Characterization of equine urinary metabolites of selective androgen receptor modulators (SARMs) S1, S4 and S22 for doping control purposes.
Selective androgen receptor modulators, SARMs, constitute a class of compounds with anabolic properties but with few androgenic side-effects. This makes them possible substances of abuse and the World Anti-Doping Agency (WADA) has banned the entire class of substances. There have been several cases of illicit use of aryl propionamide SARMs in human sports and in 2013, 13 cases were reported. These substances have been found to be extensively metabolized in humans, making detection of metabolites necessary for doping control. SARMs are also of great interest to equine doping control, but the in vivo metabolite pattern and thus possible analytical targets have not been previously studied in this species. In this study, the urinary metabolites of the SARMs S1, S4, and S22 in horses were studied after intravenous injection, using ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QToF-MS). Eight different metabolites were found for SARM S1, nine for SARM S4, and seven for SARM S22. The equine urinary metabolite profiles differed significantly from those of humans. The parent compounds were only detected for SARMs S4 and S22 and only at the first sampling time point at 3 h post administration, making them unsuitable as target compounds. For all three SARMs tested, the metabolite yielding the highest response had undergone amide hydrolysis, hydroxylation and sulfonation. The resulting phase II metabolites (4-nitro-3-trifluoro-methyl-phenylamine sulfate for SARMs S1 and S4 and 4-cyano-3-trifluoro-methyl-phenylamine sulfate for SARM S22) are proposed as analytical targets for use in equine doping control.


Rebuilding the R&D engine in big pharma.
From December 2000 to February 2008, the top 15 companies in the pharmaceutical industry lost roughly $850 billion in shareholder value. Although a number of factors--including the rise of generics, pricing pressures, regulatory requirements, and legal entanglements--are to blame, Garnier, the CEO of GlaxoSmithKline, believes that declining R&D productivity is his industry's primary problem. The way to solve it, he says, is to return power to the scientists--by reorganizing R&D into highly focused groups headed by inspirational leaders, seeking the best science outside as well as inside a company, fixing broken processes, and promoting a strong culture of innovation and passion for excellence. GSK has replaced its organizational pyramid with 12 "centers of excellence. The company has worked to untangle the quest for breakthrough drugs from the effort to develop best-in-class offerings and has overhauled incentives for the scientists who actually make discoveries. It has also pursued contractual relationships with academia and biotech companies in a bid to secure the best science, wherever it may reside. When the company began a sweeping reengineering of its R&D, it had only two products in late-stage development. Today it has 34--the most in the industry. But much more remains to be done, the author says. Significant cost efficiencies could be achieved by offshoring clinical trials. Development of new blockbuster drugs could be simplified and accelerated if researchers targeted only a limited segment of the potential patient population and then expanded to others over time. The innovation malaise in pharmaceuticals is not unique, Garnier says. Many other industries face the same challenges. A cultural revolution and a broad transformation of the organization are necessary first steps to rebuilding the R&D engine.


Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes.
1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)


Neuroprotective effect of Mulmina™ against chemotherapy-induced cognitive decline in normal mice.
The aim of the present study was to evaluate a marketed formulation against chemotherapy-induced cognitive dysfunction. The formulation, Mulmina™, contains natural compounds which are known to help in improving function as well as in preventing cognitive decline. All of the phytoconstituents in the formulation have been tested individually but this is the first study where such a formulation has been evaluated against chemotherapy-induced cognitive decline (CICD) in a mouse model. CICD was induced by cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and 5-fluorouracil (5 mg/kg) (CMF), administered intraperitonially. CMF was administered in three cycles, with one injection per week for three weeks. The decline in cognition of the mice was evaluated by a test of locomotor activity (Open Field Test) followed by a test for spatial memory (Morris Water Maze). Biochemical parameters evaluated include brain cytokine levels and BDNF levels via ELISA. Hematological counts were also performed to evaluate any changes in blood profile using a veterinary blood cell counter. Levels of oxidative stress markers with respect to catalase activity and lipid peroxidation were also evaluated in the brain using UV-spectrophotometric analysis. Mulmina™ was able to show significant improvement in cognitive function post chemotherapy when compared to the untreated animals. Apart from improvement in spatial memory, there was also an improvement in biochemical parameters. The particular combination of phytochemicals in Mulmina™ proved themselves successful in alleviating the CICD in this preliminary study and pave a path for future studies which can establish the solid grounds with respect to molecular and pharmacological basis for the mechanism of action of Mulmina™.


Managing variability in decision making in swine growing-finishing units.
Analysis of data collected from pig farms may be useful to understand factors affecting pig health and productive performance. However, obtaining these data and drawing conclusions from them can be done at different levels and presents several challenges. In the present study, information from 688 batches of growing-finishing (GF) pigs (average initial and final body weight of 19.1 and 108.5 kg respectively) from 404 GF farms integrated in 7 companies was obtained between July 2008 and July 2010 in Spain by survey. Management and facility factors associated with feed conversion ratio (FCR) and mortality were studied by multiple linear regression analysis in each single company (A to G) and in an overall database (OD). Factors studied were geographic location of the farm, trimester the pigs entered the farm, breed of sire and sex segregation in pens (BREGENSEG), use of circovirus vaccine, number of origins the pigs were obtained from, age of the farm, percentage of slatted floor, type of feeder, drinker and ventilation, number of phases and form of feed, antibiotic administration system, water source, and number and initial weight of pigs. In two or more companies studied and/or in OD, the trimester when pigs were placed in the farm, BREGENSEG, number of origins of the pigs, age of the farm and initial body weight were factors associated with FCR. Regarding mortality, trimester of placement, number of origins of the pigs, water source in the farm, number of pigs placed and the initial body weight were relevant factors. Age of the farm, antibiotic administration system, and water source were only provided by some of the studied companies and were not included in the OD model, however, when analyzed in particular companies these three variables had an important effect and may be variables of interest in companies that do not record them. Analysing data collected from farms at different levels helps better understand factors associated with productive performance of pig herds. Out of the studied factors trimester of placement and number of origins of the pigs were the most relevant factors associated with FCR and mortality.


Insulin receptor knockdown blocks filarial parasite development and alters egg production in the southern house mosquito, Culex quinquefasciatus.
Lymphatic filariasis, commonly known as elephantiasis, is a painful and profoundly disfiguring disease. Wuchreria bancrofti (Wb) is responsible for >90% of infections and the remainder are caused by Brugia spp. Mosquitoes of the genera Culex (in urban and semi-urban areas), Anopheles (in rural areas of Africa and elsewhere), and Aedes (in Pacific islands) are the major vectors of W. bancrofti. A preventive chemotherapy called mass drug administration (MDA), including albendazole with ivermectin or diethylcarbamazine citrate (DEC) is used in endemic areas. Vector control strategies such as residual insecticide spraying and long-lasting insecticidal nets are supplemental to the core strategy of MDA to enhance elimination efforts. However, increasing insecticide resistance in mosquitoes and drug resistance in parasite limit the effectiveness of existing interventions, and new measures are needed for mosquito population control and disruption of mosquito-parasite interactions to reduce transmission. Mosquito insulin signaling regulates nutrient metabolism and has been implicated in reduced prevalence and intensity of malaria parasite, Plasmodium falciparum, infection in mosquitoes. Currently no data are available to assess how insulin signaling in mosquitoes affects the development of multi-cellular parasites, such as filarial nematodes. Here, we show that insulin receptor knockdown in blood fed C. quinquefasciatus, the major vector of Wb in India, completely blocks the development of filarial nematode parasite to the infective L3 stage, and results in decreased ecdysteroid production and trypsin activity leading to fewer mosquito eggs. These data indicate that a functional mosquito insulin receptor (IR) is necessary for filarial parasite development and mosquito reproduction. Therefore, insulin signaling may represent a new target for the development of vector control or parasite blocking strategies.


Improved Classical Simulation of Quantum Circuits Dominated by Clifford Gates.
We present a new algorithm for classical simulation of quantum circuits over the Clifford+T gate set. The runtime of the algorithm is polynomial in the number of qubits and the number of Clifford gates in the circuit but exponential in the number of T gates. The exponential scaling is sufficiently mild that the algorithm can be used in practice to simulate medium-sized quantum circuits dominated by Clifford gates. The first demonstrations of fault-tolerant quantum circuits based on 2D topological codes are likely to be dominated by Clifford gates due to a high implementation cost associated with logical T gates. Thus our algorithm may serve as a verification tool for near-term quantum computers which cannot in practice be simulated by other means. To demonstrate the power of the new method, we performed a classical simulation of a hidden shift quantum algorithm with 40 qubits, a few hundred Clifford gates, and nearly 50 T gates.


Induction of the CD11b gene during activation of the monocytic cell line U937 requires a novel nuclear factor MS-2.
The differentiation of myeloid precursors into mature myelomonocytic cells is characterized by the induction of the gene encoding the beta2 integrin CD11b. The transcription factors Sp1 and PU.1 prime the CD11b promoter, but the nature of the factors responsible for its inducible expression are unknown. In addition to the CD11b gene, the homologous genes encoding CD11a and CD11c also exhibit inducible expression during myeloid differentiation. Therefore, we compared the nucleotide sequences of the CD11a, CD11b, and CD11c gene promoters to identify common elements that might contribute to inducible expression. This analysis identified one such element repeated four times within the CD11b promoter. Mutation of these elements indicated that two, MS-2beta and MS-2gamma, are critical to the induction of the CD11b gene during differentiation of the pro-monocytic cell line U937. Electrophoretic mobility shift assays indicate that MS-2beta and MS-2gamma interact with nuclear factors that are induced during U937 differentiation. These factors are detected at the time the CD11b promoter is activated. The molecular mass of these factors is approximately 28 kDa, and their DNA binding characteristics are indistinguishable from those of the novel nuclear factor MS-2. Taken together, our data indicate that MS-2 mediates induction of the CD11b gene as cells of the monocytic lineage mature. The presence of multiple potential binding sites for MS-2 in the promoter regions of a wide range of genes expressed in mature myeloid cells suggests this factor plays a general role in myeloid differentiation.


Characteristics and outcome of cardiopulmonary resuscitation in hospitalised African children.
To review the characteristics and outcome of cardiopulmonary resuscitation in children at a rural hospital in Kenya. All children aged 0-14 years who experienced > or =1 episode of respiratory or cardiopulmonary arrest during April 2002--2004 were prospectively identified. Demographic variables, cause of hospitalisation, type and duration of arrest, resuscitation measures taken and outcomes were determined. 114 children experienced at least one episode of respiratory arrest (RA) or cardiopulmonary arrest (CPA). Cardiopulmonary resuscitation (CPR) was performed on all children. "Do not resuscitate order" (DNR) was given in 15 patients after initial resuscitation. Eighty two patients (72%) had RA and 32 (28%) had CPA. 25/82 (30%) patients with RA survived initial CPR compared to 5/32 (16%) with CPA. Survival at discharge was 22% (18/82) in children who had RA while no one with CPA survived at discharge. The leading underlying diseases were severe malaria, septicaemia and severe malnutrition. Prolonged resuscitation beyond 15 min and receiving adrenaline [epinephrine] (at least one dose of 10 microg/kg IV) were predictive of poor final outcome. Cardiopulmonary arrest after admission has a very poor prognosis in our hospital. Infectious diseases are the main underlying causes of arrest. If a child fails to respond to the basic tenements of PALS within 15 min then it is unlikely that further efforts to sustain life will be fruitful in hospitals where ventilation facilities are not present.


How Women Use Digital Technologies for Health: Qualitative Interview and Focus Group Study.
A range of digital technologies are available to lay people to find, share, and generate health-related information. Few studies have directed attention specifically to how women are using these technologies from the diverse array available to them. Even fewer have focused on Australian women's use of digital health. The Australian Women and Digital Health Project aimed to investigate which types of digital technologies women used regularly for health-related purposes and which they found most helpful and useful. Qualitative methods-semistructured interviews and focus groups-were employed to shed light on the situated complexities of the participants' enactments of digital health technologies. The project adopted a feminist new materialism theoretical perspective, focusing on the affordances, relational connections, and affective forces that came together to open up or close off the agential capacities generated with and through these enactments. The project comprised two separate studies including a total of 66 women. In study 1, 36 women living in the city of Canberra took part in face-to-face interviews and focus groups, while study 2 involved telephone interviews with 30 women from other areas of Australia. The affordances of search engines to locate health information and websites and social media platforms for providing information and peer support were highly used and valued. Affective forces such as the desire for trust, motivation, empowerment, reassurance, control, care, and connection emerged in the participants' accounts. Agential capacities generated with and through digital health technologies included the capacity to seek and generate information and create a better sense of knowledge and expertise about bodies, illness, and health care, including the women's own bodies and health, that of their families and friends, and that of their often anonymous online social networks. The participants referred time and again to appreciating the feelings of agency and control that using digital health technologies afforded them. When the technologies failed to work as expected, these agential capacities were not realized. Women responded with feelings of frustration, disappointment, and annoyance, leading them to become disenchanted with the possibilities of the digital technologies they had tried. The findings demonstrate the nuanced and complex ways in which the participants were engaging with and contributing to online sources of information and using these sources together with face-to-face encounters with doctors and other health care professionals and friends and family members. They highlight the lay forms of expertise that the women had developed in finding, assessing, and creating health knowledges. The study also emphasized the key role that many women play in providing advice and health care for family members not only as digitally engaged patients but also as digitally engaged carers.


Multilocus heterozygosity, parental relatedness and individual fitness components in a wild mountain goat, Oreamnos americanus population.
Matings between relatives lead to a decrease in offspring genetic diversity which can reduce fitness, a phenomenon known as inbreeding depression. Because alpine ungulates generally live in small structured populations and often exhibit a polygynous mating system, they are susceptible to inbreeding. Here, we used marker-based measures of pairwise genetic relatedness and inbreeding to investigate the fitness consequences of matings between relatives in a long-term study population of mountain goats (Oreamnos americanus) at Caw Ridge, Alberta, Canada. We first assessed whether individuals avoided mating with kin by comparing actual and random mating pairs according to their estimated genetic relatedness, which was derived from 25 unlinked polymorphic microsatellite markers and reflected pedigree relatedness. We then examined whether individual multilocus heterozygosity H, used as a measure of inbreeding, was predicted by parental relatedness and associated with yearling survival and the annual probability of giving birth to a kid in adult females. Breeding pairs identified by genetic parentage analyses of offspring that survived to 1 year of age were less genetically related than expected under random matings. Parental relatedness was negatively correlated with offspring H, and more heterozygous yearlings had higher survival to 2 years of age. The probability of giving birth was not affected by H in adult females. Because kids that survived to yearling age were mainly produced by less genetically related parents, our results suggest that some individuals experienced inbreeding depression in early life. Future research will be required to quantify the levels of gene flow between different herds, and evaluate their effects on population genetic diversity and dynamics.


New gene-immunotherapy combining TRAIL-lymphocytes and EpCAMxCD3 Bispecific antibody for tumor targeting.
To enhance T-cell responsiveness toward cancer cells, we overexpressed TRAIL in lymphocytes, as this death ligand induces tumor-specific apoptosis. To increase contact time of lymphocytes with tumor cells and thereby of TRAIL with its death receptors, lymphocytes were linked to the CD3 arm of bispecific antibody EpCAMxCD3, to guide the lymphocytes to tumor cells positive for the cancer stem cell marker EpCAM/ESA. Lymphocytes were transduced with TRAIL lentivirus and the antitumor effect in presence and absence of EpCAMxCD3 was evaluated in vitro and in xenograft studies using epithelial cell adhesion molecule (EpCAM)-positive pancreatic and prostate cancer cells. Compared with control lymphocytes, TRAIL-lymphocytes increased cytotoxicity and further induced expression of several apoptosis-related molecules. Cotransplantation of TRAIL-lymphocytes and tumor cells in mice or peritumoral injection of TRAIL-lymphocytes in larger xenografts retarded growth and induced apoptosis. Combination of TRAIL-lymphocytes with EpCAMxCD3 potentiated tumor eradication by enhancing antiapoptotic and antiproliferative signaling and by decreasing tumor vasculature. Intratumoral cyst formation was involved and associated with enhanced chemokine secretion and infiltration of mouse macrophages, suggesting contribution of an inflammatory host response. Most importantly, tumorigenicity of pancreatic cancer cells with cancer stem cell features resistant to conventional chemotherapy was strongly reduced. This gene-immunotherapeutic approach may be a new tool to support endogenous immune responses toward cancer even in its advanced stages.


A mesoderm-inducing factor is produced by Xenopus cell line.
Inductive interactions play a major role in the diversification of cell types during vertebrate development. These interactions have been extensively studied in amphibian embryos (usually Xenopus laevis) where the earliest is mesoderm induction, in which an equatorial mesodermal rudiment is induced from the animal hemisphere under the influence of signal from the vegetal hemisphere. The molecular basis of mesoderm induction is unknown, although Tiedemann has isolated a protein form 9- to 13-day chick embryos that has the properties one would expect of a mesoderm-inducing factor. However, the relevance of this molecule to the events of early amphibian development is unclear, and it is a matter of some importance to discover a Xenopus mesoderm-inducing factor. In this paper I show that the Xenopus XTC cell line secretes mesoderm-inducing activity into the culture medium. Isolated animal pole regions cultured in XTC-conditioned medium differentiate into muscle and notochord, while controls form 'atypical epidermis'. Three different cell lines -XL, XL177 and KR- secrete no such activity indicates that the active principle is heat stable, trypsin sensitive, nondialysable, and has an apparent relative molecular mass of about 16,000. Work is in progress to characterize the activity further and to discover whether the mesoderm-inducing factor is also present in normal embryos.


Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial.
Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4-9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2-88·1) versus 85·0% (76·8-90·5; hazard ratio [HR] 1·22; 95% CI 0·67-2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).


Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia.
The Zambian Ministry of Health provides pediatric antiretroviral therapy (ART) at primary care clinics in Lusaka, where, despite scale-up of perinatal prevention efforts, many children are already infected with the human immunodeficiency virus (HIV). To report early clinical and immunologic outcomes of children enrolled in the pediatric treatment program. Open cohort assessment using routinely collected clinical and outcome data from an electronic medical record system in use at 18 government primary health facilities in Lusaka, Zambia. Care was provided primarily by nurses and clinical officers ("physician extenders" akin to physician assistants in the United States). Patients were children (<16 years of age) presenting for HIV care between May 1, 2004, and June 29, 2007. Three-drug ART (zidovudine or stavudine plus lamivudine plus nevirapine or efavirenz) for children who met national treatment criteria. Survival, weight gain, CD4 cell count, and hemoglobin response. After enrollment of 4975 children into HIV care, 2938 (59.1%) started ART. Of those initiating ART, the median age was 81 months (interquartile range, 36-125), 1531 (52.1%) were female, and 2087 (72.4%) with World Health Organization stage information were in stage III or IV. At the time of analysis, 158 children (5.4%) had withdrawn from care and 382 (13.0%) were at least 30 days late for follow-up. Of the remaining 2398 children receiving ART, 198 (8.3%) died over 3018 child-years of follow-up (mortality rate, 6.6 deaths per 100 child-years; 95% confidence interval [CI], 5.7-7.5); of these deaths, 112 (56.6%) occurred within 90 days of therapy initiation (early mortality rate, 17.4/100 child-years; post-90-day mortality rate, 2.9/100 child-years). Mortality was associated with CD4 cell depletion, lower weight-for-age, younger age, and anemia in multivariate analysis. The mean CD4 cell percentage at ART initiation among the 1561 children who had at least 1 repeat measurement was 12.9% (95% CI, 12.5%-13.3%) and increased to 23.7% (95% CI, 23.1%-24.3%) at 6 months, 27.0% (95% CI, 26.3%-27.6%) at 12 months, 28.0% (95% CI, 27.2%-28.8%) at 18 months, and 28.4% (95% CI, 27.4%-29.4%) at 24 months. Care provided by clinicians such as nurses and clinical officers can result in good outcomes for HIV-infected children in primary health care settings in sub-Saharan Africa. Mortality during the first 90 days of therapy is high, pointing to a need for earlier intervention.


Renal Infarcts-A Perplexing Case in the Middle of the COVID-19 Pandemic.
Renal infarction is a rare finding in children. Associations between SARS-CoV-2 infections and thromboembolic events including renal infarcts have been described in adults. Although a similar association in children has not yet been described with this pandemic, the pediatric literature is still evolving with the recognition of new manifestations including the post-infectious Multisystem Inflammatory Syndrome in Children (MIS-C). We report the rare event of multiple renal infarcts in a 6-year-old boy manifesting several features of MIS-C 9 weeks following a self-limiting febrile illness characteristic of COVID-19. An underlying Factor V Leiden mutation was identified in this child but felt to be insufficient on its own to explain his clinical presentation. As SARS-CoV-2 testing was delayed, the failure to identify viral RNA or antibodies may not exclude the virus' potential role in precipitating the infarct in this host. Given that renal infarcts have been described in adult patients with COVID-19, reporting this perplexing case where SARS-CoV-2 may have played a role, may help identify this potential complication.


Four-wave mixing and phase conjugation in semiconductor laser media.
A theory of four-wave mixing in semiconductor laser media is developed by considering the contributions of both the gain and index gratings created by the carrier-density modulation occurring at the beat frequency of the pump and the probe waves. The general formalism can be applied to semiconductor lasers operating below or above threshold. As an illustration, we consider the case in which the semiconductor laser is operated as a traveling-wave amplifier. The results show that the dominant contribution to the four-wave mixing process comes from the index grating. Further, the index grating makes the probe transmission asymmetric with respect to the pump-probe detuning.


Influence of pneumatic transportation on the stability of monoclonal antibodies.
Pneumatic transportation systems (PTS) were recently proposed as a method to carry ready-for-injection diluted monoclonal antibodies (mAbs) from the pharmacy to the bedside of patients. This method reduces transportation time and improves the efficiency of drug distribution process. However, mAbs are highly sensitive molecules for which subtle alterations may lead to deleterious clinical effects. These alterations can be caused by various external factors such as temperature, pH, pressure, and mechanical forces that may occur during transportation. Hence, it is essential to ensure that the mAbs transported by PTS remain stable and active throughout the transportation process. This study aims to determine the safety profile of PTS to transport 11 routinely used mAbs in a clinical setting through assessment of critical quality attributes (CQA) and orthogonal analysis. Hence, we performed aggregation/degradation profiling, post-translational modifications identification using complementary mass spectrometry-based methods, along with visible and subvisible particle formation determination by light absorbance and light obscuration analysis. Altogether, these results highlight that PTS can be safely used for this purpose when air is removed from the bags during preparation.


Electron transport shuttle mechanism via an Fe-N-C bond derived from a conjugated microporous polymer for a supercapacitor.
A new innovative electrode material (Fe-P800) consisting of a metal complex anchored on carbon via the utilization of iron-porphyrin conjugated microporous polymer (Fe-CMP) was prepared after pyrolyzing at 800 °C. The usage of the polymer with iron-porphyrin repeating units maximized the possible formation of Fe-Nx coordination within the bulk of the sample while the thermal treatment rendered the carbon framework to form a distinct arrangement between metal, nitrogen and carbon with a high surface area of 450 m2 g-1. The formation of the M-N-C bond, confirmed through XPS analysis, established a direct interaction between metal and carbon material. Thus, an indisputable synergistic effect was observed leading to a high capacitance of 182 F g-1 at a current density of 1 A g-1 despite its low metal loading of ∼1%. It also exhibited a highly robust cycling stability of ∼100% capacitance retention even after 5000 cycles (10 A g-1). In this study, a new mechanism was proposed wherein the metal (iron) center features an electron access point via its highly reversible redox reactivity, providing a shuttle effect for charge transfer to the conductive graphitic carbon matrix.


Single-Incision Laparoscopic Deroofing and Omentalization of a Cystic Renal Adenoma in a Dog.
A 12 yr old 13.5 kg male castrated Pembroke Welsh corgi was presented for evaluation of a suspected renal cyst following multiple episodes of lethargy and abdominal pain. Abdominal imaging revealed a large, thin-walled, hypoechoic cystic lesion associated with the cranial pole of the left kidney and a second smaller cystic lesion on the caudal pole. The larger cystic lesion was repeatedly drained percutaneously, but the lesion returned to initial size and clinical signs returned within weeks. Percutaneous ethanol sclerotherapy achieved only transient improvement in lesion size and abdominal discomfort. Laparoscopic deroofing and omentalization of the larger left renal cystic lesion was performed. The resected cystic wall was histopathologically consistent with a renal adenoma. Abdominal ultrasonography performed 1 mo postoperatively found no recurrence of the cystic renal adenoma. Repeated ultrasonography at 3 mo postoperatively detected a small cystic lesion at the cranial pole of the left kidney, which remained static in appearance at 11 and 18 mo postoperatively. During all follow-up visits, the dog was reported to be doing well with no recurrence of clinical signs. Renal cysts causing clinical signs and renal adenomas are rare in veterinary medicine; laparoscopic deroofing and omentalization provides a minimally invasive treatment approach.


Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells.
We recently described that HIV latent infection can be established in vitro following incubation of resting CD4+ T-cells with chemokines that bind to CCR7. The main aim of this study was to fully define the post-integration blocks to virus replication in this model of CCL19-induced HIV latency. High levels of integrated HIV DNA but low production of reverse transcriptase (RT) was found in CCL19-treated CD4+ T-cells infected with either wild type (WT) NL4.3 or single round envelope deleted NL4.3 pseudotyped virus (NL4.3- Δenv). Supernatants from CCL19-treated cells infected with either WT NL4.3 or NL4.3- Δenv did not induce luciferase expression in TZM-bl cells, and there was no expression of intracellular p24. Following infection of CCL19-treated CD4+ T-cells with NL4.3 with enhanced green fluorescent protein (EGFP) inserted into the nef open reading frame (NL4.3- Δnef-EGFP), there was no EGFP expression detected. These data are consistent with non-productive latent infection of CCL19-treated infected CD4+ T-cells. Treatment of cells with phytohemagluttinin (PHA)/IL-2 or CCL19, prior to infection with WT NL4.3, resulted in a mean fold change in unspliced (US) RNA at day 4 compared to day 0 of 21.2 and 1.1 respectively (p = 0.01; n = 5), and the mean expression of multiply spliced (MS) RNA was 56,000, and 5,000 copies/million cells respectively (p = 0.01; n = 5). In CCL19-treated infected CD4+ T-cells, MS-RNA was detected in the nucleus and not in the cytoplasm; in contrast to PHA/IL-2 activated infected cells where MS RNA was detected in both. Virus could be recovered from CCL19-treated infected CD4+ T-cells following mitogen stimulation (with PHA and phorbyl myristate acetate (PMA)) as well as TNFα, IL-7, prostratin and vorinostat. In this model of CCL19-induced HIV latency, we demonstrate HIV integration without spontaneous production of infectious virus, detection of MS RNA in the nucleus only, and the induction of virus production with multiple activating stimuli. These data are consistent with ex vivo findings from latently infected CD4+ T-cells from patients on combination antiretroviral therapy, and therefore provide further support of this model as an excellent in vitro model of HIV latency.


Enhancing Human Cognition with Cocoa Flavonoids.
Enhancing cognitive abilities has become a fascinating scientific challenge, recently driven by the interest in preventing age-related cognitive decline and sustaining normal cognitive performance in response to cognitively demanding environments. In recent years, cocoa and cocoa-derived products, as a rich source of flavonoids, mainly the flavanols sub-class, have been clearly shown to exert cardiovascular benefits. More recently, neuromodulation and neuroprotective actions have been also suggested. Here, we discuss human studies specifically aimed at investigating the effects of acute and chronic administration of cocoa flavanols on different cognitive domains, such as executive functions, attention and memory. Through a variety of direct and indirect biological actions, in part still speculative, cocoa and cocoa-derived food have been suggested to possess the potential to counteract cognitive decline and sustain cognitive abilities, particularly among patients at risk. Although still at a preliminary stage, research investigating the relations between cocoa and cognition shows dose-dependent improvements in general cognition, attention, processing speed, and working memory. Moreover, cocoa flavanols administration could also enhance normal cognitive functioning and exert a protective role on cognitive performance and cardiovascular function specifically impaired by sleep loss, in healthy subjects. Together, these findings converge at pointing to cocoa as a new interesting nutraceutical tool to protect human cognition and counteract different types of cognitive decline, thus encouraging further investigations. Future research should include complex experimental designs combining neuroimaging techniques with physiological and behavioral measures to better elucidate cocoa neuromodulatory properties and directly compare immediate versus long-lasting cognitive effects.


Inferring the timing and strength of natural selection and gene migration in the evolution of chicken from ancient DNA data.
With the rapid growth of the number of sequenced ancient genomes, there has been increasing interest in using this new information to study past and present adaptation. Such an additional temporal component has the promise of providing improved power for the estimation of natural selection. Over the last decade, statistical approaches for the detection and quantification of natural selection from ancient DNA (aDNA) data have been developed. However, most of the existing methods do not allow us to estimate the timing of natural selection along with its strength, which is key to understanding the evolution and persistence of organismal diversity. Additionally, most methods ignore the fact that natural populations are almost always structured, which can result in an overestimation of the effect of natural selection. To address these issues, we introduce a novel Bayesian framework for the inference of natural selection and gene migration from aDNA data with Markov chain Monte Carlo techniques, co-estimating both timing and strength of natural selection and gene migration. Such an advance enables us to infer drivers of natural selection and gene migration by correlating genetic evolution with potential causes such as the changes in the ecological context in which an organism has evolved. The performance of our procedure is evaluated through extensive simulations, with its utility shown with an application to ancient chicken samples.


High iron intake is associated with poor cognition among Chinese old adults and varied by weight status-a 15-y longitudinal study in 4852 adults.
High body iron status has been shown to be associated with adverse health outcomes. However, the relation between high body iron status, body mass index (BMI), and cognition is still understudied. This study aimed to examine the association between iron intake and cognitive function in Chinese adults and tested the interaction effect of iron intake and BMI on cognition. Longitudinal study data from a nationwide sample (n = 4852; age ≥55 y) from the China Health and Nutrition Survey during 1991-2006 were used. Of the participants, 3302 had completed cognitive screening tests in ≥2 surveys. Cognitive function was assessed in 1997, 2000, 2004, and 2006. Dietary iron intake was obtained from a 3-d food record during home visits in 1991, 1993, 1997, 2000, 2004, and 2006. Multivariable mixed linear regression and logistic regression were used. The cumulative mean ± SD iron intake in 1997 of tested subjects was 23.7 ± 11.3 mg/d (25.4 mg/d in men and 22.2 mg/d in women). High iron intake was associated with poor cognition. In fully adjusted models, across the quartiles of iron intake the regression coefficients (95% CIs) were 0, -0.39 (-0.77, -0.01), -0.55 (-0.95, -0.15), and -0.90 (-1.33, -0.47), respectively. Comparing extreme quartiles of iron intake (high), the OR (95% CI) for poor cognitive function was 1.30 (1.04, 1.64). There was a significant interaction between iron intake and BMI. The association between high iron intake and poor cognition was stronger among those with a high BMI than those with a low BMI. Among those with a BMI (kg/m2) >24, across quartiles of iron intake the ORs (95% CIs) for poor cognitive function were 1.00, 1.27 (0.91, 1.78), 1.41 (0.97, 2.04), and 2.04 (1.38, 3.01), respectively. Higher iron intake is associated with poor cognition in Chinese adults, especially among those with a high BMI.


TAR-DNA binding protein-43 and alterations in the hippocampus.
Immunocytochemistry for transactive response binding protein-43 (TDP43) was assessed in the granular cell layer of the dentate gyrus in 250 cases displaying hippocampal pathology identified by haematoxylin-eosin staining. 18%, nearly one in five displayed TDP43 immunoreactive pathology in the granular cell layer of hippocampus. This percentage increased to 43% when only subjects with hippocampal pathology other than vascular in origin were included. When only subjects with severe Alzheimer's disease-related pathology were included, 42% displayed TDP43-immunoreactive pathology, increasing to 60% when concomitant Alzheimer's disease and α-synuclein pathology were present. Within this setting, TDP43-immunoreactive pathology was observed to be present in 6% of subjects with hippocampal pathology but without any cognitive impairment. Our findings justify assessment of TDP43 pathology in every case where a pathological alteration is observed in the hippocampus using a routine stain.


Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-kappaB activation.
Endothelial activation is an important step in atherogenesis. In addition to established cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, and homocysteinemia, high plasma levels of triglyceride-rich lipoproteins may be an important cause of endothelial activation as well. Free fatty acids hydrolyzed from core triglycerides of these particles can exert both pro- and anti-inflammatory effects on the vascular wall. omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to inhibit cytokine-induced endothelial activation. In contrast, we and others have previously shown that the omega-6 fatty acid linoleate activates transcription factor nuclear factor-kappaB (NF-kappaB) in endothelial cells. In this study, we show that linoleic acid stimulates vascular adhesion molecule-1 (VCAM-1) protein and mRNA expression in cultured human endothelial cells, as assessed by immunofluorescence and Northern blotting. Release of shedded soluble VCAM-1 from cultured human endothelial cells was also increased by the addition of linoleic acid, as determined by enzyme-linked immunosorbent assay (ELISA). By use of cultured rat aortic endothelial cells transfected with an IkappaB super-repressor (DeltaN2 cells), we provide evidence that NF-kappaB signalling is required in the linoleic acid-induced VCAM-1 expression in endothelial cells, whereas other transcription factors appear to be involved in the increased endothelial plasminogen activator inhibitor-1 (PAI-1) production in response to linoleic acid. These findings suggest that diets rich in linoleic acid may be proinflammatory and thus atherogenic by activating vascular endothelial cells.


Radiological and histopathological comparison of microporous polysaccharide hemospheres and oxidized regenerated cellulose in the rabbit brain: a study of efficacy and safety.
Topical hemostatic agents are widely used in brain surgery but they have some disadvantages such as foreign body reaction, being a focus for infection and causing artifacts in radiological examinations. The purpose of this study is to compare the effectiveness and safety of microporous polysaccharide hemospheres (MPH) with a well known agent, oxidized regenerated cellulose (ORC), histopathologically and radiologically. Standard brain lesions (4x1mm) were created in 24 hemispheres in 12 New-Zealand rabbits. Animals were divided into three groups; control, ORC and MPH. Twenty-four hours later, all rabbits magnetic resonance brain imaging. After imaging, the animals were sacrificed and the brains were removed for histopathological analysis. Histopathological analysis showed no significant difference between the groups. Radiological examination showed no significant difference between the MPH and ORC groups in terms of edema but the edema in control group was significantly prominent than MPH and ORC groups (p < 0.001). A new agent (MPH) provides safe and effective hemostasis in the brain in this study. The most important advantage of microporous polysaccharide hemospheres is their rapid clearance from the surgical field and therefore having the potential of causing less imaging artifacts.


Preoperative prognostic classification system for hemispheric low-grade gliomas in adults.
Hemispheric low-grade gliomas (LGGs) have an unpredictable progression and overall survival (OS) profile. As a result, the objective in the present study was to design a preoperative scoring system to prognosticate long-term outcomes in patients with LGGs. The authors conducted a retrospective review with long-term follow-up of 281 adults harboring hemispheric LGGs (World Health Organization Grade II lesions). Clinical and radiographic data were collected and analyzed to identify preoperative predictors of OS, progression-free survival (PFS), and extent of resection (EOR). These variables were used to devise a prognostic scoring system. The 5-year estimated survival probability was 0.86. Multivariate Cox proportional hazards modeling demonstrated that 4 factors were associated with lower OS: presumed eloquent location (hazard ratio [HR] 4.12, 95% confidence interval [CI] 1.71-10.42), Karnofsky Performance Scale score < or = 80 (HR 3.53, 95% CI 1.56-8.00), patient age > 50 years (HR 1.96, 95% CI 1.47-3.77), and tumor diameter > 4 cm (HR 3.43, 95% CI 1.43-8.06). A scoring system calculated from the sum of these factors (range 0-4) demonstrated risk stratification across study groups, with the following 5-year cumulative survival estimates: Scores 0-1, OS = 0.97, PFS = 0.76; Score 2, OS = 0.81, PFS = 0.49; and Scores 3-4, OS = 0.56, PFS = 0.18 (p < 0.001 for both OS and PFS, log-rank test). This proposed scoring system demonstrated a high degree of interscorer reliability (kappa = 0.86). Four illustrative cases are described. The authors propose a simple and reliable scoring system that can be used to preoperatively prognosticate the degree of lesion resectability, PFS, and OS in patients with LGGs. The application of a standardized scoring system for LGGs should improve clinical decision-making and allow physicians to reliably predict patient outcome at the time of the original imaging-based diagnosis.


Effect of acidosis on intracellular pH and calcium concentration in the newborn and adult rabbit myocardium.
This study investigated developmental changes in the effect of acidosis on intracellular pH (pHi) and [Ca]i in the isolated heart and isolated myocyte preparations. The whole heart or myocytes of newborn (5-7 days old) and adult rabbits were loaded with the fluorescent pH indicator 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) or calcium indicator fura-2. Left ventricular pressure in the isolated heart preparation and the magnitude of cell contraction in the single-cell preparation were monitored. The heart and single cell were illuminated with excitation lights (340 and 380 nm, respectively, for fura-2 and 438 and 490 nm for BCECF). The intensity of fluorescence from the ventricular surface or from the cell was detected. [Ca]i was estimated from the following ratio: fluorescence at 505 nm during excitation at 340 nm/fluorescence at 505 nm during excitation at 380 nm. pHi was estimated from the following ratio: fluorescence at 530 nm during excitation at 490 nm/fluorescence at 530 nm during excitation at 438 nm. In the newborn, depression of contractile function during respiratory acidosis or metabolic acidosis was less than in the adult. Diastolic and systolic [Ca]i increased during respiratory acidosis in both the newborn and adult, and the net changes in [Ca]i were similar in the two age groups. During respiratory or metabolic acidosis, pHi decreased, but the decrease in the newborn was significantly less than in the adult. These data suggest that the greater resistance of the newborn myocardium to acidosis is due to the smaller change of pHi in this age group and not due to the difference in [Ca]i alteration.


T cell responses to the human papillomavirus type 16 E7 protein in mice of different haplotypes.
The response of murine T cells to the E7 molecule of human papillomavirus type 16 (HPV-16) was studied using eight different mouse strains of six distinct H-2 haplotypes. HPV-16 E7 protein was prepared as a fusion protein with glutathione-S-transferase, purified by affinity chromatography and used for immunization. Cells from the lymph nodes were cultured with whole fusion protein, glutathione-S-transferase or HPV-16 E7 protein synthetic peptides. All the mouse strains tested, with the exception of BALB/c, recognized the E7 molecule, as evidenced by a proliferative response to at least two of the peptides. The profile of responses to peptides varied between and within a strain, but five distinct immunodominant regions could be identified. These regions were defined on the basis of a reaction to one or more peptides in a given part of the E7 molecule by at least four strains. The five regions were encompassed by amino acid residues 1 to 9, 17 to 32, 42 to 59, 62 to 77 and 87 to 98. The findings suggest that in an outbred population, such as man, the E7 molecule of HPV-16 would be recognized by a large proportion of the population. However, the poor response of two mouse strains [B10.RIII (71NS) and BALB/c] could also have a corollary in man.


Progress in limb salvage by reconstructive arterial surgery combined with new or improved adjunctive procedures.
In the past nine years, 1196 patients whose lower extremity was threatened because of infrainguinal arteriosclerosis have been treated at Montefiore Hospital. In the last six years, limb salvage was attempted in 679 or 90% of 755 patients. Femoropopliteal (318), small vessel (204) and axillopopliteal (29) bypasses were used along with transluminal angioplasty (128) and aggressive local operations to obtain a healed foot. Immediate (one month) limb salvage was achieved in 583 or 86% of the 679 patients in whom revascularization was possible. The 30-day mortality rate was 3%. The cumulative life table (LT) survival rate of all the patients undergoing reconstructive arterial operations was 48% at five years. The cumulative LT limb salvage rate after all reconstructive arterial operations was 66% at five years. The cumulative LT patency rate of femoropopliteal bypasses was not influenced by angiographic outflow characteristics of the popliteal artery but was increased 15% by appropriate reoperations to 67% at five years. Cumulative LT patency and limb salvage rates of small vessel and axillopopliteal bypasses were more than 50% at two years. Of patients undergoing arterial reconstruction, 88% of those who died within five years did so without losing their limbs. Of all the patients in whom limb salvage was attempted, 68% lived more than one year with a viable, useable extremity, and 54% lived over two years with an intact limb. We believe this aggressive approach to limb salvage is justified, and can be undertaken with a low cost in mortality, knee loss and morbidity.


[En route in Switzerland - tick-borne and hantavirus infections].
Tick-borne infections are endemic in Switzerland with borreliosis being the most frequent one, followed by the vaccine-preventable tick-borne encephalitis and more rarely by anaplasmosis, rickettsioses and babesiosis. Short characteristics of these infections are presented. The main preventive measures for stays in endemic regions include not leaving forest tracks and wearing closely fitted clothes and shoes, impregnated with an insecticide. Following at-risk activities, clothes as well as the body should be searched for ticks and they have to be removed using a tick removing tool. The body area of the tick bite has to be observed and a physician visit is strongly urged in case of rising fever and/or of erythema migrans. Hantavirus infections: Nephropathia epidemica is a zoonosis caused by the Puumala type of hantavirus and transmission occurs by inhaling aerolized excretions of the bank vole. There is no known human to human transmission. The incidence of this infection varies in a cyclic fashion and typical clinical symptoms include sudden onset of fever, headache, abdominal and back pain and transient renal impairment with initial oliguria and later polyuria. At-risk activities include camping and cleaning of rodent infestations. In these cases, face masks should be worn and the excretions be moistened before cleaning is started. In Germany, 2 - 3 years-cycles of outbreaks were observed between 2005 and 2012 with regional clusters approaching Switzerland. Therefore, disease awareness of physicians and infection surveillance are essential.


Timeliness in breast cancer care as an indicator of quality.
The current study sought to define best practice for timeliness for a breast cancer program at each diagnostic step. The study was a retrospective review of patients newly diagnosed with invasive breast cancer who were enrolled in the breast cancer database from 2009-2011. A convenience sampling methodology was used for patient selection, and descriptive statistics for various time intervals were calculated for identified data points from abnormal imaging to surgery. No evidence-based practice standards exist for access to breast cancer care. Practice guidelines that include benchmarks for quality measures and an established process to measure patient outcomes would promote high-quality care. An understanding of how practice sites function also would help healthcare providers identify and develop resources to improve patient outcomes. In the current study, the advanced practice nurse (APN) in the practice setting was identified as a key point person in facilitating patients' timely access to healthcare services. The physician and APN practice model was instrumental in influencing the process. The results of the current study provided clinical data to identify benchmarks that a breast oncology practice can use to monitor timeliness as a quality indicator.


Evaluation and nonsurgical management of rotator cuff calcific tendinopathy.
Rotator cuff calcific tendinopathy is a common finding that accounts for about 7% of patients with shoulder pain. There are numerous theories on the pathogenesis of rotator cuff calcific tendinopathy. The diagnosis is confirmed with radiography, MRI or ultrasound. There are numerous conservative treatment options available and most patients can be managed successfully without surgical intervention. Nonsteroidal anti-inflammatory drugs and multiple modalities are often used to manage pain and inflammation; physical therapy can help improve scapular mechanics and decrease dynamic impingement; ultrasound-guided needle aspiration and lavage techniques can provide long-term improvement in pain and function in these patients.


Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer.
Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To determine the biological role of satellite RNAs in carcinogenesis in vivo, we constructed mouse major satellite (MajSAT) RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT RNA expression accelerates oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase.Implications: Aberrant expression of satellite RNAs accelerates oncogenesis through a mechanism involving increased DNA damage. Mol Cancer Res; 16(8); 1255-62. ©2018 AACR.


Qualitative analysis of gene networks.
In this paper, we review the qualitative tools developed by our group for the analysis of regulatory networks. Focusing on the dynamical and biological roles of feedback circuits, this method can be applied in the context of both logical and differential formalisms. This approach already led to several interesting results about the relation between the network structure and the corresponding dynamical properties. In particular, it could be shown that at least one positive regulatory circuit is necessary to generate multistationarity (i.e., alternative states of gene expression), whereas at least one negative circuit is necessary to generate a stable oscillatory behavior. Applications to the analysis of complex gene networks, as well as to the synthesis of regulatory models to account for global expression data are discussed.


Analysis with specific polyclonal antiserum indicates that the E1A-associated 300-kDa product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification.
Binding of a 300-kDa host cell protein (p300) is tightly correlated with the ability of the adenovirus E1A products to induce quiescent baby rat kidney cells to proliferate. We have generated rabbit polyclonal antibodies against p300 to characterize this protein further. We have found p300 to be a nuclear phosphoprotein that is actively synthesized in both quiescent and proliferating baby rat kidney cells. In partially purified mitotic cell populations, we observe a form of p300 with decreased electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that shares a nearly identical partial proteolytic digest pattern with p300. The slower-migrating form of p300 is greatly reduced by treating immune complexes with potato acid phosphatase. The relative stability and presence of p300 even in resting cells suggests that p300 has a basal cell function, but the appearance of differentially modified forms during the cell cycle suggests the possibility that p300 function is modulated specifically in growing cells.


Probing individual point defects in graphene via near-field Raman scattering.
The Raman scattering D-peak in graphene is spatially localised in close proximity to defects. Here, we demonstrate the capability of tip-enhanced Raman spectroscopy (TERS) to probe individual point defects, even for a graphene layer with an extremely low defect density. This is of practical interest for future graphene electronic devices. The measured TERS spectra enable a direct determination of the average inter-defect distance within the graphene sheet. Analysis of the TERS enhancement factor of the graphene Raman peaks highlights the preferential enhancement and symmetry-dependent selectivity of the D-peak intensity caused by zero-dimensional Raman scatterers.


Unbiased equations for ⁹⁵Zr-⁹⁵Nb chronometry.
Formulae are presented for (95)Zr-(95)Nb chronometry of a nuclear event. In particular, they allow for a bias-free calculation of the moment of a nuclear explosion, based solely on a measurement of the produced activity ratio of (95)Zr and (95)Nb in a finite time interval. Also uncertainty propagation factors are presented, which relate the relative uncertainty on the nuclear decay data and activity ratio measurements with the relative uncertainty on the elapsed time. This allows for the calculation of an uncertainty budget, without the need for Monte Carlo simulations. The equations are applied to a set of measurement data and consistency is demonstrated.


Clinical field-strength MRI of amyloid plaques induced by low-level cholesterol feeding in rabbits.
Two significant barriers have limited the development of effective treatment of Alzheimer's disease. First, for many cases the aetiology is unknown and likely multi-factorial. Among these factors, hypercholesterolemia is a known risk predictor and has been linked to the formation of beta-amyloid plaques, a pathological hallmark this disease. Second, standardized diagnostic tools are unable to definitively diagnose this disease prior to death; hence new diagnostic tools are urgently needed. Magnetic resonance imaging (MRI) using high field-strength scanners has shown promise for direct visualization of beta-amyloid plaques, allowing in vivo longitudinal tracking of disease progression in mouse models. Here, we present a new rabbit model for studying the relationship between cholesterol and Alzheimer's disease development and new tools for direct visualization of beta-amyloid plaques using clinical field-strength MRI. New Zealand white rabbits were fed either a low-level (0.125-0.25% w/w) cholesterol diet (n = 5) or normal chow (n = 4) for 27 months. High-resolution (66 x 66 x 100 microm(3); scan time = 96 min) ex vivo MRI of brains was performed using a 3-Tesla (T) MR scanner interfaced with customized gradient and radiofrequency coils. Beta-amyloid-42 immunostaining and Prussian blue iron staining were performed on brain sections and MR and histological images were manually registered. MRI revealed distinct signal voids throughout the brains of cholesterol-fed rabbits, whereas minimal voids were seen in control rabbit brains. These voids corresponded directly to small clusters of extracellular beta-amyloid-positive plaques, which were consistently identified as iron-loaded (the presumed source of MR contrast). Plaques were typically located in the hippocampus, parahippocampal gyrus, striatum, hypothalamus and thalamus. Quantitative analysis of the number of histologically positive beta-amyloid plaques (P < 0.0001) and MR-positive signal voids (P < 0.05) found in cholesterol-fed and control rabbit brains corroborated our qualitative observations. In conclusion, long-term, low-level cholesterol feeding was sufficient to promote the formation of extracellular beta-amyloid plaque formation in rabbits, supporting the integral role of cholesterol in the aetiology of Alzheimer's disease. We also present the first evidence that MRI is capable of detecting iron-associated beta-amyloid plaques in a rabbit model of Alzheimer's disease and have advanced the sensitivity of MRI for plaque detection to a new level, allowing clinical field-strength scanners to be employed. We believe extension of these technologies to an in vivo setting in rabbits is feasible and that our results support future work exploring the role of MRI as a leading imaging tool for this debilitating and life-threatening disease.


External resonator design for high-power laser diodes that yields 400mW of TEM(00) power.
Normal diode lasers with average output powers of 1 W or more exhibit bad beam quality and therefore cannot be applied for high-precision applications or nonlinear optics. Therefore an external output coupling mirror was used in our experiments. Diffraction-limited operation was achieved, which yielded 400 mW of power and a factor-of-12 improvement in brightness. With this resonator type 1.1 W of average output power was also obtained, with a beam propagation factor of 2.6 in the slow axis; fast axis emission is always diffraction limited.


The epidemiology of malaria in an epidemic area of the Peruvian Amazon.
A longitudinal study of malariometric indicators and their association with potential risk factors was conducted during August 1997-July 1998 at Padre Cocha, a village of 1,400 residents in the Peruvian Amazon. The incidence of Plasmodium falciparum infections during the study year was 166/1,000 persons; that of P. vivax was 826/1,000 persons. The mean duration of symptoms prior to diagnosis was 2 days; presenting geometric mean parasite densities were 3,976 parasites/microl for P. falciparum infections and 2,282 parasites/microl for P. vivax. There were no malaria-associated deaths. Consistent with the epidemic nature of malaria in the area, the incidence of both parasite species increased with age and there were no age-specific differences in mean parasite densities. No specific occupational risks for malaria were identified. Activities significantly associated with malaria risk reflected local vector behavior and included strolling outdoors after 6:00 PM and arising before 6:00 AM for adults, and attending evening church services for children.


Lateral Anal Sphincterotomy for Chronic Anal Fissures- A Comparison of Outcomes and Complications under Local Anaesthesia Versus Spinal Anaesthesia.
Fissure-in-Ano is one of the common and most painful anorectal conditions encountered in surgical practice. Inspite of several conservative treatment options, surgical treatment in the form of Lateral Anal Spincterotomy (LAS) remains the gold standard of treatment for Chronic Anal Fissures (CAF). However, LAS is often done under spinal or general anaesthesia incurring huge treatment costs and hospital stay. To study if LAS can be treated with Local Anaesthesia (LA) thereby, reducing the costs and the anaesthetic risk to patients with no significant change in the surgical ease or clinical outcome. A total of 79 patients with chronic fissure underwent randomized allocation to two treatment arms - The first to undergo LAS under LA and the second under Spinal Anaesthesia (SA). The primary outcome variables studied were complications like post-operative pain, infections, healing rate of fissure and incontinence rates. Secondary outcome variables studied were cost, hospital stay and need for additional anaesthetic. A total of 79 patients underwent LAS procedure. A total of 42 patients had LA and 39 patients had SA. There was no statistically significant difference in the healing rate, pain, infection and incontinence rates between the two groups. Moreover, the LA group incurred lower cost, reduced hospital stay and reduced risk of anaesthesia. LAS can be satisfactorily performed under local anaesthesia with no increased risk of pain or complications, and is best suited for resource-poor surgical settings.


Impact of routine bedside infectious disease consultation on clinical management and outcome of Staphylococcus aureus bacteraemia in adults.
Staphylococcus aureus bacteraemia (SAB) is a common, serious infection that is associated with high rates of morbidity and mortality. Evidence suggests that infectious disease consultation (IDC) improves clinical management in patients with SAB. We examined whether the introduction of a routine bedside IDC service for adults with SAB improved clinical management and outcomes compared to telephone consultation. We conducted an observational cohort study of 571 adults with SAB at a teaching hospital in the United Kingdom between July 2006 and December 2012. A telephone consultation was provided on the day of positive blood culture in all cases, but an additional bedside IDC was provided after November 2009 (routine IDC group). Compared to patients in the pre-IDC group, those in the routine IDC group were more likely to have a removable focus of infection identified, echocardiography performed and follow-up blood cultures performed. They also received longer courses of antimicrobial therapy, were more likely to receive combination antimicrobial therapy and were more likely to have SAB recorded in the hospital discharge summary. There was a trend towards lower mortality at 30 days in the routine IDC group compared to the pre-IDC group (12% vs. 22%, p 0.07). Our findings suggest that routine bedside IDC should become the standard of care for adults with SAB.


Not just a research method: If used with caution, can job-exposure matrices be a useful tool in the practice of occupational medicine and public health?
The recent editorial by Dr Susan Peters "Although a valuable method in occupational epidemiology, job-exposure matrices are no magic fix" ably describes the strengths and limitations of job-exposure matrix (JEM) approaches in occupational epidemiology research (1). In addition to their use in research, we would like to add that JEM may also be of use in compensation and surveillance efforts in occupational health. JEM could assist the compensation process by supporting the assessment of relevant exposures related to specific health conditions (2). The potential usefulness of a JEM as a decision tool for compensation of work-related musculoskeletal disorders has been examined (3). Because occupational diseases are often under-recognized, another practical application is using a JEM to screen for occupational exposures as part of health surveillance. Use of JEM to screen for asbestos and wood dust exposure in the clinical setting has shown promising results (4-6). By summarizing multiple exposures at a job level (7), JEM may also assist policy-makers in setting priorities for hazards and controls at work, as well as occupational practitioners to target prevention efforts and direct the conduct of more precise exposure measures to particular jobs. Sharing JEM across different countries may be useful in providing estimates of exposures across larger populations to calculate global burden of disease related to occupational exposure. The JEMINI (JEM InterNatIonal) initiative was launched to explore the possibility of developing international JEM that could be used across countries (8). Beginning with physical (biomechanical) exposures, this open group has started homogenizing job coding systems and comparing some available JEM. Estimating differences in the level of exposure between countries will require much more work, without guaranteed success. As Peters mentioned, many limitations exist in the use of JEM. Users of JEM must consider the source of exposure data - expert assessments, data collected from individual workers, or environmental sampling. The coding of occupations is time consuming and can introduce error (9), and more testing of and comparison with automated job coding systems is needed (10). JEM reflect an "average" level of exposure within a job at the expense of individual variation. At population level, JEM can offer a useful estimate of exposures. If used at an individual level in a clinical or compensation setting, JEM cannot replace the professionals involved in exposure assessment but may help them focus their action more effectively on complex situations that require their expertise. In conclusion, these JEM developed for research might also be used as a public health tool, provided that their limitations are properly taken into account. References 1. Peters S. Although a valuable method in occupational epidemiology, job-exposure matrices are no magic fix. Scand J Work Environ Health 2020;46:2314. https://doi.org/10.5271/sjweh.3894 2. Kerbrat J, Descatha A. (The recognition of health consequences of difficult working conditions in France and its evaluation with the use of a job-exposure matrix). Arch Mal Prof Environ. 2018;79:493500. https://doi.org/10.1016/j.admp.2017.12.001 3. Fadel M, Valter R, Quignette A, Descatha A. Usefulness of a job-exposure matrix « MADE » as a decision tool for compensation of work-related musculoskeletal disorders. Eur J Public Health 2019;29:86870. https://doi.org/10.1093/eurpub/cky274 4. Lorentz E, Despreaux T, Quignette A, Chinet T, Descatha A. (Screening of occupational exposure to asbestos and silica by job-exposure matrix among patients with lung cancer and mesothelioma). Rev Mal Respir. 2019;36:108895. https://doi.org/10.1016/j.rmr.2019.08.006 5. Imbernon E, Goldberg M, Spyckerell Y, Steinmetz J, Bonenfant S, Fournier B. (Use of a job-exposure matrix for the screening of occupational exposure to asbestos). Rev Epidemiol Sante Publique 2004;52:717. https://doi.org/10.1016/S0398-7620(04)99018-9 6. Carton M, Bonnaud S, Nachtigal M, Serrano A, Carole C, Bonenfant S, et al. Post-retirement surveillance of workers exposed to asbestos or wood dust: first results of the French national SPIRALE Program. Epidemiol Prev. 2011;35:31523. 7. Guéguen A, Goldberg M, Bonenfant S, Martin JC. Using a representative sample of workers for constructing the SUMEX French general population based job-exposure matrix. Occup Environ Med. 2004;61:58693. https://doi.org/10.1136/oem.2003.010660 8. Descatha A, Evanoff BA, Andersen JH, Fadel M, Ngabirano L, Leclerc A, et al. JEMINI (Job Exposure Matrix InterNatIonal) Initiative: a Utopian Possibility for Helping Occupational Exposure Assessment All Around the World? J Occup Environ Med. 2019;61:e3201. https://doi.org/10.1097/JOM.0000000000001631 9. Petersen SB, Flachs EM, Svendsen SW, Marott JL, Budtz-Jørgensen E, Hansen J, et al. Influence of errors in job codes on job exposure matrix-based exposure assessment in the register-based occupational cohort DOC*X. Scand J Work Environ Health 2020;46:25967. https://doi.org/10.5271/sjweh.3857 10. Buckner-Petty S, Dale AM, Evanoff BA. Efficiency of autocoding programs for converting job descriptors into standard occupational classification (SOC) codes. Am J Ind Med. 2019;62:5968. https://doi.org/10.1002/ajim.22928.


Induction of multidrug resistance protein 3 (mrp3) in vivo is independent of constitutive androstane receptor.
We previously demonstrated that multidrug resistance protein 3 (Mrp3/ABCC3) is induced in rat liver by phenobarbital (PB) and several other microsomal enzyme inducers that induce cytochrome P450 2B (CYP2B). CYP2B is induced by constitutive androstane receptor (CAR)-retinoid X receptor (RXR) heterodimer binding to a phenobarbital-responsive promoter element in the CYP2B promoter. Hepatic mRNA levels of CYP2B and Mrp3 were measured in three models of altered CAR activity to determine whether CAR is also involved in the induction of Mrp3. In Wistar Kyoto rats, where males express higher CAR protein levels than females, the induction of CYP2B1/2 was significantly higher in males than in females by PB, diallyl sulfide, and trans-stilbene oxide but not oltipraz. Mrp3 was induced by each of these treatments, but in contrast to CYP2B1/2, to a similar magnitude in males and females. In male hepatocyte-specific RXRalpha-/- mice, CYP2B10 was not induced by diallyl sulfide or oltipraz but remained inducible by PB and trans-stilbene oxide after considering the decrease in basal CYP2B10 expression. Mrp3, however, was induced by PB, diallyl sulfide, trans-stilbene oxide and oltipraz in both wild-type and RXRalpha-/- mice. Additionally, constitutive expression of Mrp3 was significantly reduced in RXRalpha-/- mice. In CAR-/- mice, the robust induction of CYP2B10 by PB was completely absent. However, Mrp3 was equally induced both in wild-type and CAR-/- mice by PB. These data clearly demonstrate that induction of hepatic Mrp3 by PB and other microsomal enzyme inducers is CAR-independent and implies a role for RXRalpha in the constitutive expression of Mrp3.


Membrane-anchored prolyl hydroxylase with an export signal from the endoplasmic reticulum.
We cloned a novel prolyl 4-hydroxylase (PH; EC 18.104.22.168) homolog cDNA from tobacco (Nicotiana tabacum) BY-2 cells based on expression sequence tag information. Like other PHs, this tobacco PH polypeptide has two conserved histidine residues, and it comprises 286 amino acids with a calculated molecular mass of 32 kDa. Interestingly, this protein and homologs in Arabidopsis and rice have predicted transmembrane sequences in their N-terminal regions. This PH homolog was expressed in BY-2 cells as a His-tagged protein, and the expressed protein showed PH activity. Incubation of membranes with high salt, urea, and protease with or without detergents indicated that this protein is an integral membrane protein with a type II configuration. Its membrane-anchored nature is specific for plants because no integral membrane PH has been found in animals. A membrane fractionation study and immunocytochemical studies indicate that this protein localizes in both the endoplasmic reticulum (ER) and Golgi apparatus. Analysis of this protein fused to green fluorescent protein indicated that basic amino acids in the cytoplasmic, N-terminal region of the PH play a role in its export from the ER.


Infant outcome at four years of age after intrapartum sampling of scalp blood lactate for fetal assessment. A cohort study.
To correlate the value of lactate in fetal scalp blood at delivery and the outcomes of the offspring at four years of age. Cases where scalp blood lactate was taken within sixty minutes before delivery were identified from the randomized trial "Determination of pH or lactate in fetal scalp blood in management of intrapartum fetal distress". Data were grouped according to the generally accepted cutoffs for normality, pre-acidemia, acidemia and concentrations above mean +2 SD during the second stage. The outcome measures included gross-/fine motor function, vision, hearing, speaking and cognitive disorders, signs of central motor damage and referral to specialized pediatric services. 307 cases were available for final analyse. With normal scalp lactate concentration, the number of children with a diagnosed disorder was lower compared to the pre-acidemic/acidemic groups, although the findings were only significant for fine motor dysfunction (p = 0.036). Elevated lactate values were significantly associated with increased risk for a poorer capacity of attention and understanding of instructions (OR 1.37, 95% CI 1.07-1.74), and for fine motor dysfunction (OR 1.22, 95% CI 1.00-1.49) at the age of four. Higher levels of lactate in fetal scalp blood seems to be associated with increased risk of an aberrant developmental outcome at four years of age in some areas.


Use of EPA collaborative problem-solving model to obtain environmental justice in North Carolina.
The West End Revitalization Association (WERA), a community-based organization (CBO) in Mebane, North Carolina, was awarded a Collaborative Problem-Solving (CPS) grant from the U.S. Environmental Protection Agency's Office of Environmental Justice (EPA OEJ). The purpose of this paper is to highlight WERA's efforts to bring stakeholders in three low-income African-American communities where environmental hazards created public health risks together for collaboration rather than litigation. WERA's board and staff organized nine working groups with specific areas of expertise that would facilitate research, identify lack of basic amenities, and encourage funding for corrective action and participation in progress reporting workshops. WERA used consensus building, dispute resolution, and resource mobilization as part of the CPS model to address noncompliance with environmental laws, including the Clean Air Act, Clean Water Act, Safe Drinking Water Act, Toxic Substances Control Act, and Solid Waste Disposal Act. WERA's CPS "Right to Basic Amenities" project produced a framework for (1) grassroots management and ownership of a collaborative problem-solving process; (2) bringing stakeholders together with diverse and conflicting viewpoints; (3) implementation of an innovative community-owned and managed (COMR) research model; and (4) leveraging millions of dollars to fund installation of first-time municipal water/sewer services, street paving, and relocation of the 119-bypass to advance environmental health solutions. The structure and successes of WERA's Right to Basic Amenities project have been discussed at demonstration and training sessions to help others replicate the model in comparable low-income communities of color in North Carolina and across the United States.


Effects of hypoxia on the discharge of group III and IV muscle afferents in cats.
The reflex pressor response evoked by static muscular contraction is widely believed to be caused by the stimulation of group III and IV afferents. Although the specific nature of the contraction-induced stimulus to these thin-fiber afferents is unknown, they are thought to be stimulated in part by a condition arising from a mismatch between blood supply and demand in the exercising muscle. Hypoxia, a condition found in skeletal muscle during such a mismatch, may stimulate these afferents. We have therefore tested the hypothesis that perfusion of the triceps surae muscles with hypoxic blood stimulates group III and IV afferents in barbiturate-anesthetized cats. We found that 3-3.5 min of hypoxia with the triceps surae muscles at rest significantly (P < 0.05) increased the average discharge rate of contraction-sensitive group IV afferents but had no effect on the average discharge rate of contraction-sensitive group III afferents. Hypoxia had only trivial effects on the discharge of contraction-insensitive group III and IV afferents. Hypoxia stimulated 4 of 11 contraction-sensitive group IV afferents and 2 of 13 contraction-sensitive group III afferents. The responses of the afferents stimulated by hypoxia were small in magnitude. Hypoxia with the muscles at rest appeared to have no effect on either hydrogen or lactate ion concentrations in the femoral venous blood. In addition, hypoxia increased the responses to contraction in only 3 of 22 group III and 4 of 21 group IV afferents tested. We conclude that muscle tissue hypoxia is a minor stimulus to afferents that sense a mismatch between blood supply and demand during static contraction.


Machine learning as a supportive tool to recognize cardiac arrest in emergency calls.
Emergency medical dispatchers fail to identify approximately 25% of cases of out of hospital cardiac arrest, thus lose the opportunity to provide the caller instructions in cardiopulmonary resuscitation. We examined whether a machine learning framework could recognize out-of-hospital cardiac arrest from audio files of calls to the emergency medical dispatch center. For all incidents responded to by Emergency Medical Dispatch Center Copenhagen in 2014, the associated call was retrieved. A machine learning framework was trained to recognize cardiac arrest from the recorded calls. Sensitivity, specificity, and positive predictive value for recognizing out-of-hospital cardiac arrest were calculated. The performance of the machine learning framework was compared to the actual recognition and time-to-recognition of cardiac arrest by medical dispatchers. We examined 108,607 emergency calls, of which 918 (0.8%) were out-of-hospital cardiac arrest calls eligible for analysis. Compared with medical dispatchers, the machine learning framework had a significantly higher sensitivity (72.5% vs. 84.1%, p < 0.001) with lower specificity (98.8% vs. 97.3%, p < 0.001). The machine learning framework had a lower positive predictive value than dispatchers (20.9% vs. 33.0%, p < 0.001). Time-to-recognition was significantly shorter for the machine learning framework compared to the dispatchers (median 44 seconds vs. 54 s, p < 0.001). A machine learning framework performed better than emergency medical dispatchers for identifying out-of-hospital cardiac arrest in emergency phone calls. Machine learning may play an important role as a decision support tool for emergency medical dispatchers.


Cardiac BNP gene delivery prolongs survival in aged spontaneously hypertensive rats with overt hypertensive heart disease.
Hypertension is a highly prevalent disease associated with cardiovascular morbidity and mortality. Recent studies suggest that patients with hypertension also have a deficiency of certain cardiac peptides. Previously we demonstrated that a single intravenous injection of the myocardium-tropic adeno-associated virus (AAV) 9-based vector encoding for proBNP prevented the development of hypertensive heart disease (HHD) in spontaneously hypertensive rats (SHRs). The current study was designed to determine the duration of cardiac transduction after a single AAV9 injection and to determine whether cardiac BNP overexpression can delay the progression of previously established HHD, and improve survival in aged SHRs with overt HHD. To evaluate the duration of cardiac transduction induced by the AAV9 vector, we used four week old SHRs. Effective long-term selective cardiac transduction was determined by luciferase expression. A single intravenous administration of a luciferase-expressing AAV9 vector resulted in efficient cardiac gene delivery for up to 18-months. In aged SHRs (9-months of age), echocardiographic studies demonstrated progression of HHD in untreated controls, while AAV9-BNP vector treatment arrested the deterioration of cardiac function at six months post-injection (15-months of age). Aged SHRs with established overt HHD were further monitored to investigate survival. A single intravenous injection of the AAV9-vector encoding rat proBNP was associated with significantly prolonged survival in the treated SHRs (613?38 days, up to 669 days) compared to the untreated rats (480±69 days, up to 545 days)(p<0.05). A single intravenous injection of AAV9 vector elicited prolonged cardiac transduction (up to 18 months post-injection). AAV9 induced cardiac BNP overexpression prevented development of congestive heart failure, and significantly prolonged the survival of aged SHRs with previously established overt HHD. These findings support the beneficial effects of chronic supplementation of BNP in a frequent and highly morbid condition such as HHD.


Amorphous SiC/c-ZnO-Based Quasi-Lamb Mode Sensor for Liquid Environments.
The propagation of the quasi-Lamb modes along a-SiC/ZnO thin composite plates was modeled and analysed with the aim to design a sensor able to detect the changes in parameters of a liquid environment, such as added mass and viscosity changes. The modes propagation was modeled by numerically solving the system of coupled electro-mechanical field equations in three media. The mode shape, the power flow, the phase velocity, and the electroacoustic coupling efficiency (K²) of the modes were calculated, specifically addressing the design of enhanced-coupling, microwave frequency sensors for applications in probing the solid/liquid interface. Three modes were identified that have predominant longitudinal polarization, high phase velocity, and quite good K²: the fundamental quasi symmetric mode (qS₀) and two higher order quasi-longitudinal modes (qL₁ and qL₂) with a dominantly longitudinal displacement component in one plate side. The velocity and attenuation of these modes were calculated for different liquid viscosities and added mass, and the gravimetric and viscosity sensitivities of both the phase velocity and attenuation were theoretically calculated. The present study highlights the feasibility of the a-SiC/ZnO acoustic waveguides for the development of high-frequency, integrated-circuit compatible electroacoustic devices suitable for working in a liquid environment.


Antiscorbutic activity of L-ascorbic acid 2-glucoside and its availability as a vitamin C supplement in normal rats and guinea pigs.
Bioavailability of a newly-synthesized and chemically-stable 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) as a vitamin C supplement was investigated in rats and guinea pigs. Oral administration of AA-2G to the animals resulted in an increase of serum ascorbic acid (AA) levels. However, in these sera the intact form was not detectable by the high performance liquid chromatography (HPLC) method, indicating its hydrolysis through the process of absorption. After an intravenous injection of AA-2G, the intact form diminished rapidly from the serum, followed by prolonged and marked elevation of serum AA levels. Various tissue homogenates from rats and guinea pigs were examined for their releasing activity of AA from AA-2G. High activity was observed in kidney, small intestine and serum of rats and in small intestine and kidney of guinea pigs. These hydrolytic activities were completely inhibited by castanospermine, a specific alpha-glucosidase inhibitor, suggesting the participation of alpha-glucosidase in the in vivo hydrolysis of AA-2G. AA-2G was found to exhibit obvious therapeutic effect in scorbutic guinea pigs by its repeated oral administrations. These results indicate that AA-2G is a readily available source of vitamin C activity in vivo.


Public requests for cancer cluster investigations: a survey of state health departments.
This study examined the frequency of requests that state health departments investigate cancer clusters, the nature of those requests, and the resources available for the investigations. A mail survey was sent to state health departments requesting data for 1997. Approximately 1100 cluster investigation requests were made in 1997. Most requests were made by citizens, and no pattern emerged for types of cancer or hazards suspected. States rate this work as average in importance and feel satisfied with the successfullness of their communication efforts. Few cluster inquiries require further investigation. Nonetheless, this interaction represents resources well spent in terms of public service and education.


European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias.
The introduction of novel agents in the management of multiple myeloma and related plasma cell dyscrasias has changed our treatment approaches and subsequently the outcome of patients. Due to current advances, the European Myeloma Network updated the diagnostic and therapeutic recommendations for patients with Waldenström's macroglobulinemia (WM), AL-amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), POEMS syndrome, and primary plasma cell leukemia. For patients with WM, the combination of rituximab with chemotherapy remains the treatment cornerstone, while the Bruton-tyrosine kinase inhibitor ibrutinib has been introduced and approved for relapsed/refractory disease. The management of light chain amyloidosis depends on the presence and severity of heart disfunction. If present, intensification with an autologous stem cell transplantation (ASCT) is not recommended. Further aggregation of misfolded light chains could be prevented by doxycycline or monoclonal antibodies targeting amyloid deposits. Initial treatment generally consists of melphalan/dexamethasone or bortezomib-based regimens. For relapsing patients, one can consider proteasome inhibitors, immunomodulatory agents, melphalan or daratumumab. Because intact or light-chain immunoglobulins are also the culprits for MIDD, the small monoclonal plasma cells' clones should be treated and generally respond well to bortezomib-based treatment. POEMS syndrome is a well-defined clinical entity that can present as solitary bone lesions or disseminated disease. Radiation therapy is used for patients with localized disease and result in long-lasting response. Systemic treatment should be proposed to patients with disseminated disease, but regimens that can worsen a pre-existing polyneuropathy should be avoided. PPCL is located at the other end of the spectrum of plasma cell disorders and is associated with an aggressive disease course and poor prognosis. It requires an imminent, multi-phase and novel agents-based therapy, including induction, ASCT, consolidation and maintenance, with short treatment-free intervals. Patients not eligible for transplant procedures require personalized, intensive therapeutic approach. Allogeneic stem cell transplantation can be used in selected patients.


Communicating with a human voice: developing a relational model of empathy.
The medical profession has adopted a cognitive model of empathy, or detached concern, in its professionalism and practice. As a consequence there is now an empathy gap which has been demonstrated by lapses in patient care in the UK. There may also be an empathy gap developing in medical students during their training. This paper argues for the adoption of a relational view of empathy which embraces emotional and moral dimensions of the concept, acknowledges the importance of the clinical context and prioritises the relationship between the doctor and patient. A relational model extends to encompass the patient's family and all members of the healthcare team. By exploring the process of empathising in clinical practice I develop a relational model that is more appropriate for modern patterns of patient care and medical education than detached concern. Adoption of a relational model of empathy in training and practice can help bridge the empathy gap.