Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury.
Lack of axon regeneration in the adult CNS has been attributed partly to myelin inhibitors and the properties of astrocytes. After spinal cord injury, proliferating astrocytes not only represent a physical barrier to regenerating axons but also express and secrete molecules that inhibit nerve growth, including chondroitin sulfate proteoglycans (CSPGs). Epidermal growth factor receptor (EGFR) activation triggers astrocytes into becoming reactive astrocytes, and EGFR ligands stimulate the secretion of CSPGs as well as the formation of cribriform astrocyte arrangements that contribute to the formation of glial scars. Recently, it was shown that EGFR inhibitors promote nerve regeneration in vitro and in vivo. Blocking a novel Nogo receptor interacting mechanism and/or effects of EGFR inhibition on astrocytes may underlie these effects. Here we show that rats subjected to weight-drop spinal cord injury can be effectively treated by direct delivery of a potent EGFR inhibitor to the injured area, leading to significantly better functional and structural outcome. Motor and sensory functions are improved and bladder function is restored. The robust effects and the fact that other EGFR inhibitors are in clinical use in cancer treatments make these drugs particularly attractive candidates for clinical trials in spinal cord injury.


Structural basis for protein-protein interactions in the 14-3-3 protein family.
The seven members of the human 14-3-3 protein family regulate a diverse range of cell signaling pathways by formation of protein-protein complexes with signaling proteins that contain phosphorylated Ser/Thr residues within specific sequence motifs. Previously, crystal structures of three 14-3-3 isoforms (zeta, sigma, and tau) have been reported, with structural data for two isoforms deposited in the Protein Data Bank (zeta and sigma). In this study, we provide structural detail for five 14-3-3 isoforms bound to ligands, providing structural coverage for all isoforms of a human protein family. A comparative structural analysis of the seven 14-3-3 proteins revealed specificity determinants for binding of phosphopeptides in a specific orientation, target domain interaction surfaces and flexible adaptation of 14-3-3 proteins through domain movements. Specifically, the structures of the beta isoform in its apo and peptide bound forms showed that its binding site can exhibit structural flexibility to facilitate binding of its protein and peptide partners. In addition, the complex of 14-3-3 beta with the exoenzyme S peptide displayed a secondary structural element in the 14-3-3 peptide binding groove. These results show that the 14-3-3 proteins are adaptable structures in which internal flexibility is likely to facilitate recognition and binding of their interaction partners.


Cellular scaffolds in mammalian eggs.
Cellular scaffolds serve as structural components to which various elements of signal transduction pathways can be associated. The association of components on a scaffold can have several important functions, for example they can: 1) associate upstream regulatory components in a cascade that can increase the speed of response to a stimulus; 2) restrict access of substrates to enzymes associated with the scaffold; 3) permit cross talk between distinct signaling pathways, and; 4) aid in the establishment of cellular polarity. The conversion of the mammalian egg into the zygote requires many rapid alterations during a distinct time frame to mediate the biochemical and structural changes that occur. Cellular scaffolds provide a mechanism that can perform these rapid, highly orchestrated changes. They can permit interaction between distinct calcium-dependent pathways and also can provide a means for the calcium signal, that is initiated by fertilization, to act on calcium-independent pathways. This review considers various lines of evidence suggesting that in the mammalian egg, the meiotic spindle serves as a cellular scaffold that permits coordination among several signaling pathways essential for fertilization and the initiation of early development.


A global dataset for the projected impacts of climate change on four major crops.
Reliable estimates of the impacts of climate change on crop production are critical for assessing the sustainability of food systems. Global, regional, and site-specific crop simulation studies have been conducted for nearly four decades, representing valuable sources of information for climate change impact assessments. However, the wealth of data produced by these studies has not been made publicly available. Here, we develop a global dataset by consolidating previously published meta-analyses and data collected through a new literature search covering recent crop simulations. The new global dataset builds on 8703 simulations from 202 studies published between 1984 and 2020. It contains projected yields of four major crops (maize, rice, soybean, and wheat) in 91 countries under major emission scenarios for the 21st century, with and without adaptation measures, along with geographical coordinates, current temperature and precipitation levels, projected temperature and precipitation changes. This dataset provides a solid basis for a quantitative assessment of the impacts of climate change on crop production and will facilitate the rapidly developing data-driven machine learning applications.


Anti-Apoptotic Effects of Resistance Training and Tribulus Terrestris Consumption in the Heart Tissue of Rats Exposed to Stanozolol.
Nowadays, the use of energetic substances has become a complex problem in sports, such that the role of anabolic-androgenic steroids is undeniable. This study aimed to investigate the antiapoptotic effect of resistance training and Tribulus terrestris in the heart tissue of rats exposed to stanozolol. 35 rats divided into 7 groups including (1) sham, (2) stanozolol-treated, (3) stanozolol+50 mg/kg Tribulus terrestris-treated, (4) stanozolol+100 mg/kg Tribulus terrestris-treated, (5) stanozolol+resistance training-treated, (6) stanozolol+resistance training+50 mg/kg Tribulus terrestris-treated, and (7) stanozolol+resistance training+100 mg/kg Tribulus terrestris-treated. During 8 weeks, groups 2-7 received 5 mg/kg stanozolol per day peritoneally; groups 5-7 performed resistance training for 3 sessions per week; and groups 3, 4, 6 and 7 received daily doses of Tribulus terrestris peritoneally. Stanozolol administration significantly increased the BAX, BCL-2, P53, and caspase 3 and BAX/BCL-2 ratio (P < .001). Resistance training, 100 mg/kg Tribulus terrestris administration, 50 mg/kg Tribulus terrestris administration, resistance training+100 mg/kg Tribulus terrestris administration, and resistance training+50 mg/kg Tribulus terrestris administration significantly decreased BAX, BCL-2, P53, and caspase 3 levels and BAX/BCL-2 ratio (P < .001); however, stanozolol+resistance training+100 mg/kg Tribulus terrestris administration caused more decrease than stanozolol+resistance training+50 mg/kg Tribulus terrestris administration in BAX (P < .001). Resistance training and Tribulus terrestris administration alone appear to have antiapoptotic effects; however, resistance training combined with Tribulus terrestris administration, especially at higher doses, have more desirable effects than resistance training or Tribulus terrestris administration alone on the apoptosis markers.


Association between axial length and choroidal thickness in early age-related macular degeneration.
The clinical course of age-related macular degeneration (AMD) is related to choroidal conditions, and can be determined by the evaluation of the central choroidal thickness (CCT). The aim of this study was to determine the association between the axial length (AL) and choroidal thickness in AMD by measuring these parameters in patients with and without AMD. Seventy eyes of 70 patients (34 men and 36 women; age, 64-88 years; mean age, 77.0 ± 6.5 years) who underwent cataract surgery from February 2015 to March 2020 at the Department of Ophthalmology, Keio University School of Medicine were retrospectively analyzed. The AMD group (29 patients, 29 eyes) included eyes with early AMD, whereas the control group (41 patients, 41 eyes) included those without ocular diseases other than cataract. Optical coherence tomography images were used to measure the CCT and the choroidal vessel diameter (CVD). The IOL Master was used to measure the AL. The results revealed that mean CCT was greater in the AMD group (238.3 ± 108.3 μm) compared with the age-matched control group (187.2 ± 66.8 μm) (p = 0.03). The CCT was negatively correlated with AL in the overall sample (r = -0.42, p = 0.001), the AMD group (r = -0.42, p = 0.02), and the control group (r = -0.42, p = 0.006). Note that all eyes with CCT > 350 μm were included in the AMD group. CCT and CVD were positively correlated in the overall sample (r = 0.76, p < 0.001) as well as in the individual groups (AMD: r = 0.82, p < 0.001; control: r = 0.76, p = 0.004). Given that CCT is an important parameter for predicting the prognosis of subfoveal diseases, routine evaluation of AL may be valuable for a better understanding of the pathogenesis of AMD.


An approach to identify a minimum and rational proportion of caesarean sections in resource-poor settings: a global network study.
Caesarean section prevalence is increasing in Asia and Latin America while remaining low in most African regions. Caesarean section delivery is effective for saving maternal and infant lives when they are provided for medically-indicated reasons. On the basis of ecological studies, caesarean delivery prevalence between 9% and 19% has been associated with better maternal and perinatal outcomes, such as reduced maternal land fetal mortality. However, the specific prevalence of obstetric and medical complications that require caesarean section have not been established, especially in low-income and middle-income countries (LMICs). We sought to provide information to inform the approach to the provision of caesarean section in low-resource settings. We did a literature review to establish the prevalence of obstetric and medical conditions for six potentially life-saving indications for which caesarean section could reduce mortality in LMICs. We then analysed a large, prospective population-based dataset from six LMICs (Argentina, Guatemala, Kenya, India, Pakistan, and Zambia) to determine the prevalence of caesarean section by indication for each site. We considered that an acceptable number of events would be between the 25th and 75th percentile of those found in the literature. Between Jan 1, 2010, and Dec 31, 2013, we enrolled a total of 271 855 deliveries in six LMICs (seven research sites). Caesarean section prevalence ranged from 35% (3467 of 9813 deliveries in Argentina) to 1% (303 of 16 764 deliveries in Zambia). Argentina's and Guatemala's sites all met the minimum 25th percentile for five of six indications, whereas sites in Zambia and Kenya did not reach the minimum prevalence for caesarean section for any of the indications. Across all sites, a minimum overall caesarean section of 9% was needed to meet the prevalence of the six indications in the population studied. In the site with high caesarean section prevalence, more than half of the procedures were not done for life-saving conditions, whereas the sites with low proportions of caesarean section (below 9%) had an insufficient number of caesarean procedures to cover those life-threatening causes. Attempts to establish a minimum caesarean prevalence should go together with focusing on the life-threatening causes for the mother and child. Simple methods should be developed to allow timely detection of life-threatening conditions, to explore actions that can remedy those conditions, and the timely transfer of women with those conditions to health centres that could provide adequate care for those conditions. Eunice Kennedy Shriver National Institute of Child Health and Human Development.


Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.


CMTM4 regulates angiogenesis by promoting cell surface recycling of VE-cadherin to endothelial adherens junctions.
Vascular endothelial (VE) cadherin is a key component of endothelial adherens junctions (AJs) and plays an important role in maintaining vascular integrity. Endocytosis of VE-cadherin regulates junctional strength and a decrease of surface VE-cadherin reduces vascular stability. However, disruption of AJs is also a requirement for vascular sprouting. Identifying novel regulators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we evaluated the angiogenic potential of (CKLF-like MARVEL transmembrane domain 4) CMTM4 and assessed in which molecular pathway CMTM4 is involved during angiogenesis. Using a 3D vascular assay composed of GFP-labeled HUVECs and dsRED-labeled pericytes, we demonstrated in vitro that siRNA-mediated CMTM4 silencing impairs vascular sprouting. In vivo, CMTM4 silencing by morpholino injection in zebrafish larvae inhibits intersomitic vessel growth. Intracellular staining revealed that CMTM4 colocalizes with Rab4+ and Rab7+ vesicles, both markers of the endocytic trafficking pathway. CMTM4 colocalizes with both membrane-bound and internalized VE-cadherin. Adenovirus-mediated CMTM4 overexpression enhances the endothelial endocytic pathway, in particular the rapid recycling pathway, shown by an increase in early endosomal antigen-1 positive (EEA1+), Rab4+, Rab11+ , and Rab7+ vesicles. CMTM4 overexpression enhances membrane-bound VE-cadherin internalization, whereas CMTM4 knockdown decreases internalization of VE-cadherin. CMTM4 overexpression promotes endothelial barrier function, shown by an increase in recovery of transendothelial electrical resistance (TEER) after thrombin stimulation. We have identified in this study a novel regulatory function for CMTM4 in angiogenesis. CMTM4 plays an important role in the turnover of membrane-bound VE-cadherin at AJs, mediating endothelial barrier function and controlling vascular sprouting.


Limited occurrence of denitrification in four shallow aquifers in agricultural areas of the United States.
The ability of natural attenuation to mitigate agricultural nitrate contamination in recharging aquifers was investigated in four important agricultural settings in the United States. The study used laboratory analyses, field measurements, and flow and transport modeling for monitoring well transects (0.5 to 2.5 km in length) in the San Joaquin watershed, California, the Elkhorn watershed, Nebraska, the Yakima watershed, Washington, and the Chester watershed, Maryland. Ground water analyses included major ion chemistry, dissolved gases, nitrogen and oxygen stable isotopes, and estimates of recharge date. Sediment analyses included potential electron donors and stable nitrogen and carbon isotopes. Within each site and among aquifer-based medians, dissolved oxygen decreases with ground water age, and excess N(2) from denitrification increases with age. Stable isotopes and excess N(2) imply minimal denitrifying activity at the Maryland and Washington sites, partial denitrification at the California site, and total denitrification across portions of the Nebraska site. At all sites, recharging electron donor concentrations are not sufficient to account for the losses of dissolved oxygen and nitrate, implying that relict, solid phase electron donors drive redox reactions. Zero-order rates of denitrification range from 0 to 0.14 micromol N L(-1)d(-1), comparable to observations of other studies using the same methods. Many values reported in the literature are, however, orders of magnitude higher, which is attributed to a combination of method limitations and bias for selection of sites with rapid denitrification. In the shallow aquifers below these agricultural fields, denitrification is limited in extent and will require residence times of decades or longer to mitigate modern nitrate contamination.


ID3 may protect mice from anti‑GBM glomerulonephritis by regulating the differentiation of Th17 and Treg cells.
Anti‑glomerular basement membrane glomerulonephritis (anti‑GBM GN) is an autoimmune disease that leads to severe and rapidly progressive renal injury. Inhibition of DNA‑binding factor 3 (ID3) serves a key role in autoimmune diseases, such as asthma and Sjögren's syndrome, and in experimental allergic encephalitis models. However, the role of ID3 in the progression of anti‑GBM GN remains unknown. In the present study, ID3 mRNA expression increased between 3‑ and 20‑fold in the renal tissues of anti‑GBM GN mice compared with the Control group, with a peak at day 14 post‑induction. In addition, ID3 protein expression was upregulated from day 7 onwards. The expression of ID3 was also examined in the spleen, and was demonstrated to be increased in the spleen of nephritic mice. T helper 17 (Th17) cells and regulatory T (Treg) cells were present throughout the entire period of observation (from day 7 to day 28) in anti‑GBM GN mice, which may vary at different time points, accompanied with the expression of ID3. In vitro, ID3 expression was increased when CD4+ T cells differentiated into Tregs; however, expression was lower in Th17 cells. Following treatment with ID3 small interfering RNA, RAR‑related orphan receptor γt, but not forkhead box P3, expression increased. Furthermore, increased expression of interleukin‑17A was also observed when ID3 was blocked. In addition, ID3 was able to interact with transcription factor E2A. A significant increase in binding between ID3 and E2A was observed in anti‑GBM GN from day 7 onwards, with a peak at day 14 in both renal tissue and spleen. In conclusion, ID3 may be involved in the differentiation of Th17 and Tregs by downregulating Th17 cells, which is probably associated with binding to E2A. The present results suggested that ID3 may offer protection against anti‑GBM GN in mice.


Rtt107 is required for recruitment of the SMC5/6 complex to DNA double strand breaks.
Genome integrity is maintained by a network of DNA damage response pathways, including checkpoints and DNA repair processes. In Saccharomyces cerevisiae, the BRCT domain-containing protein Rtt107/Esc4 is required for the restart of DNA replication after successful repair of DNA damage and for cellular resistance to DNA-damaging agents. In addition to its well characterized interaction with the endonuclease Slx4, Rtt107 interacts with a number of other DNA repair and recombination proteins. These include the evolutionarily conserved SMC5/6 complex, which is involved in numerous chromosome maintenance activities, such as DNA repair, chromosome segregation, and telomere function. The interaction between Rtt107 and the SMC5/6 complex was mediated through the N-terminal BRCT domains of Rtt107 and the Nse6 subunit of SMC5/6 and was independent of methyl methane sulfonate-induced damage and Slx4. Supporting a shared function in the DNA damage response, Rtt107 was required for recruitment of SMC5/6 to DNA double strand breaks. However, this functional relationship did not extend to other types of DNA lesions such as protein-bound nicks. Interestingly, Rtt107 was phosphorylated when SMC5/6 function was compromised in the absence of DNA-damaging agents, indicating a connection beyond the DNA damage response. Genetic analyses revealed that, although a subset of Rtt107 and SMC5/6 functions was shared, these proteins also contributed independently to maintenance of genome integrity.


Increasing costs due to ocean acidification drives phytoplankton to be more heavily calcified: optimal growth strategy of coccolithophores.
Ocean acidification is potentially one of the greatest threats to marine ecosystems and global carbon cycling. Amongst calcifying organisms, coccolithophores have received special attention because their calcite precipitation plays a significant role in alkalinity flux to the deep ocean (i.e., inorganic carbon pump). Currently, empirical effort is devoted to evaluating the plastic responses to acidification, but evolutionary considerations are missing from this approach. We thus constructed an optimality model to evaluate the evolutionary response of coccolithophorid life history, assuming that their exoskeleton (coccolith) serves to reduce the instantaneous mortality rates. Our model predicted that natural selection favors constructing more heavily calcified exoskeleton in response to increased acidification-driven costs. This counter-intuitive response occurs because the fitness benefit of choosing a better-defended, slower growth strategy in more acidic conditions, outweighs that of accelerating the cell cycle, as this occurs by producing less calcified exoskeleton. Contrary to the widely held belief, the evolutionarily optimized population can precipitate larger amounts of CaCO(3) during the bloom in more acidified seawater, depending on parameter values. These findings suggest that ocean acidification may enhance the calcification rates of marine organisms as an adaptive response, possibly accompanied by higher carbon fixation ability. Our theory also provides a compelling explanation for the multispecific fossil time-series record from ∼200 years ago to present, in which mean coccolith size has increased along with rising atmospheric CO(2) concentration.


Standardization of a Carbon Dioxide Automated System for Endovascular Aortic Aneurysm Repair.
Endovascular aortic repair (EVAR) is presently the preferred treatment for abdominal aortic aneurysm; however, it requires the injection of a contrast medium, which can hamper the renal function. Other nontoxic agents such as carbon dioxide (CO2) have been sporadically tested in this setting with uncertain results. The aim of the study is to investigate the efficacy of a new standardized CO2 injection method in standard EVAR procedures. Between August and October 2016, 31 consecutive patients (median age 76.1 [interquartile range {IQR}: 7.4] years) were submitted to standard EVAR. Proximal and distal endograft landing zones were identified by the injection of 100 mL of CO2 at 300 mm Hg, through an 11 cm 10F femoral sheath by a specifically manufactured automated injection device (Angiodroid Srl, San Lazzaro, Bologna, Italy). Before EVAR deployment, a confirmative injection with a conventional contrast medium was accomplished. The possibility of precisely visualizing the proximal and distal landing zones by CO2 digital subtraction angiography (DSA) was evaluated considering the contrast medium injection obtained in the same procedure as a gold standard. Similarly, the possible presence of endoleak was assessed at the end of the procedure by the 2 techniques. CO2 DSA allowed to identify the juxtarenal landing zone of the endograft in 19/31 cases (61%) and the distal one in 31/31 (100%). In 12 (39%) cases, CO2 injection failed to visualize at least the lowest renal artery. This occurred in large aneurysms with scarce thrombotic apposition and a luminal volume greater than 95.9 (IQR: 25.2) mm3. Completion CO2 DSA detected type II endoleaks (ELIIs) in 10 cases compared with 2 of conventional contrast media. The injection of nontoxic CO2 through an automated device allowed to perform EVAR procedures effectively, in the majority of cases. In some cases, a single injection of a minimum amount of conventional contrast medium can be used to overcome the lack of renal artery visualization by CO2. ELIIs are more frequently visualized with CO2 compared with standard contrast medium. Although the CO2 injection technique needs further amelioration particularly in the renal arteries detection, this technique appears promising and possibly substitutive of the standard contrast medium, with significant benefit for the renal function.


The impact of abuse and gender on psychopathology, behavioral disturbance, and psychotropic medication count for youth in residential treatment.
This study examined the relationship between gender, abuse history, and clinical change in a residential treatment program for youth with emotional and behavioral disturbance. Admission data and data collected after 1 year of treatment or at discharge were examined for 1,303 youth. Measures included the Suicide Probability Scale, Child Behavior Checklist, and the Diagnostic Interview Schedule for Children. Data also included medication count, demographic data, and history of sexual or physical abuse or both. At intake, girls scored significantly more pathologically than boys on 9 out of 12 measures. At intake, abused youth indicated more hostility, anxiety, and mood disorder symptoms as well as psychotropic medication usage than nonabused youth. Youth improved significantly on all outcome measures with treatment, although interaction effects indicate some differing treatment responses by abuse history or gender. After treatment, girls still scored significantly higher than boys on 6 of 8 outcome measures, and abused youth, especially youth experiencing both sexual and physical abuse, had significantly higher anxiety, affective, behavior, and eating disorder symptom counts and were on more psychotropic medications than nonabused youth. Although behaviorally focused treatment was associated with improvement on every measure, the most important implication of our study is that a singular treatment approach does not fit all youth completely as reflected by continuing treatment needs in our most troubled youth. Additional symptom-focused treatment and research attention must be given to girls and abused youth in residential care to maximize their therapeutic outcomes.


Dead cell counts during serum cultivation are underestimated by the fluorescent live/dead assay.
The live/dead fluorescent assay provides a quick method for assessing the proportion of live and dead cells in cell culture systems or tissues and is widely used. Dead cells are detected by the fluorescence produced when propidium iodide (PI) binds to DNA; PI and similar molecules are excluded from live cells but can penetrate dead cells because of their loss of membrane integrity. Here we investigated the effect of serum in the culture medium on the reliability of the method. We assessed viability of chondrocytes with/without serum using both a live/dead assay kit and also trypan blue staining. We found that after 2 days of culture, the DNA-binding dye PI could no longer detect dead cells if serum was present but they were readily detected in serum-free medium or if an inhibitor to DNase I was added to the serum-containing medium. Dead cells could be detected by trypan blue staining in all cultures. Hence dead cells are no longer detected as the DNase I present in serum degrades their DNA. DNA-binding dyes may thus not give a reliable estimate of the number of dead cells in systems that have been cultured in the presence of serum for several days.


Implication of prostaglandin receptors in the accumulation of osteoprotegerin in human osteoblast cultures.
Prostaglandins are important mediators in bone metabolism and in pathologies such as rheumatoid arthritis and osteoarthritis. We investigated the roles of cyclooxygenases (COX) and prostaglandin receptors in the accumulation of osteoprotegerin (OPG) in the supernatants of human osteoblasts in culture. Three different cellular models were used, the human osteosarcoma cell lines MG-63 and Saos-2, and primary cultures of human osteoblasts. OPG concentrations were determined by ELISA. RT-PCR analysis showed that, like primary human osteoblasts, MG-63 cells express DP, EP4, FP, IP, and TP receptors, whereas the Saos-2 cells lack IP. Concentration of OPG was highest in MG-63 cell supernatants (36 +/- 12.5 ng/ml), followed by human osteoblasts (12.77 +/- 2.2 ng/ml) and Saos-2 (3.6 +/- 0.76 ng/ml). COX inhibitors did not alter these values. Prostaglandin E2 and BW 245C (a synthetic DP receptor agonist) decreased OPG in the supernatants of human osteoblasts but not in immortalized cell lines. These effects were concentration-dependent and were inhibited by EP4 and DP receptor antagonists. Fluprostenol, an FP receptor agonist, increased the accumulation of OPG in MG-63 but not in primary human osteoblasts or Saos-2. Our results show that activation of EP4 or DP receptors decreased the accumulation of OPG in supernatants of osteoblasts in culture, and suggest that these receptors could be interesting pharmacological targets in bone diseases. They also demonstrate important differences between primary osteoblasts and immortalized cell lines, both in the distribution and in the effects mediated by prostaglandin receptors.


Oral poly(ADP-ribose) polymerase-1 inhibitor BSI-401 has antitumor activity and synergizes with oxaliplatin against pancreatic cancer, preventing acute neurotoxicity.
Development of novel agents and drug combinations are urgently needed for treatment of pancreatic cancer. Oxaliplatin belongs to an important class of DNA-damaging organoplatinum agents, useful in pancreatic cancer therapy. However, increased ability of cancer cells to recognize and repair DNA damage enables resistance to these agents. Poly (ADP ribose) polymerase-1 is a sensor of DNA damage with key roles in DNA repair. Here, we report the therapeutic activity of the poly (ADP ribose) polymerase-1 inhibitor BSI-401, as a single agent and in combination with oxaliplatin in orthotopic nude mouse models of pancreatic cancer, and its effect on oxaliplatin-induced acute neurotoxicity. We determined in vitro the effect of BSI-401 and its synergism with oxaliplatin on the growth of pancreatic cancer cells. Activity of different dosages of parenteral and oral BSI-401, alone and in combination with oxaliplatin, was evaluated in orthotopic nude mouse models with luciferase-expressing pancreatic cancer cells. The effect of BSI-401 in preventing oxaliplatin-induced acute cold allodynia was measured in rats using a temperature-controlled plate. BSI-401 alone and in synergism with oxaliplatin significantly inhibited the growth of pancreatic cancer cells in vitro. In nude mice, i.p. [200 mg/kg once a week (QW) x 4] and oral [400 mg/kg days 1-5 of each week (QD5 + R2) x 4] administration of BSI-401 significantly reduced tumor burden and prolonged survival (46 versus 144 days, P = 0.0018; 73 versus 194 days, P = 0.0017) compared with no treatment. BSI-401 combined with oxaliplatin had potent synergistic antitumor activity (46 versus 132 days, P = 0.0063), and significantly (P = 0.0148) prevented acute oxaliplatin-induced neurotoxicity. BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer.


Stereotactic body radiation therapy in the re-irradiation situation--a review.
Although locoregional relapse is frequent after definitive radiotherapy (RT) or multimodal treatments, re-irradiation is only performed in few patients even in palliative settings like e.g. vertebral metastasis. This is most due to concern about potentially severe complications, especially when large volumes are exposed to re-irradiation. With technological advancements in treatment planning the interest in re-irradiation as a local treatment approach has been reinforced. Recently, several studies reported re-irradiation for spinal metastases using SBRT with promising local and symptom control rates and simultaneously low rates of toxicity. These early data consistently indicate that SBRT is a safe and effective treatment modality in this clinical situation, where other treatment alternatives are rare. Similarly, good results have been shown for SBRT in the re-irradiation of head and neck tumors. Despite severe late adverse effects were reported in several studies, especially after single fraction doses >10 Gy, they appear less frequently compared to conventional radiotherapy. Few studies with small patient numbers have been published on SBRT re-irradiation for non-small cell lung cancer (NSCLC). Overall survival (OS) is limited by systemic progression and seems to depend particularly on patient selection. SBRT re-irradiation after primary SBRT should not be practiced in centrally located tumors due to high risk of severe toxicity. Only limited data is available for SBRT re-irradiation of pelvic tumors: feasibility and acceptable toxicity has been described, suggesting SBRT as a complementary treatment modality for local symptom control.


Between-breed variability of stillbirth and its relationship with sow and piglet characteristics.
Litter characteristics at birth were recorded in 4 genetic types of sows with differing maternal abilities. Eighty-two litters from F(1) Duroc x Large White sows, 651 litters from Large White sows, 63 litters from Meishan sows, and 173 litters from Laconie sows were considered. Statistical models included random effects of sow, litter, or both; fixed effects of sow genetic type, parity, birth assistance, and piglet sex, as well as gestation length, farrowing duration, piglet birth weight, and litter size as linear covariates. The quadratic components of the last 2 factors were also considered. For statistical analyses, GLM were first considered, assuming a binomial distribution of stillbirth. Hierarchical models were also fitted to the data to take into account correlations among piglets from the same litter. Model selection was performed based on deviance and deviance information criterion. Finally, standard and robust generalized estimating equations (GEE) procedures were applied to quantify the importance of each effect on a piglet's probability of stillbirth. The 5 most important factors involved were, in decreasing order (contribution of each effect to variance reduction): difference between piglet birth weight and the litter mean (2.36%), individual birth weight (2.25%), piglet sex (1.01%), farrowing duration (0.99%), and sow genetic type (0.94%). Probability of stillbirth was greater for lighter piglets, for male piglets, and for piglets from small or very large litters. Probability of stillbirth increased with sow parity number and with farrowing duration. Piglets born from Meishan sows had a lower risk of stillbirth (P < 0.0001) and were little affected by the sources of variation mentioned above compared with the 3 other sow genetic types. Standard and robust GEE approaches gave similar results despite some disequilibrium in the data set structure highlighted with the robust GEE approach.


Superior diagnostic performance of perfusion-cardiovascular magnetic resonance versus SPECT to detect coronary artery disease: The secondary endpoints of the multicenter multivendor MR-IMPACT II (Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial).
Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. The goal was to compare in a multicenter setting the diagnostic performance of perfusion-CMR and gated-SPECT for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference. In 33 centers (in US and Europe) 533 patients, eligible for CXA or SPECT, were enrolled in this multivendor trial. SPECT and CXA were performed within 4 weeks before or after CMR in all patients. Prevalence of CAD in the sample was 49% and 515 patients received MR contrast medium. Drop-out rates for CMR and SPECT were 5.6% and 3.7%, respectively (ns). The study was powered for the primary endpoint of non-inferiority of CMR vs SPECT for both, sensitivity and specificity for the detection of CAD (using a single-threshold reading), the results for the primary endpoint were reported elsewhere. In this article secondary endpoints are presented, i.e. the diagnostic performance of CMR versus SPECT in subpopulations such as multi-vessel disease (MVD), in men, in women, and in patients without prior myocardial infarction (MI). For diagnostic performance assessment the area under the receiver-operator-characteristics-curve (AUC) was calculated. Readers were blinded versus clinical data, CXA, and imaging results. The diagnostic performance (= area under ROC = AUC) of CMR was superior to SPECT (p = 0.0004, n = 425) and to gated-SPECT (p = 0.018, n = 253). CMR performed better than SPECT in MVD (p = 0.003 vs all SPECT, p = 0.04 vs gated-SPECT), in men (p = 0.004, n = 313) and in women (p = 0.03, n = 112) as well as in the non-infarct patients (p = 0.005, n = 186 in 1-3 vessel disease and p = 0.015, n = 140 in MVD). In this large multicenter, multivendor study the diagnostic performance of perfusion-CMR to detect CAD was superior to perfusion SPECT in the entire population and in sub-groups. Perfusion-CMR can be recommended as an alternative for SPECT imaging. ClinicalTrials.gov, Identifier: NCT00977093.


Ginsenoside Rh2 ameliorates scopolamine-induced learning deficit in mice.
To understand memory-enhancing effect of red ginseng biotransformed by Bifidobacterium longum H-1 (RGB), which more potently improved scopolamine-induced learning deficit than red ginseng in the preliminary experiment, its main constituents, ginsenosides Rb1, Rg3 and Rh2, were isolated and their memory-enhancing effects investigated in scopolamine-treated mice by using passive avoidance and Y-maze tests. Among them, ginsenoside Rh2 most potently reversed memory impairment caused by scopolamine. Ginsenoside Rh2 also significantly shortened the escape latencies prolonged by scopolamine in the Morris water maze test (p<0.001) and increased the swimming time shorten by scopolamine within the platform quadrant (p<0.05). The ginsenoside Rh2 (3 muM) reversed scopolamine (10 muM)-induced suppression of long-term potentiation. It recovered field excitatory post synaptic potential (fEPSP) amplitude potentiation to 152.3+/-8.7% of the control (p<0.05). Based on these findings, RGB and its main constituent, ginsenoside Rh2, might improve learning deficits. Also the memory-enhancing effects of RGB may be dependent on the content of ginsenoside Rh2.


Efficacy of insurance for organisational disaster recovery: case study of the 2010 and 2011 Canterbury earthquakes.
Insurance is widely acknowledged to be an important component of an organisation's disaster preparedness and resilience. Yet, little analysis exists of how well current commercial insurance policies and practices support organisational recovery in the wake of a major disaster. This exploratory qualitative research, supported by some quantitative survey data, evaluated the efficacy of commercial insurance following the sequence of earthquakes in Canterbury, New Zealand, in 2010 and 2011. The study found that, generally, the commercial insurance sector performed adequately, given the complexity of the events. However, there are a number of ways in which insurers could improve their operations to increase the efficacy of commercial insurance cover and to assist organisational recovery following a disaster. The most notable of these are: (i) better wording of policies; (ii) the availability of sector-specific policies; (iii) the enhancement of claims assessment systems; and (iv) risk-based policy pricing to incentivise risk reduction measures.


Insomnia and paranoia.
Insomnia is a potential cause of anxiety, depression, and anomalies of experience; separate research has shown that anxiety, depression and anomalies of experience are predictors of paranoia. Thus insomnia may contribute to the formation and maintenance of persecutory ideation. The aim was to examine for the first time the association of insomnia symptoms and paranoia in the general population and the extent of insomnia in individuals with persecutory delusions attending psychiatric services. Assessments of insomnia, persecutory ideation, anxiety, and depression were completed by 300 individuals from the general population and 30 individuals with persecutory delusions and a diagnosis of non-affective psychosis. Insomnia symptoms were clearly associated with higher levels of persecutory ideation. Consistent with the theoretical understanding of paranoia, the association was partly explained by the presence of anxiety and depression. Moderate or severe insomnia was present in more than 50% of the delusions group. The study provides the first direct evidence that insomnia is common in individuals with high levels of paranoia. It is plausible that sleep difficulties contribute to the development of persecutory ideation. The intriguing implication is that insomnia interventions for this group could have the added benefit of lessening paranoia.


Characterization of a biogas-producing microbial community by short-read next generation DNA sequencing.
Renewable energy production is currently a major issue worldwide. Biogas is a promising renewable energy carrier as the technology of its production combines the elimination of organic waste with the formation of a versatile energy carrier, methane. In consequence of the complexity of the microbial communities and metabolic pathways involved the biotechnology of the microbiological process leading to biogas production is poorly understood. Metagenomic approaches are suitable means of addressing related questions. In the present work a novel high-throughput technique was tested for its benefits in resolving the functional and taxonomical complexity of such microbial consortia. It was demonstrated that the extremely parallel SOLiD™ short-read DNA sequencing platform is capable of providing sufficient useful information to decipher the systematic and functional contexts within a biogas-producing community. Although this technology has not been employed to address such problems previously, the data obtained compare well with those from similar high-throughput approaches such as 454-pyrosequencing GS FLX or Titanium. The predominant microbes contributing to the decomposition of organic matter include members of the Eubacteria, class Clostridia, order Clostridiales, family Clostridiaceae. Bacteria belonging in other systematic groups contribute to the diversity of the microbial consortium. Archaea comprise a remarkably small minority in this community, given their crucial role in biogas production. Among the Archaea, the predominant order is the Methanomicrobiales and the most abundant species is Methanoculleus marisnigri. The Methanomicrobiales are hydrogenotrophic methanogens. Besides corroborating earlier findings on the significance of the contribution of the Clostridia to organic substrate decomposition, the results demonstrate the importance of the metabolism of hydrogen within the biogas producing microbial community. Both microbiological diversity and the regulatory role of the hydrogen metabolism appear to be the driving forces optimizing biogas-producing microbial communities. The findings may allow a rational design of these communities to promote greater efficacy in large-scale practical systems. The composition of an optimal biogas-producing consortium can be determined through the use of this approach, and this systematic methodology allows the design of the optimal microbial community structure for any biogas plant. In this way, metagenomic studies can contribute to significant progress in the efficacy and economic improvement of biogas production.


Participatory monitoring and evaluation approaches that influence decision-making: lessons from a maternal and newborn study in Eastern Uganda.
The use of participatory monitoring and evaluation (M&E) approaches is important for guiding local decision-making, promoting the implementation of effective interventions and addressing emerging issues in the course of implementation. In this article, we explore how participatory M&E approaches helped to identify key design and implementation issues and how they influenced stakeholders' decision-making in eastern Uganda. The data for this paper is drawn from a retrospective reflection of various M&E approaches used in a maternal and newborn health project that was implemented in three districts in eastern Uganda. The methods included qualitative and quantitative M&E techniques such as key informant interviews, formal surveys and supportive supervision, as well as participatory approaches, notably participatory impact pathway analysis. At the design stage, the M&E approaches were useful for identifying key local problems and feasible local solutions and informing the activities that were subsequently implemented. During the implementation phase, the M&E approaches provided evidence that informed decision-making and helped identify emerging issues, such as weak implementation by some village health teams, health facility constraints such as poor use of standard guidelines, lack of placenta disposal pits, inadequate fuel for the ambulance at some facilities, and poor care for low birth weight infants. Sharing this information with key stakeholders prompted them to take appropriate actions. For example, the sub-county leadership constructed placenta disposal pits, the district health officer provided fuel for ambulances, and health workers received refresher training and mentorship on how to care for newborns. Diverse sources of information and perspectives can help researchers and decision-makers understand and adapt evidence to contexts for more effective interventions. Supporting districts to have crosscutting, routine information generating and sharing platforms that bring together stakeholders from different sectors is therefore crucial for the successful implementation of complex development interventions.


Molecular characterization of helix-loop-helix peptides.
A class of regulators of eukaryotic gene expression contains a conserved amino acid sequence responsible for protein oligomerization and binding to DNA. This structure consists of an arginine- and lysine-rich basic region followed by a helix-loop-helix motif, which together mediate specific binding to DNA. Peptides were prepared that span this motif in the MyoD protein; in solution, they formed alpha-helical dimers and tetramers. They bound to DNA as dimers and their alpha-helical content increased on binding. Parallel and antiparallel four-helix models of the DNA-bound dimer were constructed. Peptides containing disulfide bonds were engineered to test the correctness of the two models. A disulfide that is compatible with the parallel model promotes specific interaction with DNA, whereas a disulfide compatible with the antiparallel model abolishes specific binding. Electron paramagnetic resonance (EPR) measurements of nitroxide-labeled peptides provided intersubunit distance measurements that also supported the parallel model.


Medical surveillance of clandestine drug laboratory investigators.
Law enforcement officers investigating clandestine drug laboratories may be exposed to a wide range of hazardous chemicals. This study was conducted to determine the extent of persistent health effects seen in California drug laboratory investigators after occupational exposure. Study participants with a minimum of 1 year of laboratory investigations completed a questionnaire evaluating occupational and personal health history and consented to review of their medical surveillance examinations and administrative records. The 40 participating investigators averaged 6.1 +/- 2.5 annual medical evaluations for the period 1991 to 1998. Average annual decline in forced expiratory volume in 1 second (FEV1) was 64.0 +/- 138.0 mL/year (median, 40.0 mL/year). For 34 subjects with valid exposure data, longer duration use of respiratory protection was associated with a less rapid decline in FEV1, whereas lack of respiratory protection during the processing phase of laboratory investigation was associated with a more rapid annual decline. There were no significant longitudinal changes in serum alanine aminotransferase, serum aspartate aminotransferase, hemoglobin, and white blood cell count, although platelets declined slightly. Law enforcement personnel investigating clandestine drug laboratories may have long-term respiratory effects from chemical exposure, for which more assiduous use of respiratory protection is recommended.


Complex parameter landscape for a complex neuron model.
The electrical activity of a neuron is strongly dependent on the ionic channels present in its membrane. Modifying the maximal conductances from these channels can have a dramatic impact on neuron behavior. But the effect of such modifications can also be cancelled out by compensatory mechanisms among different channels. We used an evolution strategy with a fitness function based on phase-plane analysis to obtain 20 very different computational models of the cerebellar Purkinje cell. All these models produced very similar outputs to current injections, including tiny details of the complex firing pattern. These models were not completely isolated in the parameter space, but neither did they belong to a large continuum of good models that would exist if weak compensations between channels were sufficient. The parameter landscape of good models can best be described as a set of loosely connected hyperplanes. Our method is efficient in finding good models in this complex landscape. Unraveling the landscape is an important step towards the understanding of functional homeostasis of neurons.


Hematocrit correction does not improve glucose monitor accuracy in the assessment of neonatal hypoglycemia.
The lack of accuracy of point of care (POC) glucose monitors has limited their use in the diagnosis of neonatal hypoglycemia. Hematocrit plays an important role in explaining discordant results. The objective of this study was to to assess the effect of hematocrit on the diagnostic performance of Abbott Precision Xceed Pro (PXP) and Nova StatStrip (StatStrip) monitors in neonates. All blood samples ordered for laboratory glucose measurement were analyzed using the PXP and StatStrip and compared with the laboratory analyzer (ABL 800 Blood Gas analyzer [ABL]). Acceptable error targets were ±15% for glucose monitoring and ±5% for diagnosis. A total of 307 samples from 176 neonates were analyzed. Overall, 90% of StatStrip and 75% of PXP values met the 15% error limit and 45% of StatStrip and 32% of PXP values met the 5% error limit. At glucose concentrations ≤4 mmol/L, 83% of StatStrip and 79% of PXP values met the 15% error limit, while 37% of StatStrip and 38% of PXP values met the 5% error limit. Hematocrit explained 7.4% of the difference between the PXP and ABL whereas it accounted for only 0.09% of the difference between the StatStrip and ABL. The ROC analysis showed the screening cut point with the best performance for identifying neonatal hypoglycemia was 3.2 mmol/L for StatStrip and 3.3 mmol/L for PXP. Despite a negligible hematocrit effect for the StatStrip, it did not achieve recommended error limits. The StatStrip and PXP glucose monitors remain suitable only for neonatal hypoglycemia screening with confirmation required from a laboratory analyzer.


Patterns of Postoperative Delirium in Children.
Intensive care delirium is a substantial problem in adults. Intensive care delirium is increasingly recognized in pediatrics in parallel with the development of specific scoring systems for children. However, little is known about the fluctuating course of intensive care delirium in children after surgery and possible implications on diagnostic and therapeutic strategies. Patients that needed treatment in the PICU following elective surgery were screened for intensive care delirium with the Cornell Assessment of Pediatric Delirium. When the patients were awake (Richmond Agitation and Sedation Score > -3), two trained investigators conducted the Cornell Assessment of Pediatric Delirium twice daily for five consecutive days. Ninety-three patients aged 0 to 17 years. Eight hundred forty-five assessments completed. Of the 845 scores, 230 were consistent with delirium (27.2%). Sixty-one patients (65.5%) were diagnosed with intensive care delirium. Half of these patients (n = 30; 32.2%) had a short-lasting delirium that resolved within 24 hours, and half (n = 31; 33.3%) had delirium of longer duration. Delirium could be clearly distinguished from sedation by analysis of individual test items of the Cornell Assessment of Pediatric Delirium. Time spent delirious had a measurable effect on outcome variables, including hospital length of stay. Most postoperative PICU patients develop intensive care delirium. Some have a short-lasting course, which underlines the need for early screening. Our findings support the view of delirium as a continuum of acute neurocognitive disorder. Further research is needed to investigate prophylactic and treatment approaches for intensive care delirium.


Epidemiology and risk factors for Staphylococcus aureus colonization in children in the post-PCV7 era.
The incidence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) has risen dramatically in the U.S., particularly among children. Although Streptococcus pneumoniae colonization has been inversely associated with S. aureus colonization in unvaccinated children, this and other risk factors for S. aureus carriage have not been assessed following widespread use of the heptavalent pneumococcal conjugate vaccine (PCV7). Our objectives were to (1) determine the prevalence of S. aureus and MRSA colonization in young children in the context of widespread use of PCV7; and (2) examine risk factors for S. aureus colonization in the post-PCV7 era, including the absence of vaccine-type S. pneumoniae colonization. Swabs of the anterior nares (S. aureus) were obtained from children enrolled in an ongoing study of nasopharyngeal pneumococcal colonization of healthy children in 8 Massachusetts communities. Children 3 months to <7 years of age seen for well child or sick visits in primary care offices from 11/03-4/04 and 10/06-4/07 were enrolled. S. aureus was identified and antibiotic susceptibility testing was performed. Epidemiologic risk factors for S. aureus colonization were collected from parent surveys and chart reviews, along with data on pneumococcal colonization. Multivariate mixed model analyses were performed to identify factors associated with S. aureus colonization. Among 1,968 children, the mean age (SD) was 2.7 (1.8) years, 32% received an antibiotic in the past 2 months, 2% were colonized with PCV7 strains and 24% were colonized with non-PCV7 strains. The prevalence of S. aureus colonization remained stable between 2003-04 and 2006-07 (14.6% vs. 14.1%), while MRSA colonization remained low (0.2% vs. 0.9%, p = 0.09). Although absence of pneumococcal colonization was not significantly associated with S. aureus colonization, age (6-11 mo vs. > or =5 yrs, OR 0.39 [95% CI 0.24-0.64]; 1-1.99 yrs vs. > or =5 yrs, OR 0.35 [0.23-0.54]; 2-2.99 yrs vs. > or =5 yrs, OR 0.45 [0.28-0.73]; 3-3.99 yrs vs. > or =5 yrs, OR 0.53 [0.33-0.86]) and recent antibiotic use were significant predictors in multivariate models. In Massachusetts, S. aureus and MRSA colonization remained stable from 2003-04 to 2006-07 among children <7 years despite widespread use of pneumococcal conjugate vaccine. S. aureus nasal colonization varies by age and is inversely correlated with recent antibiotic use.


Assessment of boreal forest historical C dynamics in the Yukon River Basin: relative roles of warming and fire regime change.
Carbon (C) dynamics of boreal forest ecosystems have substantial implications for efforts to mitigate the rise of atmospheric CO2 and may be substantially influenced by warming and changing wildfire regimes. In this study we applied a large-scale ecosystem model that included dynamics of organic soil horizons and soil organic matter characteristics of multiple pools to assess forest C stock changes of the Yukon River Basin (YRB) in Alaska, USA, and Canada from 1960 through 2006, a period characterized by substantial climate warming and increases in wildfire. The model was calibrated for major forests with data from long-term research sites and evaluated using a forest inventory database. The regional assessment indicates that forest vegetation C storage increased by 46 Tg C, but that total soil C storage did not change appreciably during this period. However, further analysis suggests that C has been continuously lost from the mineral soil horizon since warming began in the 1970s, but has increased in the amorphous organic soil horizon. Based on a factorial experiment, soil C stocks would have increased by 158 Tg C if the YRB had not undergone warming and changes in fire regime. The analysis also identified that warming and changes in fire regime were approximately equivalent in their effects on soil C storage, and interactions between these two suggests that the loss of organic horizon thickness associated with increases in wildfire made deeper soil C stocks more vulnerable to loss via decomposition. Subbasin analyses indicate that C stock changes were primarily sensitive to the fraction of burned forest area within each subbasin and that boreal forest ecosystems in the YRB are currently transitioning from being sinks to sources at -0.7% annual area burned. We conclude that it is important for international mitigation efforts focused on controlling atmospheric CO2 to consider how climate warming and changes in fire regime may concurrently affect the CO2 sink strength of boreal forests. It is also important for large-scale biogeochemical and earth system models to include organic soil dynamics in applications to assess regional C dynamics of boreal forests responding to warming and changes in fire regime.


Neural prosthetic systems: current problems and future directions.
By decoding neural activity into useful behavioral commands, neural prosthetic systems seek to improve the lives of severely disabled human patients. Motor decoding algorithms, which map neural spiking data to control parameters of a device such as a prosthetic arm, have received particular attention in the literature. Here, we highlight several outstanding problems that exist in most current approaches to decode algorithm design. These include two problems that we argue will unlikely result in further dramatic increases in performance, specifically spike sorting and spiking models. We also discuss three issues that have been less examined in the literature, and we argue that addressing these issues may result in dramatic future increases in performance. These include: non-stationarity of recorded waveforms, limitations of a linear mappings between neural activity and movement kinematics, and the low signal to noise ratio of the neural data. We demonstrate these problems with data from 39 experimental sessions with a non-human primate performing reaches and with recent literature. In all, this study suggests that research in cortically-controlled prosthetic systems may require reprioritization to achieve performance that is acceptable for a clinically viable human system.


Plastic Debris in 29 Great Lakes Tributaries: Relations to Watershed Attributes and Hydrology.
Plastic debris is a growing contaminant of concern in freshwater environments, yet sources, transport, and fate remain unclear. This study characterized the quantity and morphology of floating micro- and macroplastics in 29 Great Lakes tributaries in six states under different land covers, wastewater effluent contributions, population densities, and hydrologic conditions. Tributaries were sampled three or four times each using a 333 μm mesh neuston net. Plastic particles were sorted by size, counted, and categorized as fibers/lines, pellets/beads, foams, films, and fragments. Plastics were found in all 107 samples, with a maximum concentration of 32 particles/m3 and a median of 1.9 particles/m3. Ninety-eight percent of sampled plastic particles were less than 4.75 mm in diameter and therefore considered microplastics. Fragments, films, foams, and pellets/beads were positively correlated with urban-related watershed attributes and were found at greater concentrations during runoff-event conditions. Fibers, the most frequently detected particle type, were not associated with urban-related watershed attributes, wastewater effluent contribution, or hydrologic condition. Results from this study add to the body of information currently available on microplastics in different environmental compartments, including unique contributions to quantify their occurrence and variability in rivers with a wide variety of different land-use characteristics while highlighting differences between surface samples from rivers compared with lakes.


Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans.
We developed a method to extract differentially chondroitin sulfate proteoglycans (CSPGs) that are diffusely present in the central nervous system (CNS) matrix and CSPGs that are present in the condensed matrix of perineuronal nets (PNNs). Adult rat brain was sequentially extracted with Tris-buffered saline (TBS), TBS-containing detergent, 1 m NaCl, and 6 m urea. Extracting tissue sections with these buffers showed that the diffuse and membrane-bound CSPGs were extracted in the first three buffers, but PNN-associated CSPGs remained and were only removed by 6 m urea. Most of the CSPGs were extracted to some degree with all the buffers, with neurocan, brevican, aggrecan, and versican particularly associated with the stable urea-extractable PNNs. The CSPGs in stable complexes only extractable in urea buffer are found from postnatal day 7-14 coinciding with PNN formation. Disaccharide composition analysis indicated a different glycosaminoglycan (GAG) composition for PGs strongly associated with extracellular matrix (ECM). For CS/dermatan sulfate (DS)-GAG the content of nonsulfated, 6-O-sulfated, 2,6-O-disulfated, and 4,6-O-disulfated disaccharides were higher and for heparan sulfate (HS)-GAG, the content of 6-O-sulfated, 2-N-, 6-O-disulfated, 2-O-, 2-N-disulfated, and 2-O-, 2-N-, 6-O-trisulfated disaccharides were higher in urea extract compared with other buffer extracts. Digestions with chondroitinase ABC and hyaluronidase indicated that aggrecan, versican, neurocan, brevican, and phosphacan are retained in PNNs through binding to hyaluronan (HA). A comparison of the brain and spinal cord ECM with respect to CSPGs indicated that the PNNs in both parts of the CNS have the same composition.


What Drives National Differences in Intensive Grandparental Childcare in Europe?
Grandparents play an important role in looking after grandchildren, although intensive grandparental childcare varies considerably across Europe. Few studies have explicitly investigated the extent to which such cross-national variations are associated with national level differences in individual demographic and socio-economic distributions along with contextual-structural and cultural factors (e.g., variations in female labor force participation, childcare provision, and cultural attitudes). We used multilevel models to examine associations between intensive grandparental childcare and contextual-structural and cultural factors, after controlling for grandparent, parent, and child characteristics using nationally representative data from the Survey of Health, Ageing and Retirement in Europe. Even controlling for cross-national differences in demographic and socio-economic distributions, contextual-structural factors play an important role in explaining grandparental childcare variations in Europe. In particular, higher levels of intensive grandparental childcare are found in countries with low labor force participation among younger and older women, and low formal childcare provision, where mothers in paid work largely rely on grandparental support on an almost daily basis. Encouraging older women to remain in paid work is likely to have an impact on grandchild care which in turn may affect mothers' employment, particularly in Southern European countries where there is little formal childcare.


Racial Disparities in Nutritional Risk among Community-Dwelling Older Adults in Adult Day Health Care.
Information regarding nutritional risk among users of American adult day health centers (ADHCs), 60% of whom are racial minorities, is scant. This study examined nutritional risk and associated factors in a diverse sample ADHC users aged 50+ using secondary cross-sectional analysis of data collected between 2013 and 2017. Risk was assessed using the DETERMINE checklist, and results were stratified by race. The majority of the sample (N = 188) was at moderate (45.2%) or high (38.5%) nutritional risk, with statistically significant racial differences. Blacks were at greater risk than any other group: 65% had high nutritional risk; 76.5% ate <5 servings of fruits, vegetables, or milk daily; 21% ate <2 meals daily, 48.5% reported involuntary weight loss/gain, and 41.2% had tooth loss/mouth pain. Older adults in ADHCs are at elevated risk of malnutrition, disproportionately so amongst blacks. Both routine nutrition screening and population-specific approaches are needed to attenuate risk.


The role of conformation in ion permeation in a K+ channel.
The chemical-physical basis for K+ permeation and selectivity in K+ channels has been the focus of attention of many theoretical and computational studies since the first crystal structure was obtained by the Mackinnon lab in 1998. Most of the previous studies reported focused on atomic descriptions of permeation events in the selectivity filter of K+ channels in their closed conformation. In this Article, a comparative analysis of permeation events in the KirBac1.1 K+ channel in a closed- and an open-state model is presented. The availability of models of the same channel in two different conformations has made this comparative analysis possible. All-atom molecular dynamics simulations of both models in a membrane environment have been carried out. As previously suggested by many studies of this and other K+ channels, when the channel is closed the ion conduction involves transitions between two main sites of the selectivity filter, with two K+ ions each coordinated by eight carbonyl oxygens of the protein and separated by a water molecule. In contrast, in our open-state model, three to four K+ ions move in a concerted motion during the permeation process. The selectivity filter, though maintaining a certain degree of flexibility to cope with these cooperative events, appears to be more "symmetrical" and robust in the simulations of the open-state channel when it is occupied by an average of three ions. Therefore, it appears as if the occupation of the pore depends upon the global conformation of the channel. Due to the complexity of these systems, only single conduction events have been described by means of molecular dynamics trajectories. To complement these results and describe the energetics of ion permeation and ionic fluxes, continuum approaches (Poisson-Boltzmann and Poisson-Nernst-Planck theory) have been also employed.


From forms to focus. A new teaching model in ambulatory medicine.
We have developed a simple generalizable model of teaching ambulatory medicine that adopts successful elements of inpatient teaching and addresses deficiencies in traditional ambulatory forums. This model combines resident analysis of the patient encounter via a "clinical encounter form" (CEF) with faculty-led ambulatory medicine rounds (AMR). Its objectives are to integrate teaching and quality assessment; be explicit about the relation between the record and the physician's clinical thinking; teach around every patient; focus on selected aspects of a case in limited time; and permit appropriate rounds preparation by faculty. The CEF-AMR model, like inpatient rounds, allows teaching to be focused on real patient issues; all patients are reviewed and quality is assured, and interesting teaching points can be selected, prepared, and discussed efficiently in limited time. It is the "classroom" complement to faculty "bedside" precepting and has made teaching ambulatory medicine feasible, clinically relevant, and well-informed. Perhaps most importantly, the CEF-AMR model encourages self-analysis of clinical decisions and makes explicit the key elements of clinical judgment.


Characterization of minisatellites in Arabidopsis thaliana with sequence similarity to the human minisatellite core sequence.
A strategy based on random PCR amplification was used to isolate new repetitive elements of Arabidopsis thaliana. One of the random PCR product analyzed by this approach contained a tandem repetitive minisatellite sequence composed of 33 bp repeated units. The genomic locus corresponding to this PCR product was isolated by screening a lambda genomic library. New related loci were also isolated from the genomic library by screening with a 14 mer oligonucleotide representing a region conserved among the different repeated units. Alignment of the consensus sequence for each minisatellite locus allowed the definition of an Arabidopsis thaliana core sequence that shows strong sequence similarities with the human core sequence and with the generalized recombination signal Chi of Escherichia coli. The minisatellites were tested for their ability to detect polymorphism, and their chromosomal position was established.


The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act.
This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the US Controlled Substances Act (CSA). Research suggests the potential safety and efficacy of psilocybin in treating cancer-related psychiatric distress and substance use disorders, setting the occasion for this review. A more extensive assessment of abuse potential according to an 8-factor analysis would eventually be required to guide appropriate schedule placement. Psilocybin, like other 5-HT2A agonist classic psychedelics, has limited reinforcing effects, supporting marginal, transient non-human self-administration. Nonetheless, mushrooms with variable psilocybin content are used illicitly, with a few lifetime use occasions being normative among users. Potential harms include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders. However, scope of use and associated harms are low compared to prototypical abused drugs, and the medical model addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility. CONCLUSIONS: (1) psilocybin has an abuse potential appropriate for CSA scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable New Drug Application (NDA) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in Schedule IV may be appropriate if a psilocybin-containing medicine is approved. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.


Computerised cognitive behaviour therapy for obsessive-compulsive disorder: a systematic review.
Computer-guided therapy is an innovative treatment strategy that could have an important role in the future of psychological treatment. This paper summarises the available published evidence that assesses the effectiveness of a computerised cognitive behaviour therapy (CCBT) for obsessive-compulsive disorder (OCD). Fifteen electronic bibliographic databases including Medline, Embase, the Cochrane Library, Cinahl, PsycINFO, Biological Abstracts, HMIC and NHS CRD databases were comprehensively searched in March 2004: ['obsessive compulsive disorder' (text and indexed terms)] AND ['cognitive therapy' (text and indexed terms)] AND ['computer' (text and indexed terms)]. Reference lists of included studies, guidelines, generic research, trials registers and specialist mental health sites were hand-searched. The search produced 149 citations from which we identified two RCTs and two single-arm studies with relevant data. All four studies used one software programme - BTSteps. In the large RCT, YBOCS effect sizes for BTSteps, therapist-led cognitive behaviour therapy (TCBT) and relaxation (RLX) were 0.84, 1.22, and 0.35, respectively. The smaller RCT found significantly better outcomes with brief scheduled support compared to brief on-demand phone support. BTSteps was as good as TCBT for reducing time spent in rituals and obsessions and for improving the Work and Social Adjustment Scale (WSA), and was superior to RLX treatment. The available evidence also showed that improvement of OCD persisted beyond the end of CCBT. TCBT was more effective than CCBT for all patients overall though not in those who went on to start self-exposure. Such a system has the potential to widen the access to CBT in general and considerably shorten clinician-guided care.


Deep learning for detection and segmentation of artefact and disease instances in gastrointestinal endoscopy.
The Endoscopy Computer Vision Challenge (EndoCV) is a crowd-sourcing initiative to address eminent problems in developing reliable computer aided detection and diagnosis endoscopy systems and suggest a pathway for clinical translation of technologies. Whilst endoscopy is a widely used diagnostic and treatment tool for hollow-organs, there are several core challenges often faced by endoscopists, mainly: 1) presence of multi-class artefacts that hinder their visual interpretation, and 2) difficulty in identifying subtle precancerous precursors and cancer abnormalities. Artefacts often affect the robustness of deep learning methods applied to the gastrointestinal tract organs as they can be confused with tissue of interest. EndoCV2020 challenges are designed to address research questions in these remits. In this paper, we present a summary of methods developed by the top 17 teams and provide an objective comparison of state-of-the-art methods and methods designed by the participants for two sub-challenges: i) artefact detection and segmentation (EAD2020), and ii) disease detection and segmentation (EDD2020). Multi-center, multi-organ, multi-class, and multi-modal clinical endoscopy datasets were compiled for both EAD2020 and EDD2020 sub-challenges. The out-of-sample generalization ability of detection algorithms was also evaluated. Whilst most teams focused on accuracy improvements, only a few methods hold credibility for clinical usability. The best performing teams provided solutions to tackle class imbalance, and variabilities in size, origin, modality and occurrences by exploring data augmentation, data fusion, and optimal class thresholding techniques.


The history of Coast Salish "woolly dogs" revealed by ancient genomics and Indigenous Knowledge.
Ancestral Coast Salish societies in the Pacific Northwest kept long-haired "woolly dogs" that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from "Mutton," collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.


Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes.
T cell epitopes represent the molecular code words through which the adaptive immune system communicates. In the context of a T cell-mediated autoimmune disease such as type 1 diabetes, CD4 and CD8 T cell recognition of islet autoantigenic epitopes is a key step in the autoimmune cascade. Epitope recognition takes place during the generation of tolerance, during its loss as the disease process is initiated, and during epitope spreading as islet cell damage is perpetuated. Epitope recognition is also a potentially critical element in therapeutic interventions such as antigen-specific immunotherapy. T cell epitope discovery, therefore, is an important component of type 1 diabetes research, in both human and murine models. With this in mind, in this review we present a comprehensive guide to epitopes that have been identified as T cell targets in autoimmune diabetes. Targets of both CD4 and CD8 T cells are listed for human type 1 diabetes, for humanized [human leucocyte antigen (HLA)-transgenic] mouse models, and for the major spontaneous disease model, the non-obese diabetic (NOD) mouse. Importantly, for each epitope we provide an analysis of the relative stringency with which it has been identified, including whether recognition is spontaneous or induced and whether there is evidence that the epitope is generated from the native protein by natural antigen processing. This analysis provides an important resource for investigating diabetes pathogenesis, for developing antigen-specific therapies, and for developing strategies for T cell monitoring during disease development and therapeutic intervention.


Patient experiences with public hospital care: first benchmark survey in Hong Kong.
OBJECTIVE. To measure patient satisfaction in relation to in-patient experience in public hospitals. DESIGN. Cross-sectional study. SETTING. Twenty-five selected Hospital Authority acute and convalescence hospitals in Hong Kong. PARTICIPANTS. Eligible patients discharged between 15 June and 27 September 2010 from the selected Hospital Authority public hospitals. MAIN OUTCOME MEASURES. A total of 54 items were used to measure patient experience on aspects of hospital care. They included the process of admission to hospital, staying in the hospital and ward (environment, food and facilities; hospital staff; patient care and treatment), the process of leaving hospital, and the overall impression of hospital care. Free-text comments from respondents were also recorded. RESULTS. A total of 5030 patients were successfully interviewed, amounting to a response rate of 52%. The findings showed that 80% (confidence interval, 79-81%) of patients rated the care they received in hospital as good or better. However, there were a few areas where performance was relatively low, including waiting time for a ward bed for accident and emergency cases, food quality, infection control, information provided about their condition/treatment, seeking patient input about their opinions and quality of care, and patient engagement in the decisions about their treatment and care, as well as the discharge process. CONCLUSIONS. This patient experience survey used a validated instrument (Hong Kong Inpatient Experience Questionnaire) to provide important insights to executives and health care professionals on their care to patients and to identify areas for improvement in public hospitals. Further surveys should be carried out to monitor changes in patient experience and satisfaction on a regular basis. Such surveys could facilitate improvements through analysis of results on patient satisfaction.


Cloning and expression of genomic DNA sequences coding for putative erythrocyte membrane-associated antigens of Plasmodium falciparum.
Genomic DNA fragments of Plasmodium falciparum generated by mung bean nuclease digestion were cloned in the lambda expression vector lambda JK2. The resulting library was screened with a rabbit antiserum raised against purified membranes of P. falciparum-infected erythrocytes and with a serum pool from immune humans from an endemic area of Liberia. Positive clones were rescreened with a series of human and monkey sera. Twelve selected clones were analysed in detail. Four of them corresponded to already described membrane-associated P. falciparum antigens. The other positive clones contained inserts which, according to the nucleotide sequence, Southern blot analysis and immunological characteristics, correspond to so far unknown antigens.


How to become a uropathogen: comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains.
Uropathogenic Escherichia coli (UPEC) strain 536 (O6:K15:H31) is one of the model organisms of extraintestinal pathogenic E. coli (ExPEC). To analyze this strain's genetic basis of urovirulence, we sequenced the entire genome and compared the data with the genome sequence of UPEC strain CFT073 (O6:K2:H1) and to the available genomes of nonpathogenic E. coli strain MG1655 (K-12) and enterohemorrhagic E. coli. The genome of strain 536 is approximately 292 kb smaller than that of strain CFT073. Genomic differences between both UPEC are mainly restricted to large pathogenicity islands, parts of which are unique to strain 536 or CFT073. Genome comparison underlines that repeated insertions and deletions in certain parts of the genome contribute to genome evolution. Furthermore, 427 and 432 genes are only present in strain 536 or in both UPEC, respectively. The majority of the latter genes is encoded within smaller horizontally acquired DNA regions scattered all over the genome. Several of these genes are involved in increasing the pathogens' fitness and adaptability. Analysis of virulence-associated traits expressed in the two UPEC O6 strains, together with genome comparison, demonstrate the marked genetic and phenotypic variability among UPEC. The ability to accumulate and express a variety of virulence-associated genes distinguishes ExPEC from many commensals and forms the basis for the individual virulence potential of ExPEC. Accordingly, instead of a common virulence mechanism, different ways exist among ExPEC to cause disease.


Preschool children who are frequent attenders in emergency departments: an observational study of associated demographics and clinical characteristics.
Unscheduled visits to emergency departments (ED) have increased in the UK in recent years. Children who are repeat attenders are relatively understudied. To describe the sociodemographic and clinical characteristics of preschoolers who attend ED a large District General Hospital. Observational study analysing routinely collected ED operational data. Children attending four or more visits per year were considered as 'frequent attenders'. Poisson regression was used with demographic details (age, sex, ethnicity, sociodemographic status) to predict number of attendances seen in the year. We further analysed detailed diagnostic characteristics of a random sample of 10% of attendees. 10 169 patients visited in the 12-month period with 16 603 attendances. 655 individuals attended on 3335 occasions. 6.4% of this population accounted for 20.1% of total visits. In the 10% sample, there were 304 attendances, and 69 (23%) had an underlying chronic long-standing illness (CLSI). This group were 2.4 times more likely to be admitted as inpatients compared with those without such conditions, median length of stay of 6.2 hours versus 2.5 hours (p=NS). Frequent ED attenders fall broadly into two distinct clinical groups: those who habitually return with self-limiting conditions and those with or without exacerbation of underlying CLSI. Both groups may be amenable to both additional nursing and other forms of community support to enhance self-care and continuity of care. Further research is required to increase our understanding of specific individual family and health system factors that predict repeat attendance in this age group.


AIDS conspiracy beliefs and unsafe sex in Cape Town.
This paper uses multivariate logistic regressions to explore: (1) potential socio-economic, cultural, psychological and political determinants of AIDS conspiracy beliefs among young adults in Cape Town; and (2) whether these beliefs matter for unsafe sex. Membership of a religious organisation reduced the odds of believing AIDS origin conspiracy theories by more than a third, whereas serious psychological distress more than doubled it and belief in witchcraft tripled the odds among Africans. Political factors mattered, but in ways that differed by gender. Tertiary education and relatively high household income reduced the odds of believing AIDS conspiracies for African women (but not men) and trust in President Mbeki's health minister (relative to her successor) increased the odds sevenfold for African men (but not women). Never having heard of the Treatment Action Campaign (TAC), the pro-science activist group that opposed Mbeki on AIDS, tripled the odds of believing AIDS conspiracies for African women (but not men). Controlling for demographic, attitudinal and relationship variables, the odds of using a condom were halved amongst female African AIDS conspiracy believers, whereas for African men, never having heard of TAC and holding AIDS denialist beliefs were the key determinants of unsafe sex.


Type I interferon drives tumor necrosis factor-induced lethal shock.
Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-alpha receptor 1 (IFNAR-1) or in IFN-beta are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1(-/-) mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1(-/-) mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element-dependent genes, many of which encode chemokines. In livers of IFNAR-1(-/-) mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.


Biodegradable Laser Arrays Self-Assembled from Plant Resources.
The transition toward future sustainable societies largely depends on disruptive innovations in biobased materials to substitute nonsustainable advanced functional materials. In the field of optics, advanced devices (e.g., lasers or metamaterial devices) are typically manufactured using top-down engineering and synthetic materials. This work breaks with such concepts and switchable lasers self-assembled from plant-based cellulose nanocrystals and fluorescent polymers at room temperature and from water are shown. Controlled structure formation allows laser-grade cholesteric photonic bandgap materials, in which the photonic bandgap is matched to the fluorescence emission to function as an efficient resonator for low threshold multimode lasing. The lasers can be switched on and off using humidity, and can be printed into pixelated arrays. Additionally, the materials exhibit stiffness above typical thermoplastic polymers and biodegradability in soil. The concept showcases that highly advanced functions can be encoded into biobased materials, and opens the design space for future sustainable optical devices of unprecedented function.


Around the world, adolescence is a time of heightened sensation seeking and immature self-regulation.
The dual systems model of adolescent risk-taking portrays the period as one characterized by a combination of heightened sensation seeking and still-maturing self-regulation, but most tests of this model have been conducted in the United States or Western Europe. In the present study, these propositions are tested in an international sample of more than 5000 individuals between ages 10 and 30 years from 11 countries in Africa, Asia, Europe and the Americas, using a multi-method test battery that includes both self-report and performance-based measures of both constructs. Consistent with the dual systems model, sensation seeking increased between preadolescence and late adolescence, peaked at age 19, and declined thereafter, whereas self-regulation increased steadily from preadolescence into young adulthood, reaching a plateau between ages 23 and 26. Although there were some variations in the magnitude of the observed age trends, the developmental patterns were largely similar across countries.


High frequency of K-ras codon 12 mutations in bronchoalveolar lavage fluid of patients at high risk for second primary lung cancer.
A high frequency of K-ras mutations may indicate preneoplastic changes in the bronchial epithelium as a result of genotoxic injury. With the use of sensitive detection techniques, we report a higher prevalence of K-ras mutations in bronchoalveolar lavage than has been reported previously for lung cancer. A PCR/ligase chain reaction technique was used to determine K-ras codon 12 mutations in a group of 52 bronchoalveolar lavage specimens from patients at risk of a second lung cancer. Of the specimens examined, 84% contained at least one mutation in K-ras codon 12, corroborated by an allele-specific hybridization method. These results suggest that point mutations in K-ras codon 12 are widespread in the bronchial epithelium. Based on these preliminary findings, further evaluation of this efficient sensitive assay to monitor K-ras status should be conducted in larger clinical cohorts where clinical outcomes will ultimately be available. Such a trial will define the utility of K-ras codon 12 mutation status as a marker of lung cancer.


Elbow Arthrodesis Using a Medially Positioned Plate in 6 Dogs.
The aim of this study was to report the surgical technique, associated complications and clinical outcome of elbow arthrodesis using a medially positioned plate. This was a retrospective case series. Six cases met the inclusion criteria. In all cases, the elbow was approached medially without the requirement for ulnar osteotomy. A non-locking 2.7/3.5- mm pre-contoured elbow arthrodesis plate was applied in 5/6 cases and a 2.0-mm String of Pearls plate applied in one case. The mean angle of arthrodesis was 118° (range: 113-130°). One major intraoperative complication occurred. Three minor and 3 major postoperative complications occurred. Postoperative imaging was available for 5/6 cases. Complete arthrodesis was confirmed by imaging in 4/5 cases, partial progression of arthrodesis was documented in 1/5 cases and no further images were deemed necessary. Postoperative Liverpool Osteoarthritis in Dogs score was available for two cases with scores of 20/52 and 10/52, respectively. Subjective outcomes in the remaining three cases were rated as acceptable more than 1 year postoperatively. Positioning the plate medially for elbow arthrodesis simplified the surgical approach, could be performed with a pre-contoured plate and allowed successful revision of an arthrodesis previously stabilized with a caudally positioned plate. The cases in this series had acceptable outcomes despite a high risk of complications.


Fatal case of newborn Lassa fever virus infection mimicking late onset neonatal sepsis: a case report from northern Nigeria.
Lassa fever is a zoonotic viral infection endemic to the West Africa countries. It is highly fatal during pregnancy and as such reports of neonatal onset Lassa fever infections are rare in scientific literature. We report a fatal case of Lassa fever in a 26-day-old neonate mimicking the diagnosis of late-onset neonatal sepsis. The patient is a 26-day-old neonate who was admitted with a day history of fever, poor feeding, pre-auricular lymphadenopathy and sudden parental death. He was initially evaluated for late onset neonatal sepsis. He later developed abnormal bleeding and multiple convulsions while on admission, prompting the need to evaluate for Lassa fever using reverse transcription polymerase chain reaction (RT-PCR). He died 31 h into admission and RT-PCR result was positive for Lassa fever. Neonatal Lassa fever infection is highly fatal and can mimic neonatal sepsis. High index of suspicion is needed particularly for atypical presentations of neonatal sepsis in Lassa fever endemic areas.


Long-term research avoids spurious and misleading trends in sustainability attributes of no-till.
Agricultural management recommendations based on short-term studies can produce findings inconsistent with long-term reality. Here, we test the long-term environmental sustainability and profitability of continuous no-till agriculture on yield, soil water availability, and N2 O fluxes. Using a moving window approach, we investigate the development and stability of several attributes of continuous no-till as compared to conventional till agriculture over a 29-year period at a site in the upper Midwest, US. Over a decade is needed to detect the consistent effects of no-till. Both crop yield and soil water availability required 15 years or longer to generate patterns consistent with 29-year trends. Only marginal trends for N2 O fluxes appeared in this period. Relative profitability analysis suggests that after initial implementation, 86% of periods between 10 and 29 years recuperated the initial expense of no-till implementation, with the probability of higher relative profit increasing with longevity. Importantly, statistically significant but misleading short-term trends appeared in more than 20% of the periods examined. Results underscore the importance of decadal and longer studies for revealing consistent dynamics and emergent outcomes of no-till agriculture, shown to be beneficial in the long term.


Bias in reporting of end points of efficacy and toxicity in randomized, clinical trials for women with breast cancer.
Phase III randomized, clinical trials (RCTs) assess clinically important differences in end points that reflect benefit to patients. Here, we evaluate the quality of reporting of the primary end point (PE) and of toxicity in RCTs for breast cancer. PUBMED was searched from 1995 to 2011 to identify RCTs for breast cancer. Bias in the reporting of the PE and of toxicity was assessed using pre-designed algorithms. Associations of bias with the Journal Impact Factor (JIF), changes in the PE compared with information in ClinicalTrials.gov and funding source were evaluated. Of 164 included trials, 33% showed bias in reporting of the PE and 67% in the reporting of toxicity. The PE was more likely to be reported in the concluding statement of the abstract when significant differences favoring the experimental arm were shown; 59% of 92 trials with a negative PE used secondary end points to suggest benefit of experimental therapy. Only 32% of articles indicated the frequency of grade 3 and 4 toxicities in the abstract. A positive PE was associated with under-reporting of toxicity. Bias in reporting of outcome is common for studies with negative PEs. Reporting of toxicity is poor, especially for studies with positive PEs.