Common state mechanisms regulating tribal tobacco taxation and sales, the USA, 2015.
Native American tribes, as sovereign nations, are exempt from state tobacco excise taxation, and self-govern on-reservation activity in the USA. Under Federal law, state excise taxes are owed by non-members purchasing tobacco on tribal land, but states are limited in how they enforce or collect these taxes. This study highlights the various policy approaches that states have taken to regulate tobacco sales on tribal lands given jurisdictional challenges. State laws (statutes, regulations and case law), Attorney General opinions, and revenue notices and rulings effective as of 1 January 2015 for all 50 states and the District of Columbia were compiled using Boolean searches in Lexis-Nexis and Westlaw. Laws were limited to those addressing taxation compacts or tobacco sales involving tribal entities. Master Settlement Agreement laws and non-codified tribal codes/compacts were excluded. Twenty of the 34 states with tribal lands address tribal tobacco sales. Fourteen states address intergovernmental compacts: 11 are tobacco specific, and suggest or require specific provisions. Fifteen states address tribal tax stamps: 2 explicitly prohibit stamping tribally sold products, 9 stamp all products, and 4 stamp some. Prepayment of excise tax is required in 12 states: 6 on all products, 4 on products in excess of quota, and 2 on products sold by non-tribal retailers. 6 states use quotas to limit tax-free tobacco available to tribes. Many states with a tribal presence have no formal strategies for non-members purchasing tobacco on tribal lands. Formalising policies and harmonising tax rates may assist states in collecting tax revenue from non-tribal consumers.


Divergent responses to peptidoglycans derived from different E. coli serotypes influence inflammatory outcome in trout, Oncorhynchus mykiss, macrophages.
Pathogen-associated molecular patterns (PAMPs) are structural components of pathogens such as lipopolysaccharide (LPS) and peptidoglycan (PGN) from bacterial cell walls. PAMP-recognition by the host results in an induction of defence-related genes and often the generation of an inflammatory response. We evaluated both the transcriptomic and inflammatory response in trout (O. mykiss) macrophages in primary cell culture stimulated with DAP-PGN (DAP; meso-diaminopimelic acid, PGN; peptidoglycan) from two strains of Escherichia coli (PGN-K12 and PGN-O111:B4) over time. Transcript profiling was assessed using function-targeted cDNA microarray hybridisation (n = 36) and results show differential responses to both PGNs that are both time and treatment dependent. Wild type E. coli (K12) generated an increase in transcript number/diversity over time whereas PGN-O111:B4 stimulation resulted in a more specific and intense response. In line with this, Gene Ontology analysis (GO) highlights a specific transcriptomic remodelling for PGN-O111:B4 whereas results obtained for PGN-K12 show a high similarity to a generalised inflammatory priming response where multiple functional classes are related to ribosome biogenesis or cellular metabolism. Prostaglandin release was induced by both PGNs and macrophages were significantly more sensitive to PGN-O111:B4 as suggested from microarray data. Responses at the level of the transcriptome and the inflammatory outcome (prostaglandin synthesis) highlight the different sensitivity of the macrophage to slight differences (serotype) in peptidoglycan structure. Such divergent responses are likely to involve differential receptor sensitivity to ligands or indeed different receptor types. Such changes in biological response will likely reflect upon pathogenicity of certain serotypes and the development of disease.


Bone response to fluoride exposure is influenced by genetics.
Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined. A label-free proteomics approach was employed to identify and evaluate changes in bone protein expression in two mouse strains having different susceptibilities to develop dental fluorosis and to alter bone quality. In vivo bone formation and histomorphometry after F intake were also evaluated and related to the proteome. Resistant 129P3/J and susceptible A/J mice were assigned to three groups given low-F food and water containing 0, 10 or 50 ppmF for 8 weeks. Plasma was evaluated for alkaline phosphatase activity. Femurs, tibiae and lumbar vertebrae were evaluated using micro-CT analysis and mineral apposition rate (MAR) was measured in cortical bone. For quantitative proteomic analysis, bone proteins were extracted and analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), followed by label-free semi-quantitative differential expression analysis. Alterations in several bone proteins were found among the F treatment groups within each mouse strain and between the strains for each F treatment group (ratio ≥1.5 or ≤0.5; p<0.05). Although F treatment had no significant effects on BMD or bone histomorphometry in either strain, MAR was higher in the 50 ppmF 129P3/J mice than in the 50 ppmF A/J mice treated with 50 ppmF showing that F increased bone formation in a strain-specific manner. Also, F exposure was associated with dose-specific and strain-specific alterations in expression of proteins involved in osteogenesis and osteoclastogenesis. In conclusion, our findings confirm a genetic influence in bone response to F exposure and point to several proteins that may act as targets for the differential F responses in this tissue.


A new method for identifying rapid decline dynamics in wild vertebrate populations.
Tracking trends in the abundance of wildlife populations is a sensitive method for assessing biodiversity change due to the short time-lag between human pressures and corresponding shifts in population trends. This study tests for proposed associations between different types of human pressures and wildlife population abundance decline-curves and introduces a method to distinguish decline trajectories from natural fluctuations in population time-series. First, we simulated typical mammalian population time-series under different human pressure types and intensities and identified significant distinctions in population dynamics. Based on the concavity of the smoothed population trend and the algebraic function which was the closest fit to the data, we determined those differences in decline dynamics that were consistently attributable to each pressure type. We examined the robustness of the attribution of pressure type to population decline dynamics under more realistic conditions by simulating populations under different levels of environmental stochasticity and time-series data quality. Finally, we applied our newly developed method to 124 wildlife population time-series and investigated how those threat types diagnosed by our method compare to the specific threatening processes reported for those populations. We show how wildlife population decline curves can be used to discern between broad categories of pressure or threat types, but do not work for detailed threat attributions. More usefully, we find that differences in population decline curves can reliably identify populations where pressure is increasing over time, even when data quality is poor, and propose this method as a cost-effective technique for prioritizing conservation actions between populations.


Treating periodontitis-a systematic review and meta-analysis comparing ultrasonic and manual subgingival scaling at different probing pocket depths.
Mechanical plaque removal has been commonly accepted to be the basis for periodontal treatment. This study aims to compare the effectiveness of ultrasonic and manual subgingival scaling at different initial probing pocket depths (PPD) in periodontal treatment. English-language databases (PubMed, Cochrane Central Register of Controlled Trials, EMBASE, Medline, and ClinicalTrials.gov, by January, 2019) were searched. Weighted mean differences in primary outcomes, PPD and clinical attachment loss (CAL) reduction, were estimated by random effects model. Secondary outcomes, bleeding on probing (BOP), gingival recession (GR), and post-scaling residual dental calculus, were analyzed by comparing the results of each study. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. The GRADE approach was used to assess quality of evidence. Ten randomized controlled trials were included out of 1434 identified. Initial PPD and follow-up periods formed subgroups. For 3-months follow-up: (1) too few shallow initial pocket studies available to draw a conclusion; (2) the heterogeneity of medium depth studies was so high that could not be merged to draw a conclusion; (3) deep pocket studies showed no statistical differences in PPD and CAL reduction between ultrasonic and manual groups. For 6-months follow-up: (1) too few shallow initial PPD studies to draw a conclusion; (2) at medium pocket depth, PPD reduction showed manual subgingival scaling better than ultrasound. No statistical differences were observed in CAL reduction between the two approaches; (3) for deep initial PPD studies, both PPD and CAL reduction showed manual subgingival scaling better. GR results indicated no statistical differences at medium and deep initial pocket studies between the two methods. BOP results showed more reduction at deep pocket depths with manual subgingival scaling. No conclusion could be drawn about residual dental calculus. When initial PPD was 4-6 mm, PPD reduction proved manual subgingival scaling was superior, but CAL results showed no statistical differences between the two means. When initial PPD was ≥6 mm, PPD and CAL reductions suggested that manual subgingival scaling was superior.


Effects of bone marrow-derived mesenchymal stem cells on the axonal outgrowth through activation of PI3K/AKT signaling in primary cortical neurons followed oxygen-glucose deprivation injury.
Transplantation with bone marrow-derived mesenchymal stem cells (BMSCs) improves the survival of neurons and axonal outgrowth after stroke remains undetermined. Here, we investigated whether PI3K/AKT signaling pathway is involved in these therapeutic effects of BMSCs. (1) BMSCs and cortical neurons were derived from Sprague-Dawley rats. The injured neurons were induced by Oxygen-Glucose Deprivation (OGD), and then were respectively co-cultured for 48 hours with BMSCs at different densities (5×10(3), 5×10(5)/ml) in transwell co-culture system. The average length of axon and expression of GAP-43 were examined to assess the effect of BMSCs on axonal outgrowth after the damage of neurons induced by OGD. (2) The injured neurons were cultured with a conditioned medium (CM) of BMSCs cultured for 24 hours in neurobasal medium. During the process, we further identified whether PI3K/AKT signaling pathway is involved through the adjunction of LY294002 (a specific phosphatidylinositide-3-kinase (PI3K) inhibitor). Two hours later, the expression of pAKT (phosphorylated AKT) and AKT were analyzed by Western blotting. The length of axons, the expression of GAP-43 and the survival of neurons were measured at 48 hours. Both BMSCs and CM from BMSCs inreased the axonal length and GAP-43 expression in OGD-injured cortical neurons. There was no difference between the effects of BMSCs of 5×10(5)/ml and of 5×10(3)/ml on axonal outgrowth. Expression of pAKT enhanced significantly at 2 hours and the neuron survival increased at 48 hours after the injured neurons cultured with the CM, respectively. These effects of CM were prevented by inhibitor LY294002. BMSCs promote axonal outgrowth and the survival of neurons against the damage from OGD in vitro by the paracrine effects through PI3K/AKT signaling pathway.


Accurate prediction of histologically confirmed Alzheimer's disease and the differential diagnosis of dementia: the use of NINCDS-ADRDA and DSM-III-R criteria, SPECT, X-ray CT, and APO E4 medial temporal lobe dementias. The Oxford Project to Investigate Memory and Aging.
In a prospective study of more than 200 cases of dementia and 119 controls, annual technetium-99m-hexamethyl-propylene amineoxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) and annual medial temporal lobe (MTL) oriented X-ray computed tomography (CT) have been used to evaluate the diagnostic potential of functional and structural neuroimaging in the differential diagnosis of dementia. Some subjects have had up to 7 annual evaluations. So far, of 151 who have died, 143 (95%) have come to necropsy. Histology is known for 118, of whom 80 had Alzheimer's disease (AD), 24 had other "non-AD" dementias, and 14 controls with no cognitive deficit in life also had no significant central nervous system pathology. To compare the findings in the dementias with the profile of structural and functional imaging in the cognitively normal elderly, scan data from 105 living, elderly controls without cognitive deficit have also been included in the analysis. All clinical diagnoses were according to National Institute of Neurological and Communicable Disease and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-III-R) criteria, and all histopathological diagnoses according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Early data from this cohort have suggested that the combination of both MTL atrophy seen on CT with parietotemporal hypoperfusion on SPECT may predict the pathology of AD. The diagnostic sensitivity, specificity, accuracy, and positive and negative predictive values of the NINCDS-ADRDA and DSM-III-R criteria could be assessed in this cohort against the gold standard of histopathology. The diagnostic potential of CT evidence of MTL atrophy alone, SPECT evidence of parietotemporal hypoperfusion alone, and the combination of both of these scan changes in the same individual could then be compared against the diagnostic accuracy of clinical operational criteria in the pathologically confirmed cases. Furthermore, all of these modalities could be compared with the diagnostic accuracy of apolipoprotein E4 (Apo E4) genotyping to predict AD in the histopathologically confirmed cohort. In this population, NINCDS "probable-AD" was 100% specific, 49% sensitive, and 66% accurate; "possible-AD" was only 61% specific, but 93% sensitive and 77% accurate; and the combination of both "probable-AD" and "possible-AD" was 61% specific, 96% sensitive, and 85% accurate. DSM-III-R criteria were 51% sensitive, 97% specific, and 66% accurate. In the same cases and including the 105 living, elderly controls, the diagnostic accuracy of the Oxford Project to Investigate Memory and Aging (OPTIMA) scanning criteria showed CT alone to be 85% sensitive, 78% specific, and 80% accurate; SPECT alone had 89% sensitivity, 80% specificity, and 83% accuracy; and the combination of the two was 80% sensitive, 93% specific, and 88% accurate. The Apo E4 genotype was 74% sensitive but yielded 40% false positives in the histologically confirmed series. The diagnostic accuracy afforded by this method of CT and SPECT used alone is better than that of any established clinical criteria and reveals that the combination of MTL atrophy and parietotemporal hypoperfusion is common in AD, much less common in other dementias, and rare in normal controls. In the NINCDS-ADRDA criteria "possible-AD" cases, the combination of CT and SPECT findings alone were better in all diagnostic indices than the presence of Apo E4 alone in predicting AD. The frequent occurrence of MTL atrophy in AD and also in other "non-AD" dementias later in the course of the disease suggests the concept of medial temporal lobe dementia. This could explain some of the overlap of clinical profiles in the dementias, particularly as the dementia progresses, making clinical differential diagnosis difficult. In this context, the use of SPECT can significantly e


Identification of imaging selection patterns in acute ischemic stroke patients and the influence on treatment and clinical trial enrollment decision making.
For the STroke Imaging Research (STIR) and VISTA-Imaging Investigators The purpose of this study was to collect precise information on the typical imaging decisions given specific clinical acute stroke scenarios. Stroke centers worldwide were surveyed regarding typical imaging used to work up representative acute stroke patients, make treatment decisions, and willingness to enroll in clinical trials. STroke Imaging Research and Virtual International Stroke Trials Archive-Imaging circulated an online survey of clinical case vignettes through its website, the websites of national professional societies from multiple countries as well as through email distribution lists from STroke Imaging Research and participating societies. Survey responders were asked to select the typical imaging work-up for each clinical vignette presented. Actual images were not presented to the survey responders. Instead, the survey then displayed several types of imaging findings offered by the imaging strategy, and the responders selected the appropriate therapy and whether to enroll into a clinical trial considering time from onset, clinical presentation, and imaging findings. A follow-up survey focusing on 6 h from onset was conducted after the release of the positive endovascular trials. We received 548 responses from 35 countries including 282 individual centers; 78% of the centers originating from Australia, Brazil, France, Germany, Spain, United Kingdom, and United States. The specific onset windows presented influenced the type of imaging work-up selected more than the clinical scenario. Magnetic Resonance Imaging usage (27-28%) was substantial, in particular for wake-up stroke. Following the release of the positive trials, selection of perfusion imaging significantly increased for imaging strategy. Usage of vascular or perfusion imaging by Computed Tomography or Magnetic Resonance Imaging beyond just parenchymal imaging was the primary work-up (62-87%) across all clinical vignettes and time windows. Perfusion imaging with Computed Tomography or Magnetic Resonance Imaging was associated with increased probability of enrollment into clinical trials for 0-3 h. Following the release of the positive endovascular trials, selection of endovascular only treatment for 6 h increased across all clinical vignettes.


Environmental risk mapping of canine leishmaniasis in France.
Canine leishmaniasis (CanL) is a zoonotic disease caused by Leishmania infantum, a Trypanosomatid protozoan transmitted by phlebotomine sandflies. Leishmaniasis is endemic in southern France, but the influences of environmental and climatic factors on its maintenance and emergence remain poorly understood. From a retrospective database, including all the studies reporting prevalence or incidence of CanL in France between 1965 and 2007, we performed a spatial analysis in order to i) map the reported cases in France, and ii) produce an environment-based map of the areas at risk for CanL. We performed a Principal Component Analysis (PCA) followed by a Hierarchical Ascendant Classification (HAC) to assess if the locations of CanL could be grouped according to environmental variables related to climate, forest cover, and human and dog densities. For each group, the potential distribution of CanL in France was mapped using a species niche modelling approach (Maxent model). Results revealed the existence of two spatial groups of CanL cases. The first group is located in the Cévennes region (southern Massif Central), at altitudes of 200-1000 m above sea level, characterized by relatively low winter temperatures (1.9 degrees C average), 1042 mm average annual rainfall and much forest cover. The second group is located on the Mediterranean coastal plain, characterized by higher temperatures, lower rainfall and less forest cover. These two groups may correspond to the environments favoured by the two sandfly vectors in France, Phlebotomus ariasi and Phlebotomus perniciosus respectively. Our niche modelling of these two eco-epidemiological patterns was based on environmental variables and led to the first risk map for CanL in France. Results show how an ecological approach can help to improve our understanding of the spatial distribution of CanL in France.


Ultrafast imaging of terahertz Cherenkov waves and transition-like radiation in LiNbO₃.
We use ultrafast phase-contrast imaging to directly observethe cone-like terahertz (THz) Cherenkov wave generated by optical rectification of femtosecond laser pulses focused into bulk lithium niobate (LiNbO₃) single crystals. The transverse imaging geometry allows the Cherenkov angle, THz wave velocity, and optical pump pulse group velocity to be measured. Furthermore, transition-like THz radiation generated by the femtosecond laser pulse at the air-crystal boundary is observed. The effect of optical pump pulse polarization on the generation of THz Cherenkov waves and transition-like radiation in LiNbO₃ is also investigated.


The diet of Myotis lucifugus across Canada: assessing foraging quality and diet variability.
Variation in prey resources influences the diet and behaviour of predators. When prey become limiting, predators may travel farther to find preferred food or adjust to existing local resources. When predators are habitat limited, local resource abundance impacts foraging success. We analysed the diet of Myotis lucifugus (little brown bats) from Nova Scotia (eastern Canada) to the Northwest Territories (north-western Canada). This distribution includes extremes of season length and temperature and encompasses colonies on rural monoculture farms, and in urban and unmodified areas. We recognized nearly 600 distinct species of prey, of which ≈30% could be identified using reference sequence libraries. We found a higher than expected use of lepidopterans, which comprised a range of dietary richness from ≈35% early in the summer to ≈55% by late summer. Diptera were the second largest prey group consumed, representing ≈45% of dietary diversity early in the summer. We observed extreme local dietary variability and variation among seasons and years. Based on the species of insects that were consumed, we observed that two locations support prey species with extremely low pollution and acidification tolerances, suggesting that these are areas without environmental contamination. We conclude that there is significant local population variability in little brown bat diet that is likely driven by seasonal and geographical changes in insect diversity, and that this prey may be a good indicator of environment quality.


Demonstration of a schedule-dependent therapeutic synergism utilizing the interacting drugs methotrexate and teniposide in L1210 leukemia.
When three variables require simultaneous adjustment for treatment optimization, the experimental determination of the optimum treatment becomes more complicated than generally appreciated, especially when one variable is the interval between drug administrations. Molecular pharmacological studies at this institution suggest that teniposide, in doses that are achievable in vivo, blocks methotrexate efflux from cells, enhancing formation of methotrexate polyglutamates which are active retentive forms of the drug. Hence, the combination might show a synergistic effect if teniposide is given at an appropriate time in relation to administration of methotrexate. This paper considers the problem of estimating the optimal dose levels and timing of administration of these drugs in B6D2F1 mice bearing L1210 leukemia in vivo as a model for the analysis of multidrug regimens when time and dose are variables. Because of the complexity of these experiments, an adaptive approach was applied. Three cycles of treatment were given using methotrexate at 0-400 mg/kg, teniposide at 0-60 mg/kg, and an interval of 0-54 hours between the two drugs. The single drugs prolonged median survival up to 24 days under the conditions of these experiments. The combination given simultaneously resulted in median survival of up to 33.5 days, while use of an appropriate interval between drugs prolonged median survival to greater than 50 days. An analysis of the underlying dose-time response gives a much better appreciation of the relationships among the variables. The concept that optimal doses included less methotrexate and more teniposide as the interval between drugs is increased was developed only through modeling. This finding is critical in demonstrating the importance of including all nonnegligible variables in the experimental design if the results are to be considered valid. Confidence regions about the optimum dose and about the response at the optimum provide a sound basis for a claim of therapeutic synergism as demonstrated by use of a scheduling variable in the experiment design. A nonproportional hazards analysis permits the conclusion of nonproportionality and emphasizes the contribution of methotrexate to optimal short-term survival (15-24 days) and teniposide to long-term survival (24-39 days).


Intraocular tissue distribution of betamethasone after intrascleral administration using a non-biodegradable sustained drug delivery device.
To evaluate the tissue distribution of betamethasone (BM) after implantation of a nonbiodegradable intrascleral implant as a new, controlled intraocular delivery system. Nonbiodegradable intrascleral implants designed to release BM for at least 1 month were placed in the sclera of pigmented rabbits. The BM concentrations in the aqueous humor, vitreous, and retina-choroid were determined by high-performance liquid chromatography (HPLC) at 3, 7, 14, and 28 days after implantation. The BM concentrations in three sections of retina-choroid were also investigated. Retinal toxicity was evaluated by electroretinography and histology. The BM released from the intrascleral implant in vitro and in vivo showed zero-ordered release profiles for 4 weeks. The BM concentrations in the retina-choroid after placement of the intrascleral implants remained higher than effective concentrations for suppressing various inflammatory processes for at least 28 days. The BM concentrations in the retina-choroid around the implantation site were more than 10 times higher than in the opposite side throughout the study. No substantial toxic reactions were observed by electroretinography or histology. These findings suggested that the nonbiodegradable intrascleral implant could be a useful drug carrier for intraocular delivery of BM without producing severe retinal toxicity. The intrascleral site may be considered for effective intraocular drug distribution after implantation.


Patient and carer satisfaction with 'hospital at home': quantitative and qualitative results from a randomised controlled trial.
'Hospital At Home' schemes are set to increase in the United Kingdom (UK) in response to the NHS Plan. To date, little detailed work has been done on the acceptability of these schemes to patients and their carers. To compare Hospital at Home patient and carer satisfaction with hospital care. Pragmatic randomised controlled trial. Consecutive patients assessed as suitablefor the Leicester Hospital at Home scheme were randomised to Hospital at Home or one of three acute hospitals in the city. Patient satisfaction was assessed two weeks after randomisation, or at discharge if later using a six-item questionnaire. Patients' and carers' views of the services were assessed by semistructured interviews. One hundred and two patients were randomised to Hospital at Home and 97 to hospital. Forty-eight (47%) patients in the Hospital at Home arm and 35 (36%) in the hospital arm completed the satisfaction questionnaire, representing 96% and 85% of those eligible, respectively. Total scores were significantly higher in the Hospital at Home (median = 15) than in the hospital group (median = 12). (P<0.001, Mann-Whitney U-test.) Responses to all six questions favoured Hospital at Home, with all but one of these differences being statistically significant. In the Hospital at Homegroup, 24 patients and 18 of their carers were interviewed; in the hospital group 18 patients and seven of their carers were interviewed. Themes emerging from these interviews were that patients appreciated the more personal care and better communication offered by Hospital at Home and placed great value on staying at home, which was seen to be therapeutic. Patients largely felt safe in Hospital at Home, although some would have felt safer in hospital. Some patients and carers felt that better medical care would have been provided in hospital. Carers felt that the workload imposed by Hospital at Home was no greater than by hospital admission and that the relief from care duties at home would be counterbalanced by the added strain of hospital visiting. Patient satisfaction was greater with Hospital at Home than with hospital. Reasons included a more personal style of care and a feeling that staying at home was therapeutic. Carers did not feel that Hospital at Home imposed an extra workload.


Determination of the surface properties of kaolinite by inverse gas chromatography.
Inverse gas chromatography (IGC) was applied to characterize the surface of kaolinite. The adsorption thermodynamic parameters (the standard enthalpy (∆H0), entropy (∆S0) and free energy of adsorption (∆G0), the dispersive component of the surface energy (γsd), and the acid/base character of kaolinite surface were estimated by using the retention time of different non-polar and polar probes at infinite dilution region. The specific free energy of adsorption (∆Gsp), the specific enthalpy of adsorption (∆Hsp), and the specific entropy of adsorption (∆Ssp) of polar probes on kaolinite were determined. (∆Gsp) values were correlated with the donor and modified acceptor numbers of the probes to quantify the acidic (KA) and the basic (KD) parameters of the kaolinite surface. The values obtained for the parameters KA and KD indicated a basic character for kaolinite surface.


Dose-response tests and semi-field evaluation of lethal and sub-lethal effects of slow release pyriproxyfen granules (Sumilarv®0.5G) for the control of the malaria vectors Anopheles gambiae sensu lato.
Recently research has shown that larviciding can be an effective tool for integrated malaria vector control. Nevertheless, the uptake of this intervention has been hampered by the need to re-apply larvicides frequently. There is a need to explore persistent, environmentally friendly larvicides for malaria vector control to reduce intervention efforts and costs by reducing the frequency of application. In this study, the efficacy of a 0.5% pyriproxyfen granule (Surmilarv®0.5G, Sumitomo Chemicals) was assessed for the control of Anopheles gambiae sensu stricto and Anopheles arabiensis, the major malaria vectors in sub-Saharan Africa. Dose-response and standardized field tests were implemented following standard procedures of the World Health Organization's Pesticide Evaluation Scheme to determine: (i) the susceptibility of vectors to this formulation; (ii) the residual activity and appropriate retreatment schedule for field application; and, (iii) sub-lethal impacts on the number and viability of eggs laid by adults after exposure to Sumilarv®0.5G during larval development. Anopheles gambiae s.s. and An. arabiensis were highly susceptible to Sumilarv®0.5G. Estimated emergence inhibition (EI) values were very low and similar for both species. The minimum dosage that completely inhibited adult emergence was between 0.01-0.03 parts per million (ppm) active ingredient (ai). Compared to the untreated control, an application of 0.018 ppm ai prevented 85% (95% confidence interval (CI) 82%-88%) of adult emergence over six weeks under standardized field conditions. A fivefold increase in dosage of 0.09 ppm ai prevented 97% (95% CI 94%-98%) emergence. Significant sub-lethal effects were observed in the standardized field tests. Female An. gambiae s.s. that were exposed to 0.018 ppm ai as larvae laid 47% less eggs, and females exposed to 0.09 ppm ai laid 74% less eggs than females that were unexposed to the treatment. Furthermore, 77% of eggs laid by females exposed to 0.018 ppm ai failed to hatch, whilst 98% of eggs laid by females exposed to 0.09 ppm ai did not hatch. Anopheles gambiae s.s. and An. arabiensis are highly susceptible to Sumilarv®0.5G at very low dosages. The persistence of this granule formulation in treated habitats under standardized field conditions and its sub-lethal impact, reducing the number of viable eggs from adults emerging from treated ponds, enhances its potential as malaria vector control tool. These unique properties warrant further field testing to determine its suitability for inclusion in malaria vector control programmes.


Thirty-day readmission and reoperation rates after single-level anterior cervical discectomy and fusion versus those after cervical disc replacement.
OBJECTIVE The goal of this study was to compare 30-day readmission and reoperation rates after single-level anterior cervical discectomy and fusion (ACDF) versus those after cervical disc replacement (CDR). METHODS The authors used the 2013-2014 American College of Surgeons National Surgical Quality Improvement Program database. Included were adult patients who underwent first-time single-level ACDF or CDR for cervical spondylosis or disc herniation. Primary outcome measures were readmission and/or reoperation within 30 days of the original surgery. Logistic regression analysis was used to assess the independent effect of the procedure (ACDF or CDR) on outcome, and results are presented as odds ratios with 95% confidence intervals. RESULTS A total of 6077 patients met the inclusion criteria; 5590 (92.0%) patients underwent single-level ACDF, and 487 (8.0%) patients underwent CDR. The readmission rates were 2.6% for ACDF and 0.4% for CDR (p = 0.003). When stratified according to age groups, only patients between the ages of 41 and 60 years who underwent ACDF had a significantly higher readmission rate than those who underwent CDR (2.5% vs 0.7%, respectively; p = 0.028). After controlling for patient age, sex, body mass index, smoking status, history of chronic obstructive pulmonary disease (COPD), diabetes, hypertension, steroid use, and American Society of Anesthesiologists (ASA) class, patients who underwent CDR were significantly less likely to undergo readmission within 30 days than patients who underwent ACDF (OR 0.23 [95% CI 0.06-0.95]; p = 0.041). Patients with a history of COPD (OR 1.97 [95% CI 1.08-3.57]; p = 0.026) or hypertension (OR 1.62 [95% CI 1.10-2.38]; p = 0.013) and those at ASA Class IV (OR 14.6 [95% CI 1.69-125.75]; p = 0.015) were significantly more likely to require readmission within 30 days. The reoperation rates were 1.2% for ACDF and 0.4% for CDR (p = 0.086), and multivariate analysis revealed that CDR was not associated with lower odds of reoperation (OR 0.60 [95% CI 0.14-2.55]; p = 0.492). However, increasing age was associated with a higher risk (OR 1.02 [95% CI 1.00-1.05]; p = 0.031) of reoperation; a 2% increase in risk per year of age was found. CONCLUSIONS Patients who underwent single-level ACDF had a higher readmission rate than those who underwent single-level CDR in this study. When stratified according to age, this effect was seen only in the 41- to 60-year age group. No significant difference in the 30-day single-level ACDF and single-level CDR reoperation rates was found. Although patients in the ACDF group were older and sicker, other unmeasured covariates might have accounted for the increased rate of readmission in this group, and further investigation is encouraged.


Electrically tunable two-dimensional liquid crystals gratings induced by polarization holography.
Two-dimensional (2D) gratings made up of an array of differently twisted nematic structures are obtained by crossed assembling of 1D polarization holograms recorded at the photoaligning substrates. The rotating linear polarization pattern, produced by the interference of two opposite circularly polarized beams, is recorded on the azo-dye doped polyimide aligning layers. The 2D gratings diffract light in different directions with different polarization states, that can be optically controlled. Orthogonal circularly and linearly polarized diffraction orders are simultaneously obtained irradiating the grating with a linearly polarized beam. An external ac voltage allows to completely control the diffracted energy distribution.


Clinical Spectrum and Genetic Diagnosis of 54 Consecutive Patients Aged 0-25 with Bilateral Cataracts.
Childhood cataract affects 2.5-3.5 per 10,000 children in the UK, with a genetic mutation identified in 50-90% of bilateral cases. However, cataracts can also manifest in adolescence and early adulthood in isolation, as part of a complex ocular phenotype or with systemic features making accurate diagnosis more challenging. We investigate our real-world experience through a retrospective review of consecutive bilateral cataract patients (0-25 years) presenting to the ocular genetics service at Moorfields Eye Hospital between 2017 and 2020. Fifty-four patients from 44 unrelated families were identified, with a median age of 13.5 years (range 1 to 68 years) and a median age at diagnosis of 43.9 months IQR (1.7-140.3 months); 40.7% were female and 46.3% were Caucasian. Overall, 37 patients from 27 families (61.4%) were genetically solved (50%) or likely solved (additional 11.4%), with 26 disease-causing variants (8 were novel) in 21 genes; the most common were crystallin genes, in 8 (29.6%) families, with half occurring in the CRYBB2 gene. There was no significant difference in the molecular diagnostic rates between sporadic and familial inheritance (P = 0.287). Associated clinical diagnoses were retinal dystrophies in five (18.5%) and aniridia in three (11.1%) families. Bilateral cataracts were the presenting feature in 27.3% (6/22) of either complex or syndromic cases, and isolated cataract patients were 11.5 years younger (rank-sum Z = 3.668, P = 0.0002). Prompt genetic investigation with comprehensive panel testing can aid with diagnosis and optimise management of cataract patients.


The fluctuant nature of precipitating antibodies in dairy farmers.
Four hundred and forty five of 888 dairy farmers studied in an epidemiological survey four years previously were restudied to determine change in precipitins and in clinical features. Subjects answered the same questionnaire, which was filled in by the same nurse in the same winter months, and had blood withdrawn for precipitin analysis (double diffusion technique). Of the 445 subjects retested, 48 (10.8%) had been precipitin positive at the first study; of these, 34 remained positive four years later and 14 had reverted to negative. Twenty eight subjects previously negative for precipitins had become positive, so that 62 subjects in all were precipitin positive when restudied (13.9%). Of the 445 farmers, 369 were precipitin negative at both studies. The prevalence of symptoms, including cough, sputum production, wheezing, dyspnoea, and fever and chills, was similar for subjects who were consistently negative for precipitins and consistently positive and for those who changed from one to the other. Only one subject developed farmer's lung; he had precipitins in both studies. This study shows a fluctuation in the precipitin state of dairy farmers, suggesting that more farmers have precipitins at least once in their lifetime than are identified by screening at a single point in time. Relatively few develop farmer's lung or other respiratory symptoms. The presence of precipitins in a symptomless farmer appears to have no clinical importance.


Early relationships and paranoia: Qualitative investigation of childhood experiences associated with the development of persecutory delusions.
Research suggests a link between Persecutory Delusions (PDs) and early interpersonal difficulties. However, little research has explored the first-hand experience of navigating such adversities in those who later developed PDs. The current study reports on a qualitative investigation of the early interpersonal experiences and challenges faced by a sample of individuals who have recovered from PDs, using a semi-structured interview. A sample of seven individuals who have previously experienced PDs were recruited from two National Health Services (NHS) and an Early Intervention Psychosis service in England. Using an Interpretative Phenomenological Analytic (IPA) approach, the analysis identified three main themes (early experiences, impact of early experiences, coping with adversity). Early experiences captured early inconsistent and problematic relationships in childhood, and experiences of victimization. Exploring the impact of these early events revealed important roles for the participants' inconsistent sense of self, their negative perception of others, and their disturbed social functioning and substance use. Coping with adversity revealed distinct forms of avoidant and proactive coping. The findings are consistent with models of PDs that emphasise the impact of early interpersonal experiences, and offer support for attachment and cognitive factors.


Monitoring clinical research: an obligation unfulfilled.
The revelation that data obtained for the US-based National Surgical Adjuvant Breast and Bowel Project (NSABP) from subjects enrolled at Hôpital Saint-Luc in Montreal was falsified has eroded public trust in research. Institutions can educate researchers and help prevent unethical research practices by establishing procedures to monitor research involving human subjects. Research monitoring encompasses four categories of activity: annual reviews of continuing research, monitoring of informed consent, monitoring of adherence to approved protocols and monitoring of the integrity of data. The authors describe characteristics of research projects that may call for monitoring procedures in each category. The form taken by such monitoring depends on the nature of the protocol. Although appropriate research monitoring requires substantial investment of personnel and financial resources, it is required under guidelines regulating research involving human subjects in Canada. Research monitoring is a step forward in re-establishing public confidence in medical research.


Skill improvement among coalition members in the California Healthy Cities and Communities Program.
Community-driven, collaborative approaches to health promotion have the potential to enhance skills among community members and, in turn, increase community capacity. This study uses data from an evaluation of the California Healthy Cities and Communities (CHCC) Program to examine whether, and how, community problem-solving and collaboration skills are improved among coalition members and local coordinators in 20 participating communities. Methods include semi-structured interviews with coordinators and mailed surveys with coalition members (n=330 in planning phase and n=243 in implementation phase). The largest number of coordinators reported skill improvement in defining health broadly and assessing needs and assets. Similarly, coalition members reported greatest skill improvement for defining health broadly, assessing needs and assets and setting priorities and developing action plans. Modest correlations were observed between number of roles played in the local healthy cities and communities project and each skill area assessed. Time committed to the local CHCC coalition and its activities was not meaningfully correlated with any of the skills. Types of skill-building opportunities may be more important than number of hours devoted to meetings and activities in strengthening community problem-solving and collaboration skills among coalition members.


A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator.
A protein module called the WW domain recognizes and binds to a short oligopeptide called the PY motif, PPxY, to mediate protein-protein interactions. The PY motif is present in the transcription activation domains of a wide range of transcription factors including c-Jun, AP-2, NF-E2, C/EBPalpha and PEBP2/CBF, suggesting that it plays an important role in transcriptional activation. We show here that mutation of the PY motif in the subregion of the activation domain of the DNA-binding subunit of PEBP2, PEBP2alpha, abolishes its transactivation function. Using yeast two-hybrid screening, we demonstrate that Yes-associated protein (YAP) binds to the PY motif of PEBP2alpha through its WW domain. The C-terminal region of YAP fused to the DNA-binding domain of GAL4 showed transactivation as strong as that of GAL4-VP16. Exogenously expressed YAP conferred transcription-stimulating activity on the PY motif fused to the GAL4 DNA-binding domain as well as to native PEBP2alpha. The osteocalcin promoter was stimulated by exogenous PEBP2alphaA and a dominant negative form of YAP strongly inhibited this activity, suggesting YAP involvement in this promoter activity in vivo. These results indicate that the PY motif is a novel transcription activation domain that functions by recruiting YAP as a strong transcription activator to target genes.


Primary hyperparathyroidism mimicking vaso-occlusive crises in sickle cell disease.
We report a case of bone pain associated with primary hyperparathyroidism in a patient with sickle cell disease. A 17-year-old girl with sickle cell disease (SS phenotype) was seen for bilateral knee and back pain. She had had recurrent severe vaso-occlusive crises and acute chest syndrome in the course of her disease. In the last 2 years, she had frequent visits to the emergency department for severe bone pain. She complained of long-standing fatigue and lethargy. Her physical examination was normal. Hydroxyurea treatment, as well as and long- and short-acting narcotics were given, with little improvement in symptoms. Poor compliance with medication, family dysfunction, and potential narcotic addiction were felt to be significant contributors to the patient's symptoms. She was incidentally found to have an extremely elevated total calcium level of 3.19 mmol/L (range: 2.25-2.76) with an ionized calcium level of 1.9 mmol/L (range: 1.15-1.35). Phosphorus level was 0.82 mmol/L (range: 0.90-1.50), alkaline phosphatase level was elevated at 519 U/L (range: 10-170), and parathyroid hormone level was extremely high at 1645 pg/mL (range: 10-60). Her renal function was normal. Ultrasonography of the neck and a Sestamibi scan revealed a single left inferior parathyroid adenoma adjacent to the thyroid lobe. There was no evidence of an underlying multiple endocrine neoplasia. The patient was diagnosed with primary hyperparathyroidism. Fluid hydration, hydrocortisone, calcitonin, and bisphosphonates were initiated for acute hypercalcemia management before surgical excision of the left parathyroid adenoma. On review of previous blood work, a borderline calcium level of 2.72 was present 18 months before this admission. Two years postsurgery, she has normal renal function, calcium, and parathyroid hormone levels. The weekly visits to the emergency department for pain episodes decreased to 1 every 2 months within the first few months after her surgery. The decrease in pain episodes, even if it coincided with the treatment of primary hyperparathyroidism, may still reflect the natural evolution of sickle cell disease in this patient. However, the high morbidity associated with primary hyperparathyroidism was successfully prevented in this patient. Primary hyperparathyroidism is rare in childhood. In a recent study, it occurred more commonly in female adolescents and was because of a single adenoma, as in our patient. Significant morbidity, mainly secondary to renal dysfunction, was because of the delay in diagnosis after the onset of symptoms (2.0-4.2 years), emphasizing the need for a rapid diagnosis. Sickle cell disease affects approximately 1 of every 600 blacks in North America. Acute episodes of severe vaso-occlusive crisis account for > 90% of sickle cell-related hospitalizations and are a significant cause of morbidity in patients. There is no known association between sickle cell disease and primary hyperparathyroidism, and this case is most probably a random occurrence. However, as emphasized by this case report, pain may also be a harbinger of other disease processes in sickle cell disease. Because management may vary, we suggest that care providers consider the diagnosis of vaso-occlusive crisis as the diagnosis of exclusion and that other etiologies for pain be envisaged in this patient population, especially in the presence of prolonged pain or unusual clinical, radiologic, or biological findings.


A low technology emanator treated with the volatile pyrethroid transfluthrin confers long term protection against outdoor biting vectors of lymphatic filariasis, arboviruses and malaria.
The vapor phase of the volatile pyrethroid transfluthrin incapacitates mosquitoes and prevents them from feeding. Although existing emanator products for delivering volatile pyrethroids protect against outdoor mosquito bites, they are too short-lived to be practical or affordable for routine use in low-income settings. New transfluthrin emanators, comprised simply of treated hessian fabric strips, have recently proven highly protective against outdoor-biting vectors of lymphatic filariasis, arboviruses and malaria, but their full protective lifespan, minimum dose requirements, and range of protection have not previously been assessed. The effects of transfluthrin-treated hessian strips upon mosquito biting exposure of users and nearby non-users, as well as dependence of protection upon treatment dose, were measured outdoors in rural Tanzania using human landing catches (HLC). Strips treated with 10ml of transfluthrin prevented at least three quarters (p < 0.001) of outdoor bites by Anopheles arabiensis, Culex spp. and Mansonia spp. mosquitoes, and >90% protection against bites on warmer nights with higher evaporation rates, for at least one year. Strips treated with this high dose also reduced biting exposure of non-users at a distance of up to 5m from the strips for An. arabiensis (p < 0.001) and up to 2m for Mansonia spp. (p = 0.008), but provided no protection to non-users against Culex spp. No evidence of increased risk for non-users, caused by diversion of mosquitoes to unprotected individuals, was found at any distance within an 80m radius. A dose of only 1ml provided equivalent protection to the 10ml dose against An. arabiensis, Culex spp. and Mansonia spp. mosquitoes over 6 months (p < 0.001). Transfluthrin-treated hessian emanators provide safe, affordable, long-term protection against several different pathogen-transmitting mosquito taxa that attack humans outdoors, where they are usually active and cannot be protected by bed nets or residual sprays with conventional, solid-phase insecticides.


Common chronic conditions do not affect performance of cell cycle arrest biomarkers for risk stratification of acute kidney injury.
Identification of acute kidney injury (AKI) can be challenging in patients with underlying chronic disease, and biomarkers often perform poorly in this population. In this study we examined the performance characteristics of the novel biomarker panel of urinary tissue inhibitor of metalloproteinases-2 (TIMP2) and insulin-like growth factor-binding protein 7 ([IGFBP7]) in patients with a variety of comorbid conditions. We analyzed data from two multicenter studies of critically ill patients in which [TIMP2]•[IGFBP7] was validated for prediction of Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2 or 3 AKI within 12 h. We constructed receiver operating characteristic (ROC) curves for AKI prediction both overall and by comorbid conditions common among patients with AKI, including diabetes mellitus, congestive heart failure (CHF) and chronic kidney disease (CKD). In the overall cohort of 1131 patients, 139 (12.3%) developed KDIGO Stage 2 or 3 AKI. [TIMP2]•[IGFBP7] was significantly higher in AKI versus non-AKI patients, both overall and within each comorbidity subgroup. The AUC for [TIMP2]•[IGFBP7] in predicting AKI was 0.81 overall. Higher AUC was noted in patients with versus without CHF (0.89 versus 0.79; P = 0.026) and CKD (0.91 versus 0.80; P = 0.024). We observed no significant impairment in the performance of cell cycle arrest biomarkers due to the presence of chronic comorbid conditions.


Impact of environmental factors and biological soil crust types on soil respiration in a desert ecosystem.
The responses of soil respiration to environmental conditions have been studied extensively in various ecosystems. However, little is known about the impacts of temperature and moisture on soils respiration under biological soil crusts. In this study, CO2 efflux from biologically-crusted soils was measured continuously with an automated chamber system in Ningxia, northwest China, from June to October 2012. The highest soil respiration was observed in lichen-crusted soil (0.93 ± 0.43 µmol m-2 s-1) and the lowest values in algae-crusted soil (0.73 ± 0.31 µmol m-2 s-1). Over the diurnal scale, soil respiration was highest in the morning whereas soil temperature was highest in the midday, which resulted in diurnal hysteresis between the two variables. In addition, the lag time between soil respiration and soil temperature was negatively correlated with the soil volumetric water content and was reduced as soil water content increased. Over the seasonal scale, daily mean nighttime soil respiration was positively correlated with soil temperature when moisture exceeded 0.075 and 0.085 m3 m-3 in lichen- and moss-crusted soil, respectively. However, moisture did not affect on soil respiration in algae-crusted soil during the study period. Daily mean nighttime soil respiration normalized by soil temperature increased with water content in lichen- and moss-crusted soil. Our results indicated that different types of biological soil crusts could affect response of soil respiration to environmental factors. There is a need to consider the spatial distribution of different types of biological soil crusts and their relative contributions to the total C budgets at the ecosystem or landscape level.


An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology.
Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.


Multimodal similarity and categorization of novel, three-dimensional objects.
Similarity has been proposed as a fundamental principle underlying mental object representations and capable of supporting cognitive-level tasks such as categorization. However, much of the research has considered connections between similarity and categorization for tasks performed using a single perceptual modality. Considering similarity and categorization within a multimodal context opens up a number of important questions: Are the similarities between objects the same when they are perceived using different modalities or using more than one modality at a time? Is similarity still able to explain categorization performance when objects are experienced multimodally? In this study, we addressed these questions by having subjects explore novel, 3D objects which varied parametrically in shape and texture using vision alone, touch alone, or touch and vision together. Subjects then performed a pair-wise similarity rating task and a free sorting categorization task. Multidimensional scaling (MDS) analysis of similarity data revealed that a single underlying perceptual map whose dimensions corresponded to shape and texture could explain visual, haptic, and bimodal similarity ratings. However, the relative dimension weights varied according to modality: shape dominated texture when objects were seen, whereas shape and texture were roughly equally important in the haptic and bimodal conditions. Some evidence was found for a multimodal connection between similarity and categorization: the probability of category membership increased with similarity while the probability of a category boundary being placed between two stimuli decreased with similarity. In addition, dimension weights varied according to modality in the same way for both tasks. The study also demonstrates the usefulness of 3D printing technology and MDS techniques in the study of visuohaptic object processing.


Shared neural markers of decision confidence and error detection.
Empirical evidence indicates that people can provide accurate evaluations of their own thoughts and actions by means of both error detection and confidence judgments. This study investigates the foundations of these metacognitive abilities, specifically focusing on the relationship between confidence and error judgments in human perceptual decision making. Electroencephalography studies have identified the error positivity (Pe)--an event-related component observed following incorrect choices--as a robust neural index of participants' awareness of their errors in simple decision tasks. Here we assessed whether the Pe also varies in a graded way with participants' subjective ratings of decision confidence, as expressed on a 6-point scale after each trial of a dot count perceptual decision task. We observed clear, graded modulation of the Pe by confidence, with monotonic reduction in Pe amplitude associated with increasing confidence in the preceding choice. This effect was independent of objective accuracy. Multivariate decoding analyses indicated that neural markers of error detection were predictive of varying levels of confidence in correct decisions, including subtle shifts in high-confidence trials. These results suggest that shared mechanisms underlie two forms of metacognitive evaluation that are often treated separately, with consequent implications for current theories of their neurocognitive basis.


Social Organization in Parasitic Flatworms--Four Additional Echinostomoid Trematodes Have a Soldier Caste and One Does Not.
Complex societies where individuals exhibit division of labor with physical polymorphism, behavioral specialization, and caste formation have evolved several times throughout the animal kingdom. Recently, such complex sociality has been recognized in digenean trematodes; evidence is limited to 6 marine species. Hence, the extent to which a soldier caste is present throughout the Trematoda is sparsely documented, and there are no studies detailing the structure of a species lacking such a social structure. Here we examine colony structure for an additional 5 echinostomoid species, 4 of which infect the marine snail Cerithidea californica and 1 (Echinostoma liei) that infects the freshwater snail Biomphalaria glabrata . For all species, we present redia morphology (pharynx and body size) and the distribution of individuals of different castes throughout the snail body. When morphological evidence indicated the presence of a soldier caste, we assessed behavior by measuring attack rates of the different morphs toward heterospecific trematodes. Our findings indicate that each of the 4 species from C. californica have a permanent soldier caste while E. liei does not. The observed intra- and inter-specific variation of caste structure for those species with soldiers, and the documentation of colony structure for a species explicitly lacking permanent soldiers, emphasizes the diverse nature of trematode sociality and the promise of the group to permit comparative investigations of the evolution and ecology of sociality.


Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy?
Multiple sclerosis afflicts more than 1 million individuals worldwide and is widely considered to be an autoimmune disease. Traditionally, CD4(+) T helper cells have almost exclusively been held responsible for its immunopathogenesis, partly because certain MHC class II alleles clearly predispose for developing multiple sclerosis and also, because of their importance in inducing experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. However, several strategies that target CD4(+) T cells beneficially in EAE have failed to ameliorate disease activity in multiple sclerosis, and some have even triggered exacerbations. Recently, the potential importance of CD8(+) T cells has begun to emerge. Physiologically, CD8(+) T cells are essential for detecting and eliminating abnormal cells, whether infected or neoplastic. In multiple sclerosis, genetic associations with MHC class I alleles have now been established, and CD8(+) as well as CD4(+) T cells have been found to invade and clonally expand in inflammatory central nervous system plaques. Recent animal models induced by CD8(+) T cells show interesting similarities to multiple sclerosis, in particular, in lesion distribution (more inflammation in the brain relative to the spinal cord), although not all of the features of the human disease are recapitulated. Here we outline the arguments for a possible role for CD8(+) T cells, a lymphocyte subset that has long been underrated in multiple sclerosis and should now be considered in new therapeutic approaches.


TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice.
Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2h post-injury administration of R-7050 significantly reduced blood-brain barrier opening and attenuated edema development at 24h post-ICH. Neurological outcomes were also improved over the first 3 days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.


Brain glucose sensing and neural regulation of insulin and glucagon secretion.
Glucose homeostasis requires the tight regulation of glucose utilization by liver, muscle and white or brown fat, and glucose production and release in the blood by liver. The major goal of maintaining glycemia at ∼ 5 mM is to ensure a sufficient flux of glucose to the brain, which depends mostly on this nutrient as a source of metabolic energy. This homeostatic process is controlled by hormones, mainly glucagon and insulin, and by autonomic nervous activities that control the metabolic state of liver, muscle and fat tissue but also the secretory activity of the endocrine pancreas. Activation or inhibition of the sympathetic or parasympathetic branches of the autonomic nervous systems are controlled by glucose-excited or glucose-inhibited neurons located at different anatomical sites, mainly in the brainstem and the hypothalamus. Activation of these neurons by hyper- or hypoglycemia represents a critical aspect of the control of glucose homeostasis, and loss of glucose sensing by these cells as well as by pancreatic β-cells is a hallmark of type 2 diabetes. In this article, aspects of the brain-endocrine pancreas axis are reviewed, highlighting the importance of central glucose sensing in the control of counterregulation to hypoglycemia but also mentioning the role of the neural control in β-cell mass and function. Overall, the conclusions of these studies is that impaired glucose homeostasis, such as associated with type 2 diabetes, but also defective counterregulation to hypoglycemia, may be caused by initial defects in glucose sensing.


The Role of Oxygen in Avascular Tumor Growth.
The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.


Nuclease delivery: versatile functions of SLX4/FANCP in genome maintenance.
As a scaffold, SLX4/FANCP interacts with multiple proteins involved in genome integrity. Although not having recognizable catalytic domains, SLX4 participates in diverse genome maintenance pathways by delivering nucleases where they are needed, and promoting their cooperative execution to prevent genomic instabilities. Physiological importance of SLX4 is emphasized by the identification of causative mutations of SLX4 genes in patients diagnosed with Fanconi anemia (FA), a rare recessive genetic disorder characterized by genomic instability and predisposition to cancers. Recent progress in understanding functional roles of SLX4 has greatly expanded our knowledge in the repair of DNA interstrand crosslinks (ICLs), Holliday junction (HJ) resolution, telomere homeostasis and regulation of DNA damage response induced by replication stress. Here, these diverse functions of SLX4 are reviewed in detail.


The Nuclear Pore Complex and mRNA Export in Cancer.
Export of mRNAs from the nucleus to the cytoplasm is a key regulatory step in the expression of proteins. mRNAs are transported through the nuclear pore complex (NPC). Export of mRNAs responds to a variety of cellular stimuli and stresses. Revelations of the specific effects elicited by NPC components and associated co-factors provides a molecular basis for the export of selected RNAs, independent of bulk mRNA export. Aberrant RNA export has been observed in primary human cancer specimens. These cargo RNAs encode factors involved in nearly all facets of malignancy. Indeed, the NPC components involved in RNA export as well as the RNA export machinery can be found to be dysregulated, mutated, or impacted by chromosomal translocations in cancer. The basic mechanisms associated with RNA export with relation to export machinery and relevant NPC components are described. Therapeutic strategies targeting this machinery in clinical trials is also discussed. These findings firmly position RNA export as a targetable feature of cancer along with transcription and translation.


Visual outcome following cataract surgery in rural punjab.
In a cluster sample survey in rural areas of Punjab visual outcome after cataract surgery was assessed. Three hundred patients (428 cataract operated eyes) were included in the study from 24 sampled villages. The mean age at cataract extraction was 61.70 +/- 9.82 years. The average interval since the cataract surgery was 7.05 +/- 5.86 years (range 0.11-32 years). Of the 428 operated eyes, 72 (16.82%) were blind (VA < 3/60), 162 (37.85%) had low visual acuity (VA 3/60-< 6/18) and 194 (45.33%) eyes gained good visual acuity (VA > or = 6/18). Cataract surgery related complications were the principal causes leading to blindness in 50 of 72 eyes; these included corneal oedema, (17/72;23.3%), retinal detachment (14/72;19.4%), and aphakic glaucoma (13/72;18.05%). This study emphasizes the need to improve the qualitative aspect of cataract surgery including long-term follow up in rural India.


Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site.
We have determined the sequence of chicken talin (2,541 amino acids, M(r) 271,881) which is very similar (89% identity) to that of the mouse protein. Alignments with the Caenorhabditis elegans and Dictyostelium discoideum talin sequences show that the N- and C-terminal regions of the protein are conserved whereas the central part of the molecule is more divergent. By expressing overlapping talin polypeptides as fusion proteins, we have identified at least three regions of the protein which can bind F-actin: residues 102-497, 951-1,327 and 2,269-2,541. The N-terminal binding site contains a region with homology to the ERM family of actin-binding proteins, and the C-terminal site is homologous to the yeast actin-binding protein Sla2p. Each of the actin-binding sites is close to, but distinct from a binding site for vinculin, a protein which also binds actin. The Pro1176 to Thr substitution found in talin from Wistar-Furth rats does not destroy the capacity of this region of the protein to bind actin or vinculin. Microinjection studies showed that a fusion protein containing the N-terminal actin-binding site localised weakly to stress fibres, whereas one containing the C-terminal site initially localised predominantly to focal adhesions. The former was readily solubilised, and the latter was resistant to Triton extraction. The N-terminal talin polypeptide eventually disrupted actin stress fibres whereas the C-terminal polypeptide was without effect. However, a larger C-terminal fusion protein also containing a vinculin-binding site did disrupt stress fibres and focal adhesions. The results suggest that, although both the N- and C-terminal regions of talin bind actin, the properties of these two regions of the protein are distinct.


Boron triel bonding: a weak electrostatic interaction lacking electron-density descriptors.
In an effort to describe π-hole interactions, we undertook accurate high-resolution X-ray diffraction analyses of single crystals of 1,4-dinitrobenzene, a co-crystal of cis-tartaric acid and bis-pyridine N-oxide and the hydrochloride of B-4-pyridinylboronic acid. We selected these three compounds owing to the π-hole accessibility features that the sp2 hybridized B, C and N atoms provide, thus allowing us to compare the fundamental characteristics of π-hole interactions using Bader's Atom in Molecules (AIM) theory. This particular study required extremely accurate experimental diffraction data, because the interaction of interest is weak. As shown by the experimental charge density maps of the -YO2 (Y = B, C, N) units, we assign the depletion of electron-density present in the central boron, carbon and nitrogen atoms (electrophilic π-holes) as the main origin for the establishment of intermolecular Lewis acid-Lewis base attractive interaction with complementary electron-rich regions. Unexpectedly, the Bader's analyses of both experimentally and theoretically calculated charge distribution maps for the solid involving the - BO2H2 group do not show the presence of bond paths, neither of the bond critical points, between the interacting electron rich sites and the boron or carbon atoms featuring the electron hole. In contrast, these topological descriptors of chemical interactions for the AIM theory were easily located in the solid-state structures of the compounds involving the carboxylic and the nitro groups.


An optical trap combined with three-color FRET.
We developed a hybrid technique combining optical tweezers and single-molecule three-color fluorescence resonance energy transfer (FRET). In demonstrative experiments, we observed the force-sensitive correlated motion of three helical arms of a Holliday junction and identified the independent unfolding/folding dynamics of two DNA hairpins of the same length. With 3 times the number of observable elements of single-molecule FRET, this new instrument will enable the measurement of the complex, multidimensional effects of mechanical forces in various biomolecular systems, such as RNA and proteins.


Clusterin promotes corneal epithelial cell growth through upregulation of hepatocyte growth factor by mesenchymal cells in vitro.
Although the cornea expresses high levels of clusterin (CLU), the role of CLU in the cornea is poorly understood. This study was performed to investigate the possible role of CLU in corneal epithelial homeostasis. CLU was overexpressed in 3T3 cells by transfection of a vector encoding full-length CLU (Clu-3T3). Colony-forming efficacy (CFE) was compared in mouse corneal cell line (TKE2) and human primary corneal/limbal epithelial cells that were cocultured with Clu-3T3 and mock-3T3. To determine whether feeder cells have a contact effect, cocultures without feeder-epithelium contact were also performed. Neutralizing antibody against CLU was used to assess the effects of secretory CLU in TKE2 cells cocultured with Clu-3T3 cells. The expression of growth factors associated with limbal stem/progenitor cell maintenance and growth were analyzed by RT-PCR and Western blot analysis. TKE2 cells cocultured with Clu-3T3 feeders showed higher CFE and were larger in colony size than TKE2 cells cocultured with mock-3T3 feeders. Increased CFE of TKE2 was observed without direct contact with Clu-3T3 cells, which was significantly blocked by treatment with CLU neutralizing antibody. Clu-3T3 cells expressed higher levels of HGF than mock-3T3 cells, which were significantly suppressed with anti-HGF neutralizing antibodies. Collectively, the promotion of colony-forming and cell proliferation by Clu-3T3 cells was partially mediated by the induction of HGF. Clusterin indirectly enhances the CFE of corneal/limbal epithelial cells by inducing the production of HGF by feeder cells, suggesting a role in epithelial-mesenchymal interaction.


Planned elective repeat caesarean section versus planned vaginal birth for women with a previous caesarean birth.
When a woman has had a previous caesarean birth, there are two options for her care in a subsequent pregnancy: planned elective repeat caesarean or planned vaginal birth. While there are risks and benefits for both planned elective repeat caesarean birth and planned vaginal birth after caesarean (VBAC), current sources of information are limited to non-randomised cohort studies. Studies designed in this way have significant potential for bias and consequently conclusions based on these results are limited in their reliability and should be interpreted with caution. To assess, using the best available evidence, the benefits and harms of a policy of planned elective repeat caesarean section with a policy of planned VBAC for women with a previous caesarean birth. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013) and reference lists of retrieved studies. Randomised controlled trials with reported data that compared outcomes in mothers and babies who planned a repeat elective caesarean section with outcomes in women who planned a vaginal birth, where a previous birth had been by caesarean. Two review authors independently assessed trial quality and extracted data. Two randomised trials involving 320 women and their infants were included. However, data for maternal and infant clinical outcomes were available from one trial with very low event rates, involving 22 women only.For the primary outcomes maternal death or serious morbidity (one study; 22 women; risk ratio (RR) not estimable), and infant death or serious morbidity (one study; 22 women; RR not estimable), there were no statistically significant differences between planned caesarean birth and planned vaginal birth identified. Planned elective repeat caesarean section and planned VBAC for women with a prior caesarean birth are both associated with benefits and harms. Evidence for these care practices is largely drawn from non-randomised studies, associated with potential bias. Any results and conclusions must therefore be interpreted with caution. Randomised controlled trials are required to provide the most reliable evidence regarding the benefits and harms of both planned elective repeat caesarean section and planned vaginal birth for women with a previous caesarean birth.


A rare case of multiple subungual glomus tumours in a neurofibromatosis type 1 patient.
Glomus tumours are uncommon lesions of the digit. They tend to be solitary. Only a small number of multifocal cases have been published, most of which are linked to an underlying genetic disorder. Here we report an unusual case of multifocal glomus tumours in the same hand in a patient suffering from neurofibromatosis type 1.


Reactivity with a specific epitope of outer surface protein A predicts protection from infection with the Lyme disease spirochete, Borrelia burgdorferi.
The response to recombinant vaccines for Lyme disease was studied to determine serum antibody levels effective in protecting against tick-transmitted infection. Data presented here demonstrate a significant correlation between antibody to an epitope on outer surface protein A (OspA) and protection against infection with Borrelia burgdorferi in canines and mice. A competitive enzyme-linked immunosorbent assay was developed to measure antibody to a site on OspA, defined by monoclonal antibody LA-2. Comparison of LA-2 titers against infection of canines and mice following vaccination and challenge established a predicted value for LA-2 titers. The statistical relationship between serum antibody levels and protection was calculated by logistic regression analysis. The statistical model predicted that an LA-2 titer of 0.32 microg equivalents (eq) per ml correlated to an 80% predicted probability of protection for both mice and dogs. This value was used to classify mice and dogs as to their protected status at the time of tick exposure. The LA-2 cutoff titer (0.32 microg eq/ml) correctly classified all dogs (n = 13) and mice (n = 44) that failed to become infected. By contrast, 20 of 22 dogs and 28 of 31 mice with titers of less than 0.32 microg eq/ml became infected. On the basis of these results, we conclude that an LA-2 titer is a reliable indicator of immune status for estimating immune protection following use of OspA-based vaccines for B. burgdorferi sensu stricto.


Role of innate immunity in Helicobacter pylori-induced gastric malignancy.
Helicobacter pylori colonizes the majority of persons worldwide, and the ensuing gastric inflammatory response is the strongest singular risk factor for peptic ulceration and gastric cancer. However, only a fraction of colonized individuals ever develop clinically significant outcomes. Disease risk is combinatorial and can be modified by bacterial factors, host responses, and/or specific interactions between host and microbe. Several H. pylori constituents that are required for colonization or virulence have been identified, and their ability to manipulate the host innate immune response will be the focus of this review. Identification of bacterial and host mediators that augment disease risk has profound ramifications for both biomedical researchers and clinicians as such findings will not only provide mechanistic insights into inflammatory carcinogenesis but may also serve to identify high-risk populations of H. pylori-infected individuals who can then be targeted for therapeutic intervention.


Food Insecurity Is Prevalent in Iowa's Medicaid Expansion Population.
Food insecurity has been identified as an important social determinant of health and is associated with many health issues prevalent in Medicaid members. Despite this, little research has been done around food insecurity within Medicaid populations. Our objective was to estimate the prevalence of household food insecurity and identify factors associated with experiencing food insecurity in Iowa's Medicaid expansion population. We conducted a cross-sectional telephone survey between March and May of 2019. Our sample was drawn from Medicaid members enrolled in Iowa's expansion program at least 14 months, stratified by Federal Poverty Level (FPL) category. Members who did not have valid contact information were excluded. We selected one individual per household to reduce the interrelatedness of responses. We sampled 6,000 individuals and had 1,349 respondents in the analytic sample. Our main outcome was whether a respondent's household experienced food insecurity in the previous year, using the Hunger Vital Sign screening tool. We weighted responses to account for the sampling design and differential nonresponse between strata. We estimated the prevalence of food insecurity and used logistic regression to model food insecurity as a function of demographic (age, FPL category, gender, employment, education, race, rurality, and Supplemental Nutrition Assistance Program [SNAP] participation) and health-related (self-rated health, self-rated oral health, health literacy) factors. The estimated prevalence of experiencing food insecurity was 51.3%. Race, gender, education, employment, health literacy, and self-rated health were all significantly associated with food insecurity. Our findings show that food insecurity is prevalent in Iowa's Medicaid expansion population. Food insecurity should be more widely measured as a critical social determinant of health in Medicaid populations. Policymakers and clinicians should consider interventions that connect households experiencing food insecurity to food resources (eg, produce prescriptions and food pantry referrals) and policies that increase food access. Iowa Wellness Plan (IWP); Federal Poverty Level (FPL); Healthy Behavior Program (HBP); Supplemental Nutrition Assistance Program (SNAP).


Integrating Augmented Reality Tools in Breast Cancer Related Lymphedema Prognostication and Diagnosis.
Breast cancer related lymphedema (BCRL) is a detrimental condition characterized by fluid accumulation in the upper limb in breast cancer patients subjected to axillary surgery and/or radiations. Its etiology is multifactorial and include also tumor-specific pathological features, such as lymphovascular invasion (LVI) and extranodal extension (ENE). To date, no widely employed guidelines for the early diagnosis of BCRL are available. Here, we illustrate a protocol for a digitally assisted BCRL assessment using a 3D laser scanner (3DLS) and a tablet computer. It has been specifically optimized in a discovery cohort of high-risk breast cancer patients. This study provides a proof-of-principle that augmented reality tools, such as 3DLS, can be incorporated into the clinical workup of BCRL to allow for a precise, reproducible, reliable, and cheap diagnosis.


Exploring the impact of music concerts in promoting well-being in dementia care.
This study explores the specific effects of live music concerts on the clients with dementia, their families and nursing staff/caregivers. Researchers attended 22 concerts in care facilities in England and Japan. Interviews were carried out with clients with dementia, nursing staff and family members. Observations were also carried out before, during and after the concerts. All observations were recorded in field notes. The effect of the concerts in both countries was seen to be beneficial to all clients and nursing staff, whether or not they attended the concert. Interviews with clients with mild to mid-stage dementia noted increased levels of cooperation, interaction and conversation. Those with more advanced forms of dementia exhibited decreased levels of agitation and anti-social behaviour. Staff members reported increased levels of care, cooperation and opportunities for assessment. Family members noted an increase in the levels of well-being in their partner/parent as well as in themselves. The study also suggested that the knowledge of musical components, an awareness of the rules of music and specific musical preferences appear to remain well beyond the time when other cognitive skills and abilities have disappeared. This initial study provided some further indication in terms of the uses of music as a non-pharmacological intervention for those living with all stages of dementia. These included opportunities for assessment of physical abilities as well as facilitating an increasing level of care.


Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.
In immune-competent patients, higher vitamin D levels predicted sustained viral response (SVR) following interferon (INF) and ribavirin therapy for chronic hepatitis C. This study aimed to verify the influence of vitamin D serum levels and/or vitamin D supplementation in predicting SVR rates for recurrent hepatitis C (RHC). Forty-two consecutive patients were treated for RHC with combination therapy with INF-α and ribavirin for 48 weeks. Vitamin D serum levels were measured in all patients before antiviral therapy. In 15 patients oral vitamin D3 supplementation was administered to avoid further bone loss. SVR was observed in 13 patients; it was achieved in 1/10 severely vitamin D deficient (≤ 10 ng/ml) patients, in 6/20 deficient (>10 and ≤ 20 ng/ml) and in 6/12 with near normal (> 20 ng/ml) 25-OH vitamin D serum levels (P < 0.05). Cholecalciferol supplementation, in the presence of a normal or near normal baseline vitamin D concentration, (improvement of chi-square P < 0.05, odds ratio 2.22) and possessing a genotype other than 1 (improvement of chi-square P < 0.05, odds ratio 3.383) were the only variables independently associated to SVR. In conclusion, vitamin D deficiency predicts an unfavourable response to antiviral treatment of RHC. Vitamin D supplementation improves the probability of achieving a SVR following antiviral treatment.


Finger arterial versus intrabrachial pressure and continuous cardiac output during head-up tilt testing in healthy subjects.
1. The aims of this study were to determine the clinical feasibility of continuous, non-invasive Finapres recordings as a replacement for intrabrachial pressure during a 30 min head-up tilt, and the reliability of continuous cardiac output computation by pulse contour analysis from the finger arterial versus the brachial waveform. 2. In eight healthy subjects a 30 min 70 degrees passive head-up tilt was performed. Finger arterial (FINAP) and intrabrachial (IAP) pressures were measured simultaneously. Beat-to-beat changes in stroke volume were computed using a pulse contour algorithm. 3. Accuracy (the group-averaged FINAP-IAP difference) and precision (the SD of the difference) of Finapres measurements were 4 and 9 mmHg for systolic blood pressure, -5 and 9 mmHg for mean blood pressure and -5 and 9mmHg for diastolic blood pressure. 4. The time course of the FINAP-IAP differences during head-up tilt showed a linear trend (P < 0.001 for all pressure levels). Averaged for the group, the difference increased 7 mmHg for mean blood pressure. The difference in stroke volume computed from FINAP and IAP was 0.3 +/- 5% (mean +/- SD), and independent of the duration of the tilt (P > 0.05). This difference did not change at low blood pressure levels (0.5 +/- 6%). 5. The qualitative performance of the Finapres allows it to be used in the clinical setting as a monitor of sudden changes in blood pressure induced by a 30 min head-up tilt. Relative changes in stroke volume, as obtained by pulse contour analysis of the finger arterial waveform, closely follow intrabrachial values during long-duration head-up tilt and associated arterial hypotension.


Suppression of tumor growth by Pleurotus ferulae ethanol extract through induction of cell apoptosis, and inhibition of cell proliferation and migration.
Cancer is the second leading cause of death worldwide. Edible medicinal mushrooms have been used in traditional medicine as regimes for cancer patients. Recently anti-cancer bioactive components from some mushrooms have been isolated and their anti-cancer effects have been tested. Pleurotus ferulae, a typical edible medicinal mushroom in Xinjiang China, has also been used to treat cancer patients in folk medicine. However, little studies have been reported on the anti-cancer components of Pleurotus ferulae. This study aims to extract bioactive components from Pleurotus ferulae and to investigate the anti-cancer effects of the extracts. We used ethanol to extract anti-cancer bioactive components enriched with terpenoids from Pleurotus ferulae. We tested the anti-tumour effects of ethanol extracts on the melanoma cell line B16F10, the human gastric cancer cell line BGC 823 and the immortalized human gastric epithelial mucosa cell line GES-1 in vitro and a murine melanoma model in vivo. Cell toxicity and cell proliferation were measured by MTT assays. Cell cycle progression, apoptosis, caspase 3 activity, mitochondrial membrane potential (MMP), migration and gene expression were studied in vitro. PFEC suppressed tumor cell growth, inhibited cell proliferation, arrested cells at G0/G1 phases and was not toxic to non-cancer cells. PFEC also induced cell apoptosis and necrosis, increased caspase 3 activity, reduced the MMP, prevented cell invasion and changed the expression of genes associated with apoptosis and the cell cycle. PFEC delayed tumor formation and reduced tumor growth in vivo. In conclusion, ethanol extracted components from Pleurotus ferulae exert anti-cancer effects through direct suppression of tumor cell growth and invasion, demonstrating its therapeutic potential in cancer treatment.


Renal prostaglandin synthesis in experimental renal clip hypertension in the rat.
1. The hypothesis that suppression of prostaglandin E (PGE) synthesis by indomethacin exacerbates renal clip hypertension in the rat was investigated. 2. Indomethacin exacerbated hypertension in renal clip rats. 3. In vitro PGE synthesis determined by gas liquid chromatography (GLC) was suppressed in medullary tissue from the hypertensive animals irrespective of indomethacin treatment. 4. The findings support the concept that PGs participate in blood pressure regulation in experimental renal hypertension.


Insights of private general practitioners in group practice on the introduction of National Health Insurance in South Africa.
The South African government intends to contract with 'accredited provider groups' for capitated primary care under National Health Insurance (NHI). South African solo general practitioners (GPs) are unhappy with group practice. There is no clarity on the views of GPs in group practice on contracting to the NHI. To describe the demographic and practice profile of GPs in group practice in South Africa, and evaluate their views on NHI, compared to solo GPs. This was a descriptive survey. The population of 8721 private GPs in South Africa with emails available were emailed an online questionnaire. Descriptive statistical analyses and thematic content analysis were conducted. In all, 819 GPs responded (568 solo GPs and 251 GPs in groups). The results are focused on group GPs. GPs in groups have a different demographic practice profile compared to solo GPs. GPs in groups expected R4.86 million ($0.41 million) for a hypothetical NHI proposal of comprehensive primary healthcare (excluding medicines and investigations) to a practice population of 10 000 people. GPs planned a clinical team of 8 to 12 (including nurses) and 4 to 6 administrative staff. GPs in group practices saw three major risks: patient, organisational and government, with three related risk management strategies. GPs can competitively contract with NHI, although there are concerns. NHI contracting should not be limited to groups. All GPs embraced strong teamwork, including using nurses more effectively. This aligns well with the emergence of family medicine in Africa.


Cloning and characterization of the annexin II receptor on human marrow stromal cells.
Annexin II is a heterotetramer, consisting of two 11-kDa (p11) and two 36-kDa (p36) subunits, that is produced by osteoclasts and stimulates osteoclast formation. However, its receptor is unknown. We showed that annexin II binds to normal primary human marrow stromal cells and the Paget's marrow-derived PSV10 stromal cell line to induce osteoclast formation. 125I-Labeled annexin II binding assays with PSV10 cells demonstrated that there was a single class of annexin II receptors with a Kd of 5.79 nm and Bmax of 2.13 x 10(5) receptors/cell. Annexin III or annexin V did not bind this receptor. Using 125I-labeled annexin II binding to screen NIH3T3 transfected with a human marrow cDNA expression library, we identified a putative annexin II receptor clone, which encoded a novel 26-kDa type I membrane receptor protein when expressed in HEK 293 cells. HEK 293 cells transformed with the cloned annexin II receptor cDNA showed a similar binding affinity to annexin II as that observed in PSV10 cells. Chemical cross-linking experiments with biotinylated annexin II and intact PSV10 cells identified a 55-kDa band on Western blot analysis that reacted with both an anti-p11 antibody and streptavidin but not anti-p36 antibody. A rabbit polyclonal antibody raised against the putative recombinant annexin II receptor also recognized the same 26-kDa protein band detected in PSV10 cells. Importantly, the annexin II receptor antibody dose-dependently blocked the stimulatory effects of annexin II on human osteoclast formation, demonstrating that the receptor mediates the effects of annexin II on osteoclast formation.


Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells.
The BCR/ABL oncogenic tyrosine kinase is responsible for initiating and maintaining the leukemic phenotype of Philadelphia chromosome (Ph1)-positive cells. Phosphatidylinositol-3 (PI-3) kinase is known to interact with and be activated by receptor and nonreceptor tyrosine kinases. We investigated whether PI-3 kinase associates with and/or is regulated by BCR/ABL, whether this interaction is functionally significant for Ph1 cell proliferation, and, if so, whether inhibition of PI-3 kinase activity can be exploited to eliminate Ph1-positive cells from bone marrow. We show that the p85 alpha subunit of PI-3 kinase associates with BCR/ABL and that transient expression of BCR/ABL in fibroblasts and down-regulation of BCR/ABL expression using antisense oligodeoxynucleotides (ODNs) in Ph1 cells activates and inhibits, respectively, PI-3 kinase enzymatic activity. The use of specific ODNs or antisense constructs to downregulate p85 alpha expression showed a requirement for p85 alpha subunit in the proliferation of BCR/ABL-dependent cell lines and chronic myelogenous leukemia (CML) primary cells. Similarly, wortmannin, a specific inhibitor of the enzymatic activity of the p110 subunit of PI-3 kinase, inhibited growth of these cells. The growth of normal bone marrow and erythromyeloid, but not megakaryocyte, progenitors was inhibited by p85 alpha antisense [S]ODNs, but wortmannin, at the concentrations tested, did not affect normal hematopoiesis. The proliferation of two BCR/ABL- and growth factor-independent cell lines was not affected by downregulation of the expression of the p85 alpha subunit or inhibition of p110 enzymatic activity, confirming the specificity of the observed effects on Ph1 cells. Thus, PI-3 kinase is one of the downstream effectors of BCR/ABL tyrosine kinase in CML cells. Moreover, reverse transcriptase-polymerase chain reaction performed on single colonies to detect BCR-ABL transcripts showed that wortmannin was able to eliminate selectively CML-blast crisis cells from a mixture of normal bone marrow and Ph1 cells.