscope, high-resolution electron microscope, X-ray diffraction analysis, and UV-Vis photospectroscopy to understand the effect of initial TiO₂ phase on morphological and crystallographic features, and bandgap. Methylene blue degradation test was applied to evaluate the photoactivity of the products obtained after different stages of the process. The findings indicate that 1D TiO₂ nanostructures form by different mechanisms from dissolved aggregates during hydrothermal process, depending on the crystal structure of the initial precursor used. Photocatalytic test results reveal that protonated titanates have considerable adsorption capability, while photocatalytic degradation depends on TiO₂ transformation.


Quercetin Suppresses Early Colon Carcinogenesis Partly through Inhibition of Inflammatory Mediators.
We have demonstrated that 0.45% quercetin added to a diet containing corn oil (15% w/w), as the lipid source, and cellulose (6% w/w), as the fiber source, was able to suppress the formation of high multiplicity aberrant crypt foci (ACF > 4 AC/focus), to lower proliferation and enhance apoptosis in a rat model of colon cancer. This experiment determined whether quercetin was acting as an antiinflammatory molecule in an in vivo model of colon cancer. We used weanling (21 d old) Sprague Dawley rats (n = 40) in a 2×2 factorial experiment to determine the influence of quercetin on iNOS, COX-1 and COX-2 expressions, all of which are elevated in colon cancer. Half of the rats received a diet containing either 0 or 0.45% quercetin, and within each diet group, half of the rats were injected with saline or azoxymethane (AOM, 15 mg/kg BW, sc, 2× during wk 3 and 4). The colon was resected 4 wk after the last AOM injection, and the mucosa scraped and processed for RNA isolation. Data from this experiment were analyzed using a mixed model in SAS for main effects and their interaction. AOM injection stimulated (P < 0.0001) iNOS expression. However there was an interaction such that, relative to rats injected with saline, AOM-injected rats consuming diets without quercetin had significantly elevated iNOS expression (5.29-fold), but the expression in AOM-injected rats consuming the diet with quercetin was not significantly elevated (1.68-fold). COX-1 expression was 20.2% lower (P < 0.06) in rats consuming diets containing quercetin. COX-2 expression was 24.3% higher (P < 0.058) in rats consuming diets without quercetin. These data suggest inflammatory processes are elevated in this early stage of colon carcinogenesis, yet quercetin may protect against colon carcinogenesis by down-regulating the expressions of COX-1 and COX-2.


The Respiratory Pathogen Moraxella catarrhalis Targets Collagen for Maximal Adherence to Host Tissues.
Moraxella catarrhalis is a human respiratory pathogen that causes acute otitis media in children and is associated with exacerbations in patients suffering from chronic obstructive pulmonary disease (COPD). The first step in M. catarrhalis colonization is adherence to the mucosa, epithelial cells, and extracellular matrix (ECM). The objective of this study was to evaluate the role of M. catarrhalis interactions with collagens from various angles. Clinical isolates (n= 43) were tested for collagen binding, followed by a detailed analysis of protein-protein interactions using recombinantly expressed proteins.M. catarrhalis-dependent interactions with collagen produced by human lung fibroblasts and tracheal tissues were studied by utilizing confocal immunohistochemistry and high-resolution scanning electron microscopy. A mouse smoke-induced chronic obstructive pulmonary disease (COPD) model was used to estimate the adherence of M. catarrhalis in vivo. We found that all M. catarrhalis clinical isolates tested adhered to fibrillar collagen types I, II, and III and network-forming collagens IV and VI. The trimeric autotransporter adhesins ubiquitous surface protein A2(UspA2) and UspA2H were identified as major collagen-binding receptors.M. catarrhalis wild type adhered to human tracheal tissue and collagen-producing lung fibroblasts, whereas UspA2 and UspA2H deletion mutants did not. Moreover, in the COPD mouse model, bacteria devoid of UspA2 and UspA2H had a reduced level of adherence to the respiratory tract compared to the adherence of wild-type bacteria. Our data therefore suggest that theM. catarrhalisUspA2 and UspA2H-dependent interaction with collagens is highly critical for adherence in the host and, furthermore, may play an important role in the establishment of disease. The respiratory tract pathogen Moraxella catarrhalis adheres to the host by interacting with several components, including the ECM. Collagen accounts for 30% of total body proteins, and therefore, bacterial adherence to abundant host collagens mediates bacterial persistence and colonization. In this study, we characterized previously unknown M. catarrhalis-dependent interactions with host collagens and found that the trimeric autotransporter adhesins ubiquitous surface protein A2(UspA2) and UspA2H are highly important. Our observations also suggested that collagen-mediated adherence ofM. catarrhalis is indispensable for bacterial survival in the host, as exemplified by a mouse COPD model.


Optimal vaccine trial design when estimating vaccine efficacy for susceptibility and infectiousness from multiple populations.
Vaccination can have important indirect effects on the spread of an infectious agent by reducing the level of infectiousness of vaccinees who become infected. To estimate the effect of vaccination on infectiousness, one typically requires data on the contacts between susceptible and infected vaccinated and unvaccinated people. As an alternative, we propose a trial design that involves multiple independent and interchangeable populations. By varying the fraction of susceptible people vaccinated across populations, we obtain an estimate of the reduction infectiousness that depends only on incidence data from the vaccine and control groups of the multiple populations. One can also obtain from these data an estimate of the reduction of susceptibility to infection. We propose a vaccination strategy that is a trade-off between optimal estimation of vaccine efficacy for susceptibility and of vaccine efficacy for infectiousness. We show that the optimal choice depends on the anticipated efficacy of the vaccine as well as the basic reproduction number of the underlying infectious disease process. Smaller vaccination fractions appear desirable when vaccine efficacy is likely high and the basic reproduction number is not large. This strategy avoids the potential for too few infections to occur to estimate vaccine efficacy parameters reliably.


Technology evaluation: VEGF165 gene therapy, Valentis Inc.
Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137].


[Puncture-drainage sanation of abdominal abscesses: is it sufficient treatment?].
Some anatomical grounds of postoperative extravisceral abscess formation, methods and results of their treatment, therapeutic policy in abscesses of parenchymatous organs are presented. 681 patients with abdominal abscess of various location were examined. Detailed analysis of ultrasonic and computed tomographic semiotics of postoperative extravisceral suppurative focus was carried out in 164 patients. The risk zones of extravisceral abscess formation in the conditions of changed visceral syntopy and destroyed ligamentic structures were determined. The efficiency of puncture-drainage treatment in different variants of subdiaphragmatic abscess was 89.4%, in abscess of omental bursa--83.3%. Intracavital prolonged proteolysis by immobilized proteinases (imosimase) was applied. The injection of imosimase in abscess cavity led to its content lysis, including the thick products of inflammation, improving their secretion through the drainage. In the majority of the patients, the puncture-drainage treatment of abscesses of various etiology and pathogenesis is an adequate method of sanation.


Loss of sea turtle eggs drives the collapse of an insular reptile community.
Marine subsidies are vital for terrestrial ecosystems, especially low-productivity islands. However, the impact of losing these subsidies on the terrestrial food web can be difficult to predict. We analyzed 23 years of survey data from Orchid Island to assess the consequences of the abrupt loss of an important marine subsidy. After climate-driven beach erosion and predator exclusion efforts resulted in the abrupt loss of sea turtle eggs from the terrestrial food web, predatory snakes altered their foraging habitats. This increased predation on other reptile species in inland areas, resulting in population declines in most terrestrial reptile species. Comparisons with sea turtle-free locations where lizard populations remained stable supported these findings. Our study emphasizes the cascading effects of generalist predators and the unintended consequences of single-species conservation, highlighting the importance of understanding species interconnectedness and considering potential ripple effects in marine-dependent insular ecosystems.


A systematic review of malignancy-associated hemophagocytic lymphohistiocytosis that needs more attentions.
As an infrequent but potentially life-threatening hyperinflammatory syndrome, hemophagocytic lymphohistiocytosis (HLH) is clinically characterized with prolonged fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia and hemophagocytosis in bone marrow, liver, spleen or lymph nodes. Malignancy-associated HLH (M-HLH), one type of acquired HLH, usually presents variable overlaps of symptoms with other types of HLH, thus resulting in higher incidence of misdiagnosis and mortality. In recent years, with the increasing awareness to this disease, the diagnosis and management of HLH have gained more and more attention, and improvements have been made accordingly. As a result, the survival of patients is greatly prolonged. However, there is still no consensus on the diagnostic criteria and treatment strategies due to lack of large samples or prospective clinical trials. In order to improve recognition and diagnosis, and provide guidance regarding the treatment of M-HLH, the Study Group in HLH Subtypes of the Histiocyte Society has developed consensus recommendations for the diagnosis and management of M-HLH in 2015. In the present article, we summarized and discussed some updated understandings in M-HLH.


Exploring a New Systematic Route for Left Ventricular Pacing in Cardiac Resynchronization Therapy.
Frequency and distribution of left ventricular (LV) venous collaterals were studied in vivo to evaluate the ease and feasibility of implanting a new ultra-thin LV quadripolar microlead for cardiac resynchronization therapy (CRT).Methods and Results:Evaluable venograms were analyzed to define the prevalence of venous collaterals (>0.5 mm diameter) between: (1) different LV segments; and (2) different major LV veins in: unselected patients who underwent CRT from 2008 to 2012 at Rouen Hospital, France (retrospective); and CRT patients from the Axone Acute pilot study in 2018 (prospective). In prospective patients with evaluable venograms, LV microlead implantation was attempted. Thirty-six (21/65 retrospective, 15/20 prospective) patients had evaluable venograms with ≥1 visible venous collaterals. Collaterals were found between LV veins in all CRT patients with evaluable venograms. Regionally, prevalence was highest between: the apical inferior and apical lateral (42%); and mid inferior and mid inferolateral (42%) segments. Collateral connections were most prevalent between: the inferior interventricular vein (IIV) and lateral vein (64% [23/36]); and IIV and infero-lateral vein (36% [13/36]). Cross-vein microlead implantation was possible in 18 patients (90%), and single-vein implantation was conducted in the other 2 patients (10%). Venous collaterals were found in vivo between LV veins in all CRT patients with evaluable venograms, making this network an option for accessing multiple LV sites using a single LV microlead.


Primary cilia: cellular sensors for the skeleton.
The primary cilium is a solitary, immotile cilium that is present in almost every mammalian cell type. Primary cilia are thought to function as chemosensors, mechanosensors, or both, depending on cell type, and have been linked to several developmental signaling pathways. Primary cilium malfunction has been implicated in several human diseases, the symptoms of which include vision and hearing loss, polydactyly, and polycystic kidneys. Recently, primary cilia have also been implicated in the development and homeostasis of the skeleton. In this review, we discuss the structure and formation of the primary cilium and some of the mechanical and chemical signals to which it could be sensitive, with a focus on skeletal biology. We also raise several unanswered questions regarding the role of primary cilia as mechanosensors and chemosensors and identify potential research avenues to address these questions.


Dissecting dual specificity: Identifying key residues in L-asparaginase for enhanced acute lymphoid leukemia therapy and reduced adverse effects.
L-asparaginase from Escherichia coli (EcA) has been used for the treatment of acute lymphoid leukemia (ALL) since the 1970s. Nevertheless, the enzyme has a second specificity that results in glutaminase breakdown, resulting in depletion from the patient's body, causing severe adverse effects. Despite the huge interest in the use of this enzyme, the exact process of glutamine depletion is still unknown and there is no consensus regarding L-asparagine hydrolysis. Here, we investigate the role of T12, Y25, and T89 in asparaginase and glutaminase activities. We obtained individual clones containing mutations in the T12, Y25 or T89 residues. After the recombinant production of wild-type and mutated EcA, The purified samples were subjected to structural analysis using Nano Differential Scanning Fluorimetry, which revealed that all samples contained thermostable molecules in their active structural conformation, the homotetramer conformation. The quaternary conformation was confirmed by DLS and SEC. The activity enzymatic assay combined with molecular dynamics simulation identified the contribution of T12, Y25, and T89 residues in EcA glutaminase and asparaginase activities. Our results mapped the enzymatic behavior paving the way for the designing of improved EcA enzymes, which is important in the treatment of ALL.


Acrosome reaction-inducing substance triggers two different pathways of sperm intracellular signaling in newt fertilization.
The acrosome reaction is induced in the sperm of Cynops pyrrhogaster immediately in response to a ligand protein called acrosome reaction-inducing substance (ARIS) in the egg jelly at fertilization, whereas a spontaneous acrosome reaction occurs time-dependently in correlation with the decline of sperm quality for fertilization. The ARIS-induced acrosome reaction was recently found to be mediated by TRPV4 in association with the NMDA type glutamate receptor, although the intracellular mediators for the acrosome reaction are largely unclear. In the present study, spontaneous acrosome reaction was significantly inhibited by Ni2+, RN1734, and diltiazem, which blocks Cav3.2, TRPV4 or TRPM8, and the cyclic nucleotide-gated channel, respectively. In contrast, expression of Ca2+-activated transmembrane and soluble adenylyl cyclases was detected in the sperm of C. pyrrhogaster by reverse transcription-polymerase chain reaction. Activator of transmembrane or soluble adenylyl cyclases (forskolin or HCO 3-) independently promoted spontaneous acrosome reaction, while an inhibitor of each enzyme (MD12330A or KH7) inhibited it only in the sperm with high potential for spontaneous acrosome reaction. An inhibitor of protein kinase A (H89) inhibited spontaneous acrosome reaction in a manner independent of sperm potential for spontaneous acrosome reaction. Surprisingly, KH7 significantly inhibited ARIS-induced acrosome reaction, but its effect was seen in a small percentage of sperm. H89 had no effect on ARIS-induced acrosome reaction. These results suggest that C. pyrrhogaster sperm possess multiple intracellular pathways for acrosome reaction, involving Ca2+ permeable channels, adenylyl cyclases and PKA, and that two pathways having distinct dependencies on adenylyl cyclases may contribute to ARIS-induced acrosome reaction at fertilization.


Increasing antimicrobial resistance among uropathogens: Is fosfomycin the answer?
Urinary tract infection (UTI) is one of the most common infectious diseases in clinical practice. The choice of antibiotics for the treatment of UTI is limited by the rising rates of antibiotic resistance. There is an urgent need to discover new effective treatment solutions. Fosfomycin may be an interesting alternative to the currently used treatments of UTIs. The study was conducted over 6 months period (January to June 2013) in Department of Microbiology, JNMCH, AMU, Aligarh. A total of 1840 urine samples were submitted. Culture and sensitivity was done as per standard microbiological procedures. Methicillin-resistant Staphylococcus aureus (MRSA), high-level aminoglycoside resistance (HLAR), extended spectrum beta-lactamases (ESBL), AmpC and metallo-beta-lactamases (MBL) production was detected. Culture was positive in 504 (27.4%) cases. Gram-negative etiology was identified in 390 (73%) cases. ESBL production was detected in 154 (37.1%) while 82 (21.6%) were Amp C. No, MBL was detected. Among Gram-positive bacteria, 68 (51.5%) were MRSA, while 4 (13.3%) were vancomycin resistant enterococci (VRE). HLAR was seen in 53.3% of enterococci. Fosfomycin was effective in 100% of MRSA, VRE, ESBL, HLAR, and overall, susceptibility to fosfomycin in AmpC producers was extremely high (99%). Norfloxacin and cotrimoxazole were not proved effective as only three isolates were sensitive to norfloxacin, while all Gram-negative isolates were resistant to cotrimoxazole. Pseudomonas species showed 65% and 75% susceptibility to colistin and polymixin B, respectively. Fosfomycin has emerged as a promising option, especially in cases involving multi-drug-resistant pathogens in which previous antibiotics have failed to cure the infection.


Anytime collaborative brain-computer interfaces for enhancing perceptual group decision-making.
In this paper we present, and test in two realistic environments, collaborative Brain-Computer Interfaces (cBCIs) that can significantly increase both the speed and the accuracy of perceptual group decision-making. The key distinguishing features of this work are: (1) our cBCIs combine behavioural, physiological and neural data in such a way as to be able to provide a group decision at any time after the quickest team member casts their vote, but the quality of a cBCI-assisted decision improves monotonically the longer the group decision can wait; (2) we apply our cBCIs to two realistic scenarios of military relevance (patrolling a dark corridor and manning an outpost at night where users need to identify any unidentified characters that appear) in which decisions are based on information conveyed through video feeds; and (3) our cBCIs exploit Event-Related Potentials (ERPs) elicited in brain activity by the appearance of potential threats but, uniquely, the appearance time is estimated automatically by the system (rather than being unrealistically provided to it). As a result of these elements, in the two test environments, groups assisted by our cBCIs make both more accurate and faster decisions than when individual decisions are integrated in more traditional manners.


Understanding reduction of carbon tetrachloride at nickel surfaces.
Nickel has been found to be an effective cathode material and catalyst for reductive destruction of chlorinated solvents in contaminated water. This study investigated reductive dechlorination of carbon tetrachloride (CT) at a nickel rotating disk electrode using chronoamperometry and electrochemical impedance spectroscopy. Chronoamperometry experiments were performed to determine rates of CT reduction as a function of the electrode potential, pH, CT concentration, and temperature. The reaction products of CT dechlorination were 95 +/- 4% methane and 4.1 +/- 2.5% chloroform. Only trace levels of methylene chloride and chloromethane were produced, indicating that sequential hydrogenolysis was not the predominant pathway for methane production. Electrochemical impedance spectroscopy showed that the rate-limiting step for methane production was the transfer of the first electron to a physically adsorbed CT molecule. The temperature independence of the electron transfer coefficient and the decreasing activation energy with decreasing electrode potential indicated that the rate-limiting step involved an outer-sphere electron transfer. At neutral pH values, oxides inactivated much of the electrode surface for both CT reduction and hydrogen evolution. At lower pH values, oxide dissolution served to increase the electroactive surface area of the disk electrode. Anson analysis and kinetic modeling showed that CT adsorption to electroactive sites was a nonlinear function of the CT concentration and was in equilibrium with the bulk solution. CT dechlorination rates on nickel electrodes were 16 times slower than those on iron electrodes under similar conditions. However, CT reactions at nickel surfaces produced predominantly methane as the first detectable product, while reduction at iron surfaces produced chloroform. These results suggest that, although nickel is not a catalyst for the rate-limiting step for CT dechlorination, it may serve a catalytic role in subsequent reaction steps.


Altered behavior and neurochemistry during short-term insulin withdrawal in streptozocin-induced diabetic rats.
Amphetamine-induced stereotypy and turnover of dopamine (DA) and serotonin (5-HT) in the CNS were assessed in streptozocin-induced diabetic rats 48 h after withdrawal from insulin treatment and compared with nondiabetic controls, diabetic rats receiving continued insulin treatment, and chronically hyperglycemic diabetic rats. Stereotypy was attenuated in chronically hyperglycemic diabetic rats but normalized in insulin-treated diabetic rats. Stereotypy in insulin-withdrawn rats was intermediate, being attenuated significantly relative to controls but not significantly different from either insulin-treated diabetic rats or chronically hyperglycemic diabetic rats. DA turnover was significantly reduced in striatum and hypothalamus in all diabetic groups. 5-HT turnover was reduced in chronically hyperglycemic diabetic rats in all four brain regions but normalized in insulin-treated diabetic rats. Insulin-withdrawn diabetic rats had significantly reduced 5-HT turnover in frontal cortex. Taken together, the findings indicate that insulin replacement does not normalize diabetes-induced reduction in DA turnover and that short-term insulin withdrawal, e.g., occurring clinically with noncompliance, affects both 5-HT turnover in some brain regions and behavior.


Dermatitis after exposure to a garden plant (Euphorbia myrsinites).
Six pediatric cases of erythematous papulovescicular skin eruptions were due to exposure to Euphorbia myrsinites. These rashes may be confused with allergies, infections, or other dermatoses. Symptoms followed two to eight hours after exposure to the irritant sap, they increased in severity for an additional 12 hours, and they resolved within three to four days. No sequelae were noticed. Treatment indicated was pain relief, prevention of infection, and reduction of swelling.


cis-Cinnamic acid selective suppressors distinct from auxin inhibitors.
The activity of cis-cinnamic acid (cis-CA), one of the allelochemicals, in plants is very similar to that of indole-3-acetic acid (IAA), a natural auxin, and thus cis-CA has long been believed to be an analog of auxin. We have reported some structure-activity relationships studies by synthesizing over 250 cis-CA derivatives and estimating their inhibitory activities on root growth inhibition in lettuce. In this study, the compounds that showed low- or no-activity on root growth inhibition were recruited as candidates suppressors against cis-CA and/or auxin and tested for their activity. In the presence of cis-CA, lettuce root growth was inhibited; however, the addition of some cis-CA derivatives restored control-level root growth. Four compounds, (Z)-3-(4-isopropylphenyl)acrylic acid, (Z)-3-(3-butoxyphenyl)acrylic acid, (Z)-3-[3-(pentyloxy)phenyl]acrylic acid, and (Z)-3-(naphthalen-1-yl)acrylic acid were selected as candidates for a cis-CA selective suppressor they allowed the recovery of root growth from inhibition by cis-CA treatment without any effects on the IAA-induced effect or elongating activity by themselves. Three candidates significantly ameliorated the root shortening by the potent inhibitor derived from cis-CA. In brief, we have found some cis-CA selective suppressors which have never been reported from inactive cis-CA derivatives for root growth inhibition. cis-CA selective suppressors will play an important role in elucidating the mechanism of plant growth regulation.


The impact of total and partial inclusion or exclusion of active and inactive time invariant covariates in growth mixture models.
This article evaluates the impact of partial or total covariate inclusion or exclusion on the class enumeration performance of growth mixture models (GMMs). Study 1 examines the effect of including an inactive covariate when the population model is specified without covariates. Study 2 examines the case in which the population model is specified with 2 covariates influencing only the class membership. Study 3 examines a population model including 2 covariates influencing the class membership and the growth factors. In all studies, we contrast the accuracy of various indicators to correctly identify the number of latent classes as a function of different design conditions (sample size, mixing ratio, invariance or noninvariance of the variance-covariance matrix, class separation, and correlations between the covariates in Studies 2 and 3) and covariate specification (exclusion, partial or total inclusion as influencing class membership, partial or total inclusion as influencing class membership, and the growth factors in a class-invariant or class-varying manner). The accuracy of the indicators shows important variation across studies, indicators, design conditions, and specification of the covariates effects. However, the results suggest that the GMM class enumeration process should be conducted without covariates, and should rely mostly on the Bayesian information criterion (BIC) and consistent Akaike information criterion (CAIC) as the most reliable indicators under conditions of high class separation (as indicated by higher entropy), versus the sample size adjusted BIC or CAIC (SBIC, SCAIC) and bootstrapped likelihood ratio test (BLRT) under conditions of low class separation (indicated by lower entropy). (PsycINFO Database Record


Responder individuality in red blood cell alloimmunization.
Many different factors influence the propensity of transfusion recipients and pregnant women to form red blood cell alloantibodies (RBCA). RBCA may cause hemolytic transfusion reactions, hemolytic disease of the fetus and newborn and may be a complication in transplantation medicine. Antigenic differences between responder and foreign erythrocytes may lead to such an immune answer, in part with suspected specific HLA class II associations. Biochemical and conformational characteristics of red blood cell (RBC) antigens, their dose (number of transfusions and pregnancies, absolute number of antigens per RBC) and the mode of exposure impact on RBCA rates. In addition, individual circumstances determine the risk to form RBCA. Responder individuality in terms of age, sex, severity of underlying disease, disease- or therapy-induced immunosuppression and inflammation are discussed with respect to influencing RBC alloimmunization. For particular high-risk patients, extended phenotype matching of transfusion and recipient efficiently decreases RBCA induction and associated clinical risks.


Self-Reported Long-Term Benefits of Mindfulness-Based Cognitive Therapy in Patients with Bipolar Disorder.
This study focused on patients with bipolar disorder (BD), several years after their participation in mindfulness-based cognitive therapy (MBCT). It aimed at documenting sustained mindfulness practice, perceived long-term benefit from the program, and changes regarded as direct consequences of the intervention. This cross-sectional survey took place at least 2 years after MBCT for 70.4% of participants. It was conducted in two specialized outpatient units for BDs that are part of the Geneva University Hospitals (Switzerland) and the Sainte-Anne Hospital in Paris (France). Eligibility criteria were a diagnosis of BD according to DSM-IV and participation in at least four MBCT sessions. Response rate was 66.4%. The final sample included 71 outpatients (71.8% bipolar I, 28.2% bipolar II). A questionnaire retrospectively assessed patient-perceived change, benefit from MBCT, and current mindfulness practice. Proportions of respondents who practiced mindfulness at least once a week were 54.9% for formal practice (body scan, sitting meditation, mindful walking, or movements) and 57.7% for informal practice (mindful daily activities). Perceived benefit for the prevention of relapse was moderate, but patients acknowledged long-lasting effects and persistent changes in their way of life. Formal mindfulness practice at least once a week tended to be associated with increased long-lasting effects (p = 0.052), whereas regular informal practice and mindful breathing were significantly associated with persistent changes in daily life (p = 0.038) and better prevention of depressive relapse (p = 0.035), respectively. The most frequently reported positive change was increased awareness of being able to improve one's health. Despite methodological limitations, this survey allowed documenting mindfulness practice and perceived sustained benefit from MBCT in patients with BD. Participants particularly valued increased awareness that they can influence their own health. Both informal and formal practices, when sustained in the long term, might promote long-lasting changes.


Esophageal stricture dilatation in awake children.
Dilatation of esophageal strictures in children has generally been performed in the hospital under general anesthesia, or under deep sedation. We report here a series of 211 dilatations in 13 pediatric patients who had these procedures performed in the outpatient department, 72% of them without any sedation, during a 4-year period. This report characterizes the children, the method of outpatient dilatation, and our results. At the end of the study period, six of the patients no longer required dilatation after five to 14 procedures; four patients still required dilatation at twice-yearly intervals; and three patients remained on an active schedule of dilatations at intervals less than 5 months. Esophageal lumen diameter increased and symptoms improved in all of the children. Catch-up weight gain occurred in one-half of those initially below the 10th percentile. Dilatation without anesthesia or sedation was preferred by all of the parents, and by those children old enough to express a preference. Estimated reduction of medical costs by more than $100,000 was realized, compared with bouginage using general anesthesia. No episode of perforation, significant hemorrhage, documentable aspiration, or neurologic complication occurred. Outpatient dilatation without anesthesia is an effective method of treating esophageal strictures in children.


Determinants of health-related quality of life during the 2 years following deep vein thrombosis.
We prospectively measured change in quality of life (QOL) during the 2 years after a diagnosis of deep vein thrombosis (DVT) and evaluated determinants of QOL, including development of the post-thrombotic syndrome (PTS). Consecutive patients with acute DVT were recruited from 2001 to 2004 at eight hospitals in Canada. At study visits at baseline, and 1, 4, 8, 12 and 24 months, clinical data were collected, standardized PTS assessments were performed, and QOL questionnaires were self-completed. Generic QOL was measured using the Short-Form Health Survey-36 (SF-36) questionnaire. Venous disease-specific QOL was measured using the Venous Insufficiency Epidemiological and Economic Study (VEINES)-QOL/Sym questionnaire. The change in QOL scores over a 2-year follow-up was assessed. The influence of PTS and other characteristics on QOL at 2 years was evaluated using multivariable regression analyses. Among the 387 patients recruited, the average age was 56 years, two-thirds were outpatients, and 60% had proximal DVT. The cumulative incidence of PTS was 47%. On average, QOL scores improved during follow-up. However, patients who developed PTS had lower scores at all visits and significantly less improvement in QOL over time (P-values for PTS*time interaction were 0.001, 0.012, 0.014 and 0.006 for PCS, MCS, VEINES-QOL and VEINES-Sym). Multivariable regression analyses showed that PTS (P < 0.0001), age (P = 0.0009), proximal DVT (P = 0.01) and inpatient status (P = 0.04) independently predicted 2-year SF-36 PCS scores. PTS alone independently predicted 2-year VEINES-QOL (P < 0.0001) and VEINES-Sym (P < 0.0001) scores. Development of PTS is the principal determinant of health-related QOL 2 years after DVT. Our study provides prognostic information on patient-reported outcomes after DVT and emphasizes the need for effective prevention and treatment of the PTS.


Mouse virulence of Salmonella typhimurium mutants deficient in two major outer membrane proteins.
The role of several outer membrane components as virulence factors is well established. We have now isolated spontaneous mutants and conjugational hybrids of smooth mouse virulent Salmonella typhimurium deficient in two major outer-membrane proteins. The lack of the 34,000- and/or 36,000-dalton proteins was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Mutants and recombinants were then tested for their mouse virulence by intraperitoneal inoculation and were found to be as virulent as the parent strain.


Electrochemical Determination of Epinephrine in Pharmaceutical Preparation Using Laponite Clay-Modified Graphene Inkjet-Printed Electrode.
Epinephrine (EP, also called adrenaline) is a compound belonging to the catecholamine neurotransmitter family. It can cause neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This work describes an amperometric sensor for the electroanalytical detection of EP by using an inkjet-printed graphene electrode (IPGE) that has been chemically modified by a thin layer of a laponite (La) clay mineral. The ion exchange properties and permeability of the chemically modified electrode (denoted La/IPGE) were evaluated using multi-sweep cyclic voltammetry, while its charge transfer resistance was determined by electrochemical impedance spectroscopy. The results showed that La/IPGE exhibited higher sensitivity to EP compared to the bare IPGE. The developed sensor was directly applied for the determination of EP in aqueous solution using differential pulse voltammetry. Under optimized conditions, a linear calibration graph was obtained in the concentration range between 0.8 µM and 10 μM. The anodic peak current of EP was directly proportional to its concentration, leading to detection limits of 0.34 μM and 0.26 μM with bare IPGE and La/IPGE, respectively. The sensor was successfully applied for the determination of EP in pharmaceutical preparations. Recovery rates and the effects of interfering species on the detection of EP were evaluated to highlight the selectivity of the elaborated sensor.


Trade in human tissue products.
Trade in human tissue in Australia is prohibited by state law, and in ethical guidelines by the National Health and Medical Research Council: National statement on ethical conduct in human research; Organ and tissue donation by living donors: guidelines for ethical practice for health professionals. However, trade in human tissue products is a common practice especially for: reconstructive orthopaedic or plastic surgery; novel human tissue products such as a replacement trachea created by using human mesenchymal stem cells; biomedical research using cell lines, DNA and protein provided through biobanks. Cost pressures on these have forced consideration of commercial models to sustain their operations. Both the existing and novel activities require a robust framework to enable commercial uses of human tissue products while maintaining community acceptability of such practices, but to date no such framework exists. In this article, we propose a model ethical framework for ethical governance which identifies specific ethical issues such as: privacy; unique value of a person's tissue; commodification of the body; equity and benefit to the community; perverse incentives; and "attenuation" as a potentially useful concept to help deal with the broad range of subjective views relevant to whether it is acceptable to commercialise certain human tissue products.


Antibiotic prophylaxis at Cesarean delivery.
Our aim was to compare the efficacy of ampicillin, cefotetan, and ampicillin/sulbactam in the prevention of post-Cesarean endomyometritis. Consenting patients undergoing Cesarean delivery at the University of Louisville Hospital were enrolled in a prospective, double-blinded randomization to receive either ampicillin/sulbactam (Group 1), cefotetan (Group 2), or ampicillin (Group 3) single dose antibiotic prophylaxis following umbilical cord clamping. The primary outcome variable was the frequency of endomyometritis in the respective groups. Among 301 randomized patients, outcome data was available for 298 patients. Fourteen patients (4.7%), all of whom underwent non-elective Cesarean delivery, developed endomyometritis. The frequency of endomyometritis was not different among groups: Group 1, 4/101 (4%); Group 2, 4/96 (4.2%); and Group 3, 6/101 (5.9%). Wound infections were infrequently observed 4/298 (1.3%) without significant differences among groups. Stepwise discriminative analysis identified only last cervical dilatation as a significant predictor of endomyometritis (P = 0.006). Post-Cesarean endomyometritis occurs infrequently following single dose antibiotic prophylaxis after umbilical cord clamping. An advantage of broader spectrum antibiotics over ampicillin was not demonstrated.


Prediction of excretion of manure and nitrogen by Holstein dairy cattle.
A compilation of N balance data (n = 1801) was partitioned into four groups to define the mean excretion of manure and N and to develop empirical equations to estimate these excretions from Holstein herds. Mean excretion of manure for cows that averaged 29 kg/d of milk production was 3 kg/d per 1000 kg of body weight (BW) more than the value for dairy cows reported by the American Society of Agricultural Engineers; N excretion was 0.09 kg/d per 1000 kg of BW higher than the value reported by the American Society of Agricultural Engineers. Mean excretion of manure and N for cows that averaged 14 kg/d of milk production and that for nonlactating cows were substantially lower than the values reported by the American Society of Agricultural Engineers. Growing and replacement cattle excreted 10 kg/d per 1000 kg of BW more manure and 0.11 kg/d per 1000 kg of BW more N than was reported by the American Society for Agricultural Engineers for beef cattle. Estimation of manure and N excretion was more accurate than mean values when using regression equations that included variables for milk production, concentration of crude protein and neutral detergent fiber in the diet, BW, days in milk, and days of pregnancy. Equations that contained intake variables did not significantly affect predictions of manure and N excretion, and the use of such equations is discouraged unless dry matter intake is measured and not estimated. Accurate estimates of excreta output could improve the planning of storage and handling systems for manure and the calculation of nutrient balances on dairy farms.


Identifying Balance Measures Most Likely to Identify Recent Falls.
Falls sustained by older adults are an increasing health care issue. Early identification of those at risk for falling can lead to successful prevention of falls. Balance complaints are common among individuals who fall or are at risk for falling. The purpose of this study was to evaluate the clinical utility of a multifaceted balance protocol used for fall risk screening, with the hypothesis that this protocol would successfully identify individuals who had a recent fall (within the previous 12 months). This is a retrospective review of 30 individuals who self-referred for a free fall risk screening. Measures included case history, Activities-Specific Balance Confidence Scale, modified Clinical Test of Sensory Interaction on Balance, Timed Up and Go test, and Dynamic Visual Acuity. Statistical analyses were focused on the ability of the test protocol to identify a fall within the past 12 months and included descriptive statistics, clinical utility indices, logistic regression, receiver operating characteristic curve, area under the curve analysis, effect size (Cohen d), and Spearman correlation coefficients. All individuals who self-referred for this free screening had current imbalance complaints, and were typically women (70%), had a mean age of 77.2 years, and had a fear of falling (70%). Almost half (46.7%) reported at least 1 lifetime fall and 40.0% within the past 12 months. Regression analysis suggested that the Timed Up and Go test was the most important indicator of a recent fall. A cutoff score of 12 or more seconds was optimal (sensitivity: 83.3%; specificity: 61.1%). Older adults with current complaints of imbalance have a higher rate of falls, fall-related injury, and fear of falling than the general community-dwelling public. The Timed Up and Go test is useful for determining recent fall history in individuals with imbalance.


Promoting End-of-Life Discussions in Advanced Cancer: Effects of Patient Coaching and Question Prompt Lists.
Purpose To build on results of a cluster randomized controlled trial (RCT) of a combined patient-oncologist intervention to improve communication in advanced cancer, we conducted a post hoc analysis of the patient intervention component, a previsit patient coaching session that used a question prompt list (QPL). We hypothesized that intervention-group participants would bring up more QPL-related topics, particularly prognosis-related topics, during the subsequent oncologist visit. Patients and Methods This cluster RCT with 170 patients who had advanced nonhematologic cancer (and their caregivers) recruited from practices of 24 participating oncologists in western New York. Intervention-group oncologists (n = 12) received individualized communication training; up to 10 of their patients (n = 84) received a previsit individualized communication coaching session that incorporated a QPL. Control-group oncologists (n = 12) and patients (n = 86) received no interventions. Topics of interest identified by patients during the coaching session were summarized from coaching notes; one office visit after the coaching session was audio recorded, transcribed, and analyzed by using linear regression modeling for group differences. Results Compared with controls, more than twice as many intervention-group participants brought up QPL-related topics during their office visits (70.2% v 32.6%; P < .001). Patients in the intervention group were nearly three times more likely to ask about prognosis (16.7% v 5.8%; P =.03). Of 262 topics of interest identified during coaching, 158 (60.3%) were QPL related; 20 (12.7%) addressed prognosis. Overall, patients in the intervention group brought up 82.4% of topics of interest during the office visit. Conclusion A combined coaching and QPL intervention was effective to help patients with advanced cancer and their caregivers identify and bring up topics of concern, including prognosis, during their subsequent oncologist visits. Considering that most patients are misinformed about prognosis, more intensive steps are needed to better promote such discussions.


Serial correlations and 1/f power spectra in visual search reaction times.
In a visual search experiment, the subject must find a target item hidden in a display of other items, and their performance is measured by their reaction time (RT). Here I look at how visual search reaction times are correlated with past reaction times. Target-absent RTs (i.e. RTs to displays that have no target) are strongly correlated with past target-absent RTs and, treated as a time series, have a 1/f power spectrum. Target-present RTs, on the other hand, are effectively uncorrelated with past RTs. A model for visual search is presented which generates search RTs with this pattern of correlations and power spectra. In the model, search is conducted by matching search items up with "categorizers," which take a certain time to categorize each item as target or distractor; the RT is the sum of categorization times. The categorizers are drawn at random from a pool of active categorizers. After each search, some of the categorizers in the active pool are replaced with categorizers drawn from a larger population of unused categorizers. The categorizers that are not replaced are responsible for the RT correlations and the 1/f power spectrum.


Mitoxantrone: a novel anthracycline derivative.
The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, and adverse effects of mitoxantrone are reviewed. Mitoxantrone, an aminoanthraquinone that was synthesized in 1979, belongs to a new chemical class of agents known as the anthracenediones. It possesses antiviral, antibacterial, immunomodulatory, and antitumor activity. The drug's antitumor activity is attributed to its interaction with DNA topoisomerase II, and its interaction with human cells may also involve nonintercalary, electrostatic interactions. Mitoxantrone is poorly absorbed orally and is most commonly administered intravenously. The drug is rapidly distributed into the red blood cells, white blood cells, and platelets, followed by deep-tissue sequestration. Mitoxantrone has demonstrated clinical efficacy in the treatment of leukemia, lymphoma, and breast cancer. As a single agent, mitoxantrone has a response rate of roughly 30% in acute nonlymphocytic leukemia or acute myeloid leukemia. In combination with other standard agents (cytarabine, vincristine, and prednisone), the response rate may reach 60%. In breast cancer, mitoxantrone's response rate as a single agent is 25-30%, while combination regimens produce response rates of 60% or more. The drug can cause cardiotoxicity with cumulative doses. Other adverse effects include myelosuppression, nausea and vomiting, stomatitis, mucositis, and alopecia. The cost of mitoxantrone is comparable to that of doxorubicin, but it is substantially more expensive than daunorubicin. Mitoxantrone is an important new agent with antitumor activity in leukemia, lymphoma, and breast cancer. In most situations, mitoxantrone will be considered second-line treatment or a restricted-use item because of its high cost and because of the lack of FDA approval for indications other than acute nonlymphocytic leukemia.


Penicillin and natural immunity protect against postsplenectomy sepsis.
Prophylactic penicillin, splenic autotransplantation, and immunization using pneumococcal vaccine have all been shown to reduce the incidence and mortality of postsplenectomy sepsis. However, little is known regarding the effect of penicillin in established infection or the effect of prior infection in either asplenic controls or animals with autotransplanted splenic tissue. An animal model with bacterial introduction via the lungs was used to investigate the effect of penicillin, splenic autotransplantation, and previous exposure to the infecting organism on the mortality of postsplenectomy sepsis. One hundred fifty-nine rats underwent either sham celiotomy, intraperitoneal splenic autotransplantation, or splenectomy. Twelve weeks postoperatively all animals were challenged using Streptococcus pneumoniae delivered transtracheally. Half of each group received procaine penicillin by intramuscular injection for 5 days beginning 24 hr post bacterial inoculation and mortality was observed. Eight weeks later surviving rats that had received penicillin were reinoculated with the same organism and mortality was again observed. Splenic autotransplantation reduced the early mortality in postsplenectomy sepsis. Prior bacterial exposure reduced the mortality in postsplenectomy sepsis, even in splenectomized animals. Treatment with penicillin produced a marked reduction in mortality even when administration was postponed for 24 hr after bacterial inoculation.


The association of β-arrestin2 polymorphisms with response to antidepressant treatment in depressed patients.
The study of genetic polymorphisms involved in antidepressants (AD) response is essential to provide a personalized medicine approach in the field of depression. β-arrestin 2 (ARRB2) is a candidate gene in the pharmacogenetics of AD as it is involved in the signaling cascade downstream of numerous neurotransmitter receptors. We investigated the association between five ARRB2 single nucleotide polymorphisms (SNPs): rs1045280, rs2036657, rs4790694, rs3786047 and rs452246, and response to AD treatment in a sample of 569 patients with a major depressive episode treated for 6months. We show that GG/GT patients for rs4522461 (n=534) and AA/AC patients for rs4790694 (n=244) have a lower response to AD than other genotype groups (HDRS score of 10.9 vs 8.0 after 6months, multivariate analysis: p=0.03; 12.2 vs 9.6, p=0.02, respectively). These data provide additional evidence that β-arrestin 2 is a regulator of intracellular signal transduction processes involved in AD treatment.


Cognition Without Neural Representation: Dynamics of a Complex System.
This paper proposes an account of neurocognitive activity without leveraging the notion of neural representation. Neural representation is a concept that results from assuming that the properties of the models used in computational cognitive neuroscience (e.g., information, representation, etc.) must literally exist the system being modelled (e.g., the brain). Computational models are important tools to test a theory about how the collected data (e.g., behavioural or neuroimaging) has been generated. While the usefulness of computational models is unquestionable, it does not follow that neurocognitive activity should literally entail the properties construed in the model (e.g., information, representation). While this is an assumption present in computationalist accounts, it is not held across the board in neuroscience. In the last section, the paper offers a dynamical account of neurocognitive activity with Dynamical Causal Modelling (DCM) that combines dynamical systems theory (DST) mathematical formalisms with the theoretical contextualisation provided by Embodied and Enactive Cognitive Science (EECS).


Patient-Oriented Perspective on Chemokine Receptor Expression and Function in Glioma.
Gliomas are severe brain malignancies, with glioblastoma (GBM) being the most aggressive one. Despite continuous efforts for improvement of existing therapies, overall survival remains poor. Over the last years, the implication of chemokines and their receptors in GBM development and progression has become more evident. Recently, large amounts of clinical data have been made available, prompting us to investigate chemokine receptors in GBM from a still-unexplored patient-oriented perspective. This study aims to highlight and discuss the involvement of chemokine receptors-CCR1, CCR5, CCR6, CCR10, CX3CR1, CXCR2, CXCR4, ACKR1, ACKR2, and ACKR3-most abundantly expressed in glioma patients based on the analysis of publicly available clinical datasets. Given the strong intratumoral heterogeneity characterizing gliomas and especially GBM, receptor expression was investigated by glioma molecular groups, by brain region distribution, emphasizing tissue-specific receptor functions, and by cell type enrichment. Our study constitutes a clinically relevant and patient-oriented guide that recapitulates the expression profile and the complex roles of chemokine receptors within the highly diversified glioma landscape. Additionally, it strengthens the importance of patient-derived material for development and precise amelioration of chemokine receptor-targeting therapies.


Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway.
Abnormal HDL metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are increased in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein. We previously reported that unsaturated fatty acids destabilize ABCA1 in murine macrophages and ABCA1-transfected baby hamster kidney cells by increasing its serine phosphorylation through a phospholipase D (PLD) pathway. Here, we examined the cellular pathway downstream of PLD that mediates the ABCA1-destabilizing effects of unsaturated fatty acids. The protein kinase C delta (PKCdelta)-specific inhibitor rottlerin and PKCdelta small interfering RNA completely abolished the ability of unsaturated fatty acids to inhibit lipid transport activity, to reduce protein levels, and to increase serine phosphorylation of ABCA1, implicating a role for PKCdelta in the ABCA1-destabilizing effects of fatty acids. These data indicate that unsaturated fatty acids destabilize ABCA1 by activating a PKCdelta pathway that phosphorylates ABCA1 serines.


Palliative care/hospice and the withdrawal of dialysis.
While the majority of end-stage renal disease (ESRD) patients on dialysis lead satisfying lives, an increasing number are choosing to withdraw from dialysis before death. A partnership between nephrology and palliative care/hospice healthcare teams would seem likely in the care of ESRD patients, yet this is often not the case. In anticipation of increasing participation by palliative care/hospice teams in the care of such patients, this article reviews the decision-making process of withdrawal and the medical care of the patient who withdraws. While withdrawal can be an acceptable choice from a medical, legal, psychiatric, and ethical point of view, it can nonetheless be complex. Profound decisions are often characterized by the need for time to process, and by ambivalence among patient, family and healthcare providers. In addition to caring for the patient and family, the palliative care/hospice team will want to consider the needs of the referring nephrology team as well. A "uremic death" is characterized as painless; however, other symptoms related to the accumulation of toxins and fluid can be anticipated and managed. Pharmacological intervention of uremic symptoms, as well as the pain attendant to other, nonrenal comorbid disease is accomplished with awareness of the impact of renal failure on the excretion of various drugs and their metabolites.


A structural difference limited to one residue of the antigenic peptide can profoundly alter the biological outcome of the TCR-peptide/MHC class I interaction.
The vesicular stomatitis virus (VSV) octapeptide RGYVYQGL binds to H-2K(b) and triggers a cytotoxic T cell response in mice. A variant peptide, RGYVYEGL (E6) with a glutamic acid for glutamine replacement at position 6 of the VSV peptide, elicits a T cell response with features that are quite different from those elicited by the wild-type VSV peptide. The differences found in the nature of the T cells responding to the E6 peptide include changes in both the V beta elements and the sequences of the complementarity-determining region 3 loops of their TCRs. Further experiments found that the E6 peptide can act as an antagonist for VSV-specific T cell hybridomas. To determine whether these differences in V beta usage, complementarity-determining region 3 sequences, and the switch from agonism to antagonism are caused by a conformational change on the MHC, the peptide, or both, we determined the crystal structure of the variant E6 peptide bound to H-2K(b). This structure shows that the only significant structural difference between H-2K(b)/E6 and the previously determined H-2K(b)/VSV is limited to the side chain of position 6 of the peptide, with no differences in the MHC molecule. Thus, a minor conformational change in the peptide can profoundly alter the biological outcome of the TCR-peptide/MHC interaction.


PLDα1-knockdown soybean seeds display higher unsaturated glycerolipid contents and seed vigor in high temperature and humidity environments.
Soybean oil constitutes an important source of vegetable oil and biofuel. However, high temperature and humidity adversely impacts soybean seed development, yield, and quality during plant development and after harvest. Genetic improvement of soybean tolerance to stress environments is highly desirable. Transgenic soybean lines with knockdown of phospholipase Dα1 (PLDα1KD) were generated to study PLDα1's effects on lipid metabolism and seed vigor under high temperature and humidity conditions. Under such stress, as compared with normal growth conditions, PLDα1KD lines showed an attenuated stress-induced deterioration during soybean seed development, which was associated with elevated expression of reactive oxygen species-scavenging genes when compared with wild-type control. The developing seeds of PLDα1KD had higher levels of unsaturation in triacylglycerol (TAG) and major membrane phospholipids, but lower levels of phosphatidic acid and lysophospholipids compared with control cultivar. Lipid metabolite and gene expression profiling indicates that the increased unsaturation on phosphatidylcholine (PC) and enhanced conversion between PC and diacylglycerol (DAG) by PC:DAG acyltransferase underlie a basis for increased TAG unsaturation in PLDα1KD seeds. Meanwhile, the turnover of PC and phosphatidylethanolamine (PE) into lysoPC and lysoPE was suppressed in PLDα1KD seeds under high temperature and humidity conditions. PLDα1KD developing seeds suffered lighter oxidative stresses than did wild-type developing seeds in the stressful environments. PLDα1KD seeds contain higher oil contents and maintained higher germination rates than the wild-type seeds. The study provides insights into the roles of PLDα1 in developing soybean seeds under high temperature and humidity stress. PLDα1KD decreases pre-harvest deterioration and enhances acyl editing in phospholipids and TAGs. The results indicate a way towards improving production of quality soybean seeds as foods and biofuels under increasing environmental stress.


Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH.
The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.


Clinical audit of a new radiation oncology department in the first 20 months of establishment.
This audit was carried out to examine the workload statistics of the Radiation Oncology Department at Liverpool Hospital in its first 20 months of operation, and their implications for the delivery of radiation oncology services in the Southwestern Sydney Area Health Service (SWSAHS). Data on patient demographics, primary diagnosis and radiotherapy treatment details from April 1995 to December 1996 were analysed. In this time period, 1329 new patients were seen; 90.6% of them lived in the local area health service and approximately 30% came from a non-English-speaking background. The most common primary tumour sites were breast (25%), prostate (17%) and lung (15%). Nine hundred and ninety-eight of the new patients (74%) proceeded to have radiotherapy. Fifty-seven per cent were treated radically with curative or adjuvant intent, the remainder were treated palliatively for symptom control or local control. The most commonly used fractionation schedules were 31-35 fractions for radical treatment and 1-5 fractions for palliative treatment. Forty patients (4%) did not complete the treatment course as planned. Eighty-nine patients (9%) were retreated in the same time period. These workload statistics were helpful in determining ongoing workload and planning future expansion.


Generalized posterior keratoconus: clinical pathologic correlations.
A 73-year-old woman presented with bilateral generalized posterior keratoconus. The corneal thickness measured 0.320 mm paracentrally and 0.440 mm toward the periphery. The corneal specimen revealed absence of Bowman's layer and focal homogeneous oval stromal deposits that stained for amyloid. Our case of generalized posterior keratoconus shows absence of Bowman's layer. The amyloid deposits, which also were noted clinically in the cornea of the fellow right eye, were most consistent with a diagnosis of polymorphous amyloid degeneration. To our knowledge, this is the first histopathological report of generalized posterior keratoconus.