Differential expression of hypothalamic, metabolic and inflammatory genes in response to short-term calorie restriction in juvenile obese- and lean-prone JCR rats.
Childhood obesity is an important early predictor of adult obesity and associated comorbidities. Common forms of obesity are underpinned by both environmental and genetic factors. However, the rising prevalence of obesity in genetically stable populations strongly suggests that contemporary lifestyle is a premier factor to the disease. In pediatric population, the current treatment/prevention options for obesity are lifestyle interventions such as caloric restriction (CR) and increase physical activity. In obese individuals, CR improves many metabolic parameters in peripheral tissues. Little is known about the effect of CR on the hypothalamus. This study aimed to assess the effect of CR on hypothalamic metabolic gene expression of young obese- and lean-prone animals. Male juvenile JCR:LA-cp obese-prone rats were freely fed (Obese-FF) or pair fed (Obese-FR) to lean-prone, free-feeding animals (Lean-FF). A group of lean-prone rats (Lean-FR) were matched for relative average degree of CR to Obese-FR rats. In free-feeding conditions, obese-prone rats consumed more energy than lean-prone rats (P<0.001) and showed greater increases in body weight, fat mass, plasma glucose, insulin and lipids (P<0.01). These metabolic differences were associated with alterations of feeding-related neuropeptides expression in the hypothalamus, as well as pro-inflammatory cytokines and oxidative stress markers. When submitted to the same degree of CR, the two genotypes responded differently; hypothalamic inflammatory and oxidative stress gene expression was improved in Obese-FR, while it was worsened in Lean-FR rats. We demonstrate in JCR rats that the metabolic and inflammatory response of the brain to CR is genotype dependent.


Phylogenetic and biogeographic analysis of sphaerexochine trilobites.
Sphaerexochinae is a speciose and widely distributed group of cheirurid trilobites. Their temporal range extends from the earliest Ordovician through the Silurian, and they survived the end Ordovician mass extinction event (the second largest mass extinction in Earth history). Prior to this study, the individual evolutionary relationships within the group had yet to be determined utilizing rigorous phylogenetic methods. Understanding these evolutionary relationships is important for producing a stable classification of the group, and will be useful in elucidating the effects the end Ordovician mass extinction had on the evolutionary and biogeographic history of the group. Cladistic parsimony analysis of cheirurid trilobites assigned to the subfamily Sphaerexochinae was conducted to evaluate phylogenetic patterns and produce a hypothesis of relationship for the group. This study utilized the program TNT, and the analysis included thirty-one taxa and thirty-nine characters. The results of this analysis were then used in a Lieberman-modified Brooks Parsimony Analysis to analyze biogeographic patterns during the Ordovician-Silurian. The genus Sphaerexochus was found to be monophyletic, consisting of two smaller clades (one composed entirely of Ordovician species and another composed of Silurian and Ordovician species). By contrast, the genus Kawina was found to be paraphyletic. It is a basal grade that also contains taxa formerly assigned to Cydonocephalus. Phylogenetic patterns suggest Sphaerexochinae is a relatively distinctive trilobite clade because it appears to have been largely unaffected by the end Ordovician mass extinction. Finally, the biogeographic analysis yields two major conclusions about Sphaerexochus biogeography: Bohemia and Avalonia were close enough during the Silurian to exchange taxa; and during the Ordovician there was dispersal between Eastern Laurentia and the Yangtze block (South China) and between Eastern Laurentia and Avalonia.


Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is independent of Ras-Erk1-Erk2 and phosphatidylinositol 3'-kinase-Akt signaling pathways.
The mTOR inhibitor rapamycin induces G1 cell cycle accumulation and p53-independent apoptosis of the human rhabdomyosarcoma cell line Rh1. Insulin-like growth factor I (IGF-I) and insulin, but not epidermal growth factor or platelet-derived growth factor, completely prevented apoptosis of this cell line. Because the Ras-Erk1-Erk2 and phosphatidylinositol 3'-kinase (PI3K)-Akt pathways are implicated in the survival of various cancer cells, we determined whether protection from rapamycin-induced apoptosis by IGF-I requires one or both of these pathways. Despite the blocking of Ras-Erk signaling by the addition of PD 98059 (a MEK1 inhibitor) or by the overexpression of dominant-negative RasN17, IGF-I completely prevented rapamycin-induced death. Inhibition of Ras signaling did not prevent Akt activation by IGF-I. To determine the role of the PI3K-Akt pathway in rescuing cells from apoptosis caused by rapamycin, cells expressing dominant-negative Akt were tested. This mutant protein inhibited IGF-I-induced phosphorylation of Akt and blocked phosphorylation of glycogen synthase kinase 3. The prevention of rapamycin-induced apoptosis by IGF-I was not inhibited by expression of dominant-negative Akt either alone or under conditions in which LY 294002 inhibited PI3K signaling. Furthermore, IGF-I prevented rapamycin-induced apoptosis when the Ras-Erk1-Erk2 and PI3K-Akt pathways were blocked simultaneously. Similar experiments in a second rhabdomyosarcoma cell line, Rh30, using pharmacological inhibitors of PI3K or MEK1, alone or in combination, failed to block IGF-I rescue from rapamycin-induced apoptosis. Therefore, we conclude that a novel pathway(s) is responsible for the IGF-I-mediated protection against rapamycin-induced apoptosis in these rhabdomyosarcoma cells.


Identification of the P2Y(12) receptor in nucleotide inhibition of exocytosis from bovine chromaffin cells.
Nucleotides are released from bovine chromaffin cells and take part in a feedback loop to inhibit further exocytosis. To identify the nucleotide receptors involved, we measured the effects of a range of exogenous nucleotides and related antagonists on voltage-operated calcium currents (I(Ca)), intracellular calcium concentration ([Ca(2+)](i)), and membrane capacitance changes. In comparative parallel studies, we also cloned the bovine P2Y(12) receptor from chromaffin cells and determined its properties by coexpression in Xenopus laevis oocytes with inward-rectifier potassium channels made up of Kir3.1 and Kir3.4. In both systems, the agonist order of potency was essentially identical (2-methylthio-ATP approximately 2-methylthio-ADP >> ATP approximately ADP > UDP). alphabeta-Methylene-ATP and adenosine were inactive. UTP inhibited I(Ca) in chromaffin cells (pEC(50) = 4.89 +/- 0.11) but was essentially inactive at the cloned P2Y(12) receptor. The relatively nonselective P2 antagonist pyridoxal-phosphate-6-azophenyl-2',4' disulfonic acid blocked nucleotide responses in both chromaffin cells and X. laevis oocytes, whereas the P2Y(12)- and P2Y(13)-selective antagonist N(6)-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene ATP (ARC69931MX) blocked responses to ATP in both chromaffin cells and X. laevis oocytes but not to UTP in chromaffin cells. These results identify the P2Y(12) purine receptor as a key component of the nucleotide inhibitory pathway and also demonstrate the involvement of a UTP-sensitive G(i/o) -coupled pyrimidine receptor.


Influence of ionic liquids bearing functional groups in dye-sensitized solar cells.
Ionic liquids containing the nitrile and vinyl functional groups attached to imidazolium cations combined with various anions, e.g., iodide, bis[(trifluoromethyl)sulfonyl]imide ([TFSI]-), or dicyanamide ([N(CN)2]-), have been prepared and characterized. These ionic liquids have been successfully used as electrolytes for dye-sensitized solar cells based on nanocrystalline TiO2 with the amphiphilic ruthenium sensitizer [ruthenium (4,4'-dicarboxylic acid-2,2'-bipyridine)(4,4'-bis(p-hexyloxystyryl)-2,2'-bipyridine)][NCS]2 (coded K-19). The iodide salt was used in 3-methoxypropionitrile-based electrolytes, and the performances of both types of devices were evaluated on the basis of their photocurrent density-voltage characteristics and dark current measurements, demonstrating that the functional groups do not exert a detrimental effect on the performance. The solid-state structure of the nitrile-functionalized salt [C1C3CN(im)]I has also been established by single-crystal X-ray diffraction, revealing extensive hydrogen bonding between the cation protons and the iodide.


Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity.
Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count. Hispanic CCM1 patients (n=188) harboring the founder Q455X 'common Hispanic mutation' (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways. At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean ± standard deviation (SD) of 60.1±115.0 (range 0-713) for total lesions and 4.9±8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE=0.31), 0.81 (SE=0.17), and 0.48 (SE=0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p≤0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p=0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count. These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sample sizes are needed to confirm these findings.


Cross-talk between CD8(+) and CD4(+) T cells in experimental cutaneous leishmaniasis: CD8(+) T cells are required for optimal IFN-gamma production by CD4(+) T cells.
Although the importance of CD8(+) T cells for vaccination and immunity to reinfection with Leishmania parasites is well established, their role in primary infections is disputed. In the present study we further characterized the role of CD8(+) T cells in primary L. major infections. We used two groups of L. major infected BALB/c mice: both groups were immunomanipulated to heal and in one group CD8(+) T cells were depleted throughout the course of infection. Our results show that the reversal of healing caused by the absence of CD8(+) T cells did not alter the proliferation of CD4(+) T cells, however, the frequency of CD4(+) T cells expressing IFN-gamma as well as the levels of this cytokine were clearly reduced. These lower levels of IFN-gamma correlated with a higher parasite load. Our results show that transient depletion of CD4(+) T cells allows the establishment of an equilibrium between CD4(+) and CD8(+) T cells and allows CD8(+) T cell activation and effector functions to develop. In addition, our results suggest that cross-talk between CD4(+) and CD8(+) T cells is crucial for the host defence against L. major.


Protective role of small pigment epithelium-derived factor (PEDF) peptide in diabetic renal injury.
Pigment epithelium-derived factor (PEDF) is a multifunctional protein with antiangiogenic, antioxidative, and anti-inflammatory properties. PEDF is involved in the pathogenesis of diabetic retinopathy, but its direct role in the kidneys remains unclear. We hypothesize that a PEDF fragment (P78-PEDF) confers kidney protection in diabetic nephropathy (DN). The localization of the full-length PEDF protein were determined in DBA mice following multiple low doses of streptozotocin. Using immunohistochemistry, PEDF was localized in the kidney vasculature, interstitial space, glomeruli, tubules, and renal medulla. Kidney PEDF protein and mRNA expression were significantly reduced in diabetic mice. Continuous infusion of P78-PEDF for 6 wk resulted in protection from diabetic neuropathy as indicated by reduced albuminuria and blood urea nitrogen, increased nephrin expression, decreased kidney macrophage recruitment and inflammatory cytokines, and reduced histological changes compared with vehicle-treated diabetic mice. In vitro, P78-PEDF blocked the increase in podocyte permeability to albumin and disruption of the actin cytoskeleton induced by puromycin aminonucleoside treatment. These findings highlight the importance of P78-PEDF peptide as a potential therapeutic modality in early phase diabetic renal injury.


Comparative antidiarrheal and antiulcer effect of the aqueous and ethanolic stem bark extracts of Tinospora cordifolia in rats.
Tinospora cordifolia is indigenous to the tropical areas of India, Myanmar and Sri Lanka. The use of plant as remedy for diarrhea and ulcer is well-documented in Ayurvedic system of medicine. However, pharmacological evidence does not exist to substantiate its therapeutic efficacy for the same. The aim was to investigate the antidiarrheal and antiulcer activity of ethanolic and aqueous extracts of T. cordifolia in rats. The antidiarrheal activity of T. cordifolia extracts was evaluated by castor oil and magnesium sulfate-induced diarrhea using parameters such as onset of diarrhea, number of wet stools, total number of stool and weight of total number of stools. The antiulcer activity of extracts was investigated using ethanol and pylorus ligation-induced ulcer. Furthermore, tissue antioxidant parameters such as reduced glutathione, catalase activity and lipid peroxidation level were also investigated. Tinospora cordifolia extracts were more efficacious in reducing number of total stools in both the models of diarrhea and showed a dose-dependent antidiarrheal effect. The antiulcer activity of the extracts was confirmed by a reduction in ulcer index along with the decrease in gastric volume, total acidity, and an increase in pH of gastric content in both the models. The obtained results have established a pharmacological evidence for the folkloric use of the T. cordifolia as antidiarrhoeal and antiulcer agent.


Stochastic simulation and analysis of biomolecular reaction networks.
In recent years, several stochastic simulation algorithms have been developed to generate Monte Carlo trajectories that describe the time evolution of the behavior of biomolecular reaction networks. However, the effects of various stochastic simulation and data analysis conditions on the observed dynamics of complex biomolecular reaction networks have not received much attention. In order to investigate these issues, we employed a a software package developed in out group, called Biomolecular Network Simulator (BNS), to simulate and analyze the behavior of such systems. The behavior of a hypothetical two gene in vitro transcription-translation reaction network is investigated using the Gillespie exact stochastic algorithm to illustrate some of the factors that influence the analysis and interpretation of these data. Specific issues affecting the analysis and interpretation of simulation data are investigated, including: (1) the effect of time interval on data presentation and time-weighted averaging of molecule numbers, (2) effect of time averaging interval on reaction rate analysis, (3) effect of number of simulations on precision of model predictions, and (4) implications of stochastic simulations on optimization procedures. The two main factors affecting the analysis of stochastic simulations are: (1) the selection of time intervals to compute or average state variables and (2) the number of simulations generated to evaluate the system behavior.


Contractile endothelin-B (ETB) receptors in human small bronchi.
Endothelins (ETs) are a family of novel regulatory peptides and various lines of evidence suggest an important role for ETs in regulating pulmonary function. Two receptors for endothelin, ETA and ETB, have been found in the human lung, and according to recent studies a non-ETA receptor seems to mediate the contraction of large sized human bronchi. Several studies have emphasized the importance of small bronchi in the pathogenesis of airway disease. In the present paper, improved methodology was used which enables in vitro studies of small human bronchi down to a diameter of 0.5-1.0 mm. Using the new methodology we have tried to further characterize this receptor. Small bronchi from the distal parts of the bronchial tree were obtained from pulmonary tissue removed from 15 patients with lung cancer. They were dissected and cut into ring segments, in which isometric tension was recorded. ET-1, ET-2 and ET-3 elicited strong concentration-dependent contractions of the human small bronchus. Basically, the three peptides were equipotent with about the same maximal response. Upon reapplication, they all showed the same tachyphylaxis pattern, reaching half the initial contraction. Comparative analysis of IRL 1620, a selective ETB receptor agonist, revealed that the effect of the ETB agonist was, in all respects, similar to the responses induced by the ETs. PD 145065, a combined ETA/ETB receptor antagonist competitively inhibited the contractions induced by IRL 1620, whereas FR139317, a selective ETA receptor antagonist, was without effect. In conclusion, the present study shows that accurate measurements can be made in vitro on small human bronchi and all present data are in favour of an ETB receptor mediating endothelin-induced contraction of human bronchi smaller than 1.0 mm.


CD28-mediated signaling in vivo prevents activation-induced apoptosis in the thymus and alters peripheral lymphocyte homeostasis.
Activation of T lymphocytes can result in a functional immune response, anergy or apoptosis. Functional T cell activation requires the interaction of the TCR with Ag presented by MHC molecules on APC concurrent with appropriate interactions between cell surface accessory molecules. Interestingly, the level of CD28 expression is regulated during T cell development as well as during T cell activation and proliferation, suggesting that CD28 could play a role in determining the outcome of activation of TCR during T cell ontogeny. We identify, herein, a novel function of murine CD28 in the regulation of activation-induced apoptosis in thymocytes. In vivo, or combined in vivo and in vitro treatment with mAbs to CD28 prevents apoptosis of CD4+CD8+ thymocytes induced by Abs to the TCR complex. Prolonged administration of anti-CD28 Abs increased the number of both CD4+CD8- and CD4-CD8+ T cells in the thymus, while the number of CD4+CD8+ T cells is relatively unchanged. Furthermore, this treatment leads to a dramatic enlargement of peripheral lymphoid organs characterized primarily by the expansion of B cells. The number of CD4+CD8- T cells in the spleen of anti-CD28-treated mice is also moderately increased, while the number of CD4-CD8+ cells is relatively unchanged.


Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.
To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.


Dendrochemical record of historical lead contamination sources, Wells G&H Superfund site, Woburn, Massachusetts.
Laser-ablation inductively coupled-plasma mass-spectrometry analysis of red oak (Quercus rubra) from a well documented heavy metal contaminated United States Environmental Protection Agency superfund site in Woburn, Massachusetts reveals decade-long trends in Pb contaminant sources. Lead isotope ratios (207Pb/206Pb and 208Pb/206Pb) in tree rings plot along a linear trend bracketed by several local and regional contamination sources. Statistically significant interannual variations in 207Pb/206Pb suggest that atmospheric Pb is rapidly incorporated into wood, with minimal mobility subsequent to deposition in annual growth rings. We interpret the decadal trends in our record as a changing mixture of local pollution sources and gasoline-derived Pb. Between 1940 and 1970, Pb was predominantly derived from remobilization of local industrial Pb sources. An abrupt shift in 207Pb/206Pb may indicate that local Pb sources were overwhelmed by gasoline-derived Pb during the peak of leaded gasoline emissions in the late 1960s and early 1970s.


Clinical nurse specialists in palliative care. Part 1. A description of the MacMillan Nurse caseload.
Macmillan Nurses play a significant role in specialist palliative care services in the UK, providing direct and indirect services to patients with complex palliative care needs and to their families. Existing literature shows a developing understanding of the role; however, little detailed data exist regarding the clinical work that they undertake. This paper provides evidence from a major evaluation study, commissioned by Macmillan Cancer Relief. It reports the methods of data collection for the study and then goes on to use data from the evaluation to describe the caseload of Macmillan Nurses. Between September 1998 and October 1999, a team of researchers worked alongside 12 Macmillan teams for a period of 8 weeks with each team. Prospective data were gathered on all new referrals to the services within the 8-week period. This included demographic details, timing of referral, the nature and purpose of contacts, and interventions, recorded from case notes and Macmillan Nurse records. Where possible, a date of death was obtained for all patients. A total of 814 new patients were referred during the study period (range 45-114 per site). The most common reasons for referral were emotional care for the patient (57%), pain control (27%), and other physical symptoms (33%). Thirteen per cent of the patients referred to the services died within 1 week of referral while 40% died within 6 weeks; thus, a significant proportion of patient work is focused on care at the end of life. It is also noteworthy that one-third of patients were still alive, indicating that some patients are being cared for earlier in the illness trajectory. On average, each new patient referral received two or more 'face-to-face' visits and two follow-up phone calls within the 8-week period. It would appear that Macmillan Nurse teams have been successful in getting access to relevant patients. As with any service that provides a complex set of interventions, the Macmillan teams have to adapt and develop the services in each setting. Whilst it is clearly important for the development of a Macmillan service to be tailored to the local conditions, the evidence on diversity suggests that in some cases, stronger guidance, in partnership with both Macmillan Cancer Relief and core providers, may be justified.


Collective dynamics of molecular rotors in periodic mesoporous organosilica: a combined solid-state 2H-NMR and molecular dynamics simulation study.
Molecular rotors offer a platform to realize controlled dynamics and modulate the functions of solids. The motional mechanisms in arrays of rotors have not been explored in depth. Crystal-like porous organosilicas, comprising p-phenylene rotators pivoted onto a siloxane scaffold, were modelled using molecular dynamics (MD) simulations. Long simulations, on a microsecond scale, allowed to follow the reorientation statistics of rotor collections and single out group configurations and frequency distributions as a function of temperature. The motions observed in the MD simulations support a multiple-site model for rotor reorientations. Computed motional frequencies revealed a complex rotatory phenomenon combining an ultra-fast libration motion (oscillation up to 30°) with a slow and fast 180° flip reorientation. Adopting a multiple-site model provides a more accurate simulation of the 2H-NMR spectra and a rationalization of their temperature dependence. In particular, rotators endowed with distinct rates could be explained by the presence of slower rings locked in a T-shaped conformation.


Major factors influencing the efficacy of vegetated buffers on sediment trapping: a review and analysis.
Sediment is a major agricultural pollutant threatening water quality. Vegetated buffers, including vegetative filter strips, riparian buffers, and grassed waterways, are best management practices (BMPs) installed in many areas to filter sediments from tailwaters, and deter sediment transport to water bodies. Along with reducing sediment transport, the filters also help trap sediment bound nutrients and pesticides. The objectives of this study were: (i) to review vegetated buffer efficacy on sediment trapping, and (ii) to develop statistical models to investigate the major factors influencing sediment trapping. A range of sediment trapping efficacies was found in a review of over 80 representative BMP experiments. A synthesis of the literature regarding the effects of vegetated buffers on sediment trapping is needed. The meta-analysis results based on the limited data showed that buffer width and slope are two major factors influencing BMPs efficacy of vegetated buffers on sediment trapping. Regardless of the area ratio of buffer to agricultural field, a 10 m buffer and a 9% slope optimized the sediment trapping capability of vegetated buffers.


Myelodysplastic Syndromes and Acute Myeloid Leukemia in the Elderly.
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic diseases that frequently affect older adults. Treatment is challenging. Management of older adults with MDS and AML needs to be individualized, accounting for both the heterogeneity of disease biology and patient characteristics, which can influence life expectancy and treatment tolerance. Clinical trials accounting for the heterogeneity of tumor biology and physiologic changes of aging are needed to define optimal standards of care. This article highlights key evidence related to the management of older adults with MDS and AML and highlights future directions for research.


KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy.
Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.


Possible footprints of APOBEC3F and/or other APOBEC3 deaminases, but not APOBEC3G, on HIV-1 from patients with acute/early and chronic infections.
Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plus-strand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutations in vivo are always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined "footprints" of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNA pol sequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. G-to-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1 env sequences from acute/early infection. Collectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vif-specific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family.


Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome.
Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI.


Cross talk between drug-resistant epilepsy and the gut microbiome.
One-third of epilepsy patients have drug-resistant epilepsy (DRE), which is often complicated by polydrug toxicity and psychiatric and cognitive comorbidities. Advances in understanding the microbiome and gut-brain-axis are likely to shed light on epilepsy pathogenesis, anti-seizure medication (ASM) resistance, and potential therapeutic targets. Gut dysbiosis is associated with inflammation, blood-brain barrier disruption, and altered neuromodulators. High-throughput and metagenomic sequencing has advanced the characterization of microbial species and functional pathways. DRE patients show altered gut microbiome composition compared to drug-sensitive patients and healthy controls. The ketogenic and modified Atkins diets can reduce seizures in some patients with DRE. These low-carbohydrate dietary therapies alter the taxonomic and functional composition of the gut microbiome, and composition varies between diet responders and nonresponders. Murine models suggest that specific phyla are necessary to confer efficacy from the diet, and antibiotic treatment may eliminate efficacy. The impact of diet might involve alterations in microbiota, promotion of select microbial interactions, and variance in brain neurotransmitter levels that then influence seizures. Understanding the mechanics of how diet manipulates seizures may suggest novel therapies. Most ASMs act on neuronal transmission via effects on ion channels and neurotransmitters. However, ASMs may also assert their effects via the gut microbiota. In animal models, the microbiota composition (eg, abundance of certain phyla) can vary with ASM active drug metabolites. Given the developing understanding of the gut microbiome in DRE, probiotics are another potential therapy. Probiotics alter the microbiota composition, and small studies suggest that these supplements can reduce seizures in some patients. DRE has enormous consequences to patients and society, and the gut microbiome holds promise as a potential therapeutic target. However, the exact mechanism and recognition of which patients are likely to be responders remain elusive. Further studies are warranted.


Cross-sectional and longitudinal associations between physical activity and blood pressure in adolescence: birth cohort study.
To explore cross-sectional and longitudinal associations between self-reported and accelerometry-based physical activity (PA) and blood pressure (BP) between 11 and 14 years of age. Prospective birth cohort study in Pelotas, Brazil. Participants were 427 cohort members who were followed up with at 11, 12, and 14 years of age, and had questionnaire data on PA and BP at 11 and 14 years, as well as accelerometry and questionnaire data on PA at 12 years. Outcome measures were continuous systolic and diastolic BP at 14 years, and change in BP from 11 to 14 years. PA was unrelated to systolic BP in any analyses. PA measured by accelerometry at 12 years, but not questionnaire-derived PA, was inversely associated with diastolic BP at 14 years of age in fully adjusted models. Those who exceeded the 300-minutes PA threshold at all 3 visits had a 2.6 mmHg lower mean increase in DBP from 11 to 14 years compared with those classified below the threshold in all visits. Accelerometry-based PA was longitudinally inversely associated with diastolic BP. This finding was not evident when analyzing self-reported PA at a given age, suggesting a possible underestimation of the association when using subjective data.


Passive real-time identification of speech and motor cortex during an awake craniotomy.
Precise localization of eloquent cortex is a clinical necessity prior to surgical resections adjacent to speech or motor cortex. In the intraoperative setting, this traditionally requires inducing temporary lesions by direct electrocortical stimulation (DECS). In an attempt to increase efficiency and potentially reduce the amount of necessary stimulation, we used a passive mapping procedure in the setting of an awake craniotomy for tumor in two patients resection. We recorded electrocorticographic (ECoG) signals from exposed cortex while patients performed simple cue-directed motor and speech tasks. SIGFRIED, a procedure for real-time event detection, was used to identify areas of cortical activation by detecting task-related modulations in the ECoG high gamma band. SIGFRIED's real-time output quickly localized motor and speech areas of cortex similar to those identified by DECS. In conclusion, real-time passive identification of cortical function using SIGFRIED may serve as a useful adjunct to cortical stimulation mapping in the intraoperative setting.


The First Report of Globodera rostochiensis Pathotypes Ro5 Occurrence in Poland.
Potato (Solanum tuberosum L. subsp. tuberosum) is one of the most important crops in Poland. During vegetation season, pests and pathogens including a quarantine-significant nematode Globodera rostochiensis (Woll.) Behrens can infect growing plants. Regional surveys have revealed potato cyst nematodes (PCN) to be widely distributed in Poland, with the highest infestation throughout the northwest of the country. Since 1946, only pathotype Ro1 of G. rostochiensis has been recorded. Previous data revealed the occurrence of pathotype Ro5 in three separate provinces. In recent surveys, 22 soil samples from infested fields in northern and western parts of Poland were collected. Each sample comprised 10 kg of soil collected in a grid pattern. Samples of approximately 2 kg were dried for extracting nematodes. The cysts were obtained with an automatic cyst extractor (Mekku Gmbh). A molecular test was performed as a first step to discriminate G. rostochiensis from G. pallida. DNA from 30 cysts per sample was extracted with DNeasy Blood and Tissue KIT (Qiagen). Multiplex PCR analysis with two pairs of primers, GroR-GroF and PaR-PaF (1), was employed. The PCR resulted in a single 315-bp DNA fragment specific for G. rostochiensis. No amplification was shown with primers specific for G. pallida. Bioassays on differential genotypes of potato were carried out to identify the pathotype of G. rostochiensis. Five genotypes of potato: S. vernei hybr. 58.1642/4, S. vernei hybr. 62.33.3, S. vernei hybr. 65.346/19, S. multidissectum hybr. P 55/7, S. kurtzianum hybr. 60.21.19, and two varieties, Desiree and Maris Piper, were inoculated with 22 populations of G. rostochiensis cysts (2). Tests were performed in three replications. Eighteen of the cyst populations were pathotype Ro1 and four were pathotype Ro5. The abundance of cysts in locations where the new pathotype was detected suggests that there is a threat of further spread of G. rostochiensis. Consequently, producers and farmers need to grow resistant potato cultivars to keep nematode population below damaging level. To our knowledge, this is the first report of Globodera rostochiensis Ro5 in Poland. References: (1) A. Fullaondo et al. Nematology 1:157, 1999. (2) J. Kort et. al. Nematologica 23:333, 1977.


[Do general practitioners follow the therapeutical recommendations of cystitis in women? INURA study].
The management of lower urinary tract infections varies from physician to physician. The aim of this study was to assess whether general practitioners follow the evidence-based guidelines for the management of cystitis in women. Cross-sectional study carried out from March to July 2009 in which physicians consecutively registered in a template during a 8-week period the first six episodes of cystitis by means attended at the medical consultation. Age, episode of infection, associated morbidity, antibiotic prescription, and type of antibiotic course (short or long regimen) were determined. Out of 176 physicians invited to participate, 110 included 658 women with lower urinary tract infections with antibiotic treatment being administered in 634 cases. Short courses were given to 385 women (60.7%) and 249 women were given long schedules (39.3%). A total of 343 out of all noncomplicated cystitis were treated with short courses (62.9%) and 75 out of complicated cystitis were treated with long courses (66.4%). First-choice antibiotics were administered as empiric treatment in only 111 women (17.5%). These results highlight a poor adherence of general practitioners to current recommendations of clinical practice guidelines in cystitis with a low utilization of first-choice antibiotics.


Dose- and gender-dependent interactions between coffee consumption and serum GGT activity in alcohol consumers.
Coffee consumption has been recently linked with decreased blood gamma-glutamyltransferase (GGT) activities and protection from alcoholic liver disease. To explore the relationship and dose response, we assessed the impacts of coffee and alcohol intake on serum GGT activity in apparently healthy men and women with varying levels of coffee and alcohol consumption. Data on coffee, alcohol consumption and serum GGT activities were collected from 18,899 individuals (8807 men and 10,092 women), mean age 48 years, range 25-74 years, who participated in a large national cross-sectional health survey. Body mass index, smoking index and age were used as covariates in all analyses. Among the study population, 89.8% reported varying levels of coffee consumption; 6.9% were abstainers from alcohol, 86.1% moderate drinkers, 3.7% heavy drinkers and 3.3% former drinkers. In men, the elevation of GGT induced by heavy drinking (>280 g/week) was found to be significantly reduced by coffee consumption exceeding 4 cups per day. A similar trend was also observed among women, which however, did not reach statistical significance. Coffee modulates the effect of ethanol on serum GGT activities in a dose- and gender-dependent manner. These observations should be implicated in studies on the possible hepatoprotective effects of coffee in alcohol consumers.


A Urine Based Genomic Assay to Triage Patients with Hematuria for Cystoscopy.
Current clinical guidelines recommend cystoscopy in patients who present with hematuria to rule out a bladder tumor. We evaluated whether our previously developed urine assay was able to triage patients with hematuria for cystoscopy in a large prospective cohort. A urine sample was collected before cystoscopy and mutation/methylation status of 6 genes was determined on cellular DNA. The existing diagnostic model was validated on this cohort. Logistic regression was applied to investigate other potential variables. The primary end point was the model performance as indicated by the AUC. Secondary end points were sensitivity, specificity and negative predictive value. Clinical usefulness was determined by the net benefit approach. In 838 patients biomarker status could be determined for all genes. Urothelial cancer was observed in 112 patients (98 of 457 in the gross and 14 of 381 in the microscopic hematuria group). Validation of the existing model resulted in an AUC of 0.93. Logistic regression analysis identified type of hematuria as a significant additional variable. Adding type of hematuria resulted in an AUC of 0.95 (96% sensitivity, 73% specificity, 99% negative predictive value). The assay identified all upper tract tumors not visible by cystoscopy (in 6). Net benefit analysis showed that the urine assay should be preferred over current clinical practice. Implementing the urine assay as a triage tool could lead to a 53% reduction in cystoscopies. The urine assay detected urothelial cancer with a very high accuracy and can be used to triage patients presenting with hematuria for cystoscopy.


Morphologic representation of visual and antennal information in the ant brain.
Ants in general are primarily olfactory animals, but many species also express visual behaviors. We analyze in 14 species, which range from purely olfactory to predominantly visually behaving ants, how the brains are equipped to control such behavior. We take the size and manifestation of the eyes as an indicator for the prevalence of vision in a given species, and we correlate it with the size of particular brain regions. Our morphometric data show that the size of the eyes generally correlates well with that of the optic lobes. The antennal lobes and the mushroom bodies have a surprisingly constant relative volume whereas, as expected, the relative size of the optic lobes varies strongly across species. Males of different species are more similar. Compared with workers, they all have large eyes, relatively larger optic lobes, smaller mushroom bodies, and similarly sized antennal lobes. The input regions of the mushroom bodies, the lip and the collar, generally correlate with the size of the optic and antennal lobe, respectively. Accordingly, the composition of the calyx reflects the importance of vision for the animal. We present data supporting the view that the mushroom bodies may participate in spatial orientation, landmark recognition, and visual information storage.


Gun use in the United States: results from two national surveys.
To determine the relative incidence of gun victimization versus self defense gun use by civilians in the United States, and the circumstances and probable legality of the self defense uses. National random digit dial telephone surveys of the adult population were conducted in 1996 and 1999. The Harvard surveys appear unique among private surveys in two respects: asking (1) open ended questions about defensive gun use incidents and (2) detailed questions about both gun victimization and self defense gun use. Five criminal court judges were asked to assess whether the self reported defensive gun uses were likely to have been legal. Even after excluding many reported firearm victimizations, far more survey respondents report having been threatened or intimidated with a gun than having used a gun to protect themselves. A majority of the reported self defense gun uses were rated as probably illegal by a majority of judges. This was so even under the assumption that the respondent had a permit to own and carry the gun, and that the respondent had described the event honestly. Guns are used to threaten and intimidate far more often than they are used in self defense. Most self reported self defense gun uses may well be illegal and against the interests of society.


The palliative care link nurse role in nursing homes: barriers and facilitators.
This paper is a report of a study to explore link nurses' views and experiences regarding the development, barriers and facilitators to the implementation of the role in palliative care in the nursing home. The delivery of palliative care in nursing homes is widely advocated; one approach is to develop the link nurse role to cascade good practice and training to nurses and other care staff to enhance patient care. A descriptive qualitative study was conducted with a purposive sample of 14 link nurses from 10 nursing homes in Northern Ireland during 2006. Three focus groups, composed of all Registered Nurses currently acting as link nurses in their nursing homes participated, and the data were audio recorded, fully transcribed and content analysed. The link nurse system shows potential to enhance palliative care within nursing homes. However, link nurses experienced a number of difficulties in implementing education programmes. Facilitators of the role included external support, monthly meetings, access to a resource file and peer support among link nurses themselves. Lack of management support, a transient workforce and lack of adequate preparation for link nurses were barriers to fulfilling this role. Whilst palliative care link nurses can improve care for residents in nursing homes, consideration must be given to overcome the types of barriers identified in order to enable the link nurse system to function effectively.


Pulsed methylprednisolone therapy compared to high dose prednisone in systemic lupus erythematosus nephritis.
This study was done to determine whether intravenous methylprednisolone therapy given concomitantly with low-dose daily, oral prednisone would be as effective as high-dose daily prednisone in the treatment of patients with active systemic lupus erythematosus (SLE) nephritis. Thirteen patients with active SLE nephritis were started on 2 mg/kg prednisone per day, considered the high prednisone phase. Therapy was continued until remission was achieved. Prednisone administration was then tapered to less than 0.5 but more than 0.2 mg/kg per day. On later relapse, these patients received three doses of methylprednisolone (20 mg/kg per dose) on alternate days and continued on the same daily dose of prednisone (less than 0.5 greater than 0.2 mg/kg per day) prior to pulse therapy; this was the methylprednisolone phase. The 13 patients were studied in both phases, serving as their own controls. After 1 month of therapy, no significant differences were observed between treatment phases as to improvement in clinical and laboratory findings. A significant increase in the serum concentration of C3 and C4 was seen both in the high-dose prednisone and methylprednisolone phases, while the serum concentration of anti-ds DNA antibody significantly decreased. Methylprednisolone therapy seems as effective as high-dose prednisone in patients with relapse of SLE nephritis. Because side effects are minimal, methylprednisolone administration may be tried as the therapy of choice for these patients.


Detection of Panulirus argus Virus 1 (PaVI) in the Caribbean spiny lobster using fluorescence in situ hybridization (FISH).
Panulirus argus Virus 1 (PaV1) is the first virus known to be pathogenic to a wild lobster. It infects the Caribbean spiny lobster P. argus from the Florida Keys, and has a predilection for juveniles. The monitoring of the virus in wild populations and study of its behavior in the laboratory require the development of reliable diagnostic tools. A sensitive and specific fluorescence in situ hybridization (FISH) assay was developed for detection of PaV1. The lower detection limit using a 110 bp DNA probe in a dot-blot hygridization for PaV1 DNA was 10 pg of cloned template PaV1 DNA and 10 ng of genomic DNA extracted from the hemolymph of diseased spiny lobster. The fluorescein (FITC)-labeled probe specifically hybridized to PaVl-infected cells in the hepatopancreas, hindgut, gills, heart, foregut, and nerve tissues. FITC staining was observed around the inner periphery of the nuclear membrane, with lighter staining in a more dispersed pattern within the nucleus. The probe did not hybridize with host tissues of uninfected spiny lobsters, nor did it cross-react with 4 other virus samples tested. This assay will facilitate our understanding of the pathogenesis of the viral disease and help in monitoring efforts directed at determining the prevalence of PaV1 in juvenile nurseries for this lobster.


Speciation analysis of aluminium and aluminium fluoride complexes by HPIC-UVVIS.
The study presents a new analytical method for speciation analysis in fractionation of aluminium fluoride complexes and free Al(3+) in soil samples. Aluminium speciation was studied in model solutions and soil extract samples by means of high performance ion chromatography (HPIC) with UV-VIS detection using post-column reaction with tiron for the separation and detection of aluminium fluoride complex and Al(3+) forms during one analysis. The paper presents particular stages of the chromatographic process optimization involving selecting the appropriate eluent strength, type of elution or concentration and quantity of derivatization reagent. HPIC was performed on a bifunctional analytical column Dionex IonPac CS5A. The use of gradient elution and the eluents A: 1M NH(4)Cl and B: water acidified to pH of eluent phase, enabled full separation of fluoride aluminium forms as AlF(2)(+), AlF(3)(0), AlF(4)(-) (first signal), AlF(2+) (second signal) and form Al(3+) in a single analytical procedure. The proposed new method HPIC-UVVIS was applied successfully in the quantitative and qualitative analysis of soil samples.


Single-cell RT-LAMP mRNA detection by integrated droplet sorting and merging.
Recent advances in transcriptomic analysis at single-cell resolution reveal cell-to-cell heterogeneity in a biological sample with unprecedented resolution. Partitioning single cells in individual micro-droplets and harvesting each cell's mRNA molecules for next-generation sequencing has proven to be an effective method for profiling transcriptomes from a large number of cells at high throughput. However, the assays to recover the full transcriptomes are time-consuming in sample preparation and require expensive reagents and sequencing cost. Many biomedical applications, such as pathogen detection, prefer highly sensitive, reliable and low-cost detection of selected genes. Here, we present a droplet-based microfluidic platform that permits seamless on-chip droplet sorting and merging, which enables completing multi-step reaction assays within a short time. By sequentially adding lysis buffers and reactant mixtures to micro-droplet reactors, we developed a novel workflow of single-cell reverse transcription loop-mediated-isothermal amplification (scRT-LAMP) to quantify specific mRNA expression levels in different cell types within one hour. Including single cell encapsulation, sorting, lysing, reactant addition, and quantitative mRNA detection, the fully on-chip workflow provides a rapid, robust, and high-throughput experimental approach for a wide variety of biomedical studies.


TLC for pharmaceutical analysis in resource limited countries.
This review article discusses the sustainability and robust advantages of planar chromatography that are critical to the successful performance of product quality assessments in resource limited areas including field applications. Because of the robustness and ease of use, the training required for successful performance of the high performance thin layer chromatography (HPTLC) assessments is much lower than that of other technologies with comparable reproducibility such as high performance liquid chromatography (HPLC). Some of the successful applications of planar chromatography in resource limited countries are presented. It should be noted that these planar chromatographic technologies have much lower plate counts and therefore separation power than column technologies such as HPLC and gas liquid chromatography (GLC). However in finished pharmaceutical products there are generally few active ingredients which are assessed making the HPTLC adequate for these analyses. In addition at this time there is a much wider array of detection technologies available for HPLC and GLC.


Hypertrophic obstructive cardiomyopathy in an infant with an adrenocortical tumor.
Nonfamilial cardiomyopathies in childhood have been only sporadically ascribed to endocrine disorders. We report on a 4-month-old male infant presenting with Cushing's syndrome associated with excessive body weight (8.9 kg; >97th percentile) and features of virilization (Tanner stage 2 for pubic hair development). Abdominal sonography showed a large adrenal tumor. Echocardiography revealed myocardial hypertrophy with severe subaortic obstruction. Blood tests showed excessive androgen and cortisol serum levels with absent circadian rhythm as well as suppressed corticotropin. Urine catecholamine levels were within the normal range. Tumor resection with general anesthesia was performed after preparation with antihypertensive and anticongestive drug therapy. Continuous intravenous hydrocortisone substitution was started intraoperatively and subsequently tapered and switched to oral administration after 12 days. A gradual reduction in glucocorticoid substitution and its discontinuation after a total duration of 9 months were well tolerated. Histopathologic workup revealed an adrenocortical tumor of intermediate dignity. Postoperative tumor staging excluded both residual primary tumor and metastases. Both a normalization of body weight and myocardial mass were observed. The present article is, to our knowledge, the first to describe severe hypertrophic obstructive cardiomyopathy caused by an adrenocortical tumor and provides novel detailed data on postoperative glucocorticoid management.


Importance of thrombosis and thrombolysis in silent ischaemia: comparison of patients with acute myocardial infarction and unstable angina.
To investigate whether plaque rupture and thrombosis have a role in silent ischaemia as well as in unstable angina. Prospective analysis of the results of haemostatic diagnostic tests at the moment of developing silent ischaemia at rest. Coronary care unit. 22 patients with acute myocardial infarction, 12 patients with symptomatic angina (unstable angina), and 10 normal volunteers (control group). Continuous cardiac monitoring detected 15 asymptomatic episodes (silent ischaemia) in 6 patients with unstable angina. Blood samples were obtained at admission and when an asymptomatic alteration was detected and 10 minutes later. Comparisons of concentrations of tissue plasminogen activator, urokinase type plasminogen activator, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation products, von Willebrand factor, and thrombin-antithrombin III complexes in patients and controls at admission; same comparisons in patients with silent ischaemia at the start of an episode and 10 minutes later. Tissue plasminogen activator concentrations were raised at admission in patients with acute myocardial infarction (mean (SD) 14.2 (6) ng/ml) and in patients with unstable angina (10.1 (2.5) ng/ml) in comparison with controls (5.1 (2.7) ng/ml, p < 0.01 and < 0.05 respectively). There was no differences between the two groups of patients, however. Similar results were observed at the start of a silent ischaemic episode (9.8 (1.9) ng/ml) and 10 minutes later (10.5 (2.9) ng/ml) compared with controls (p < 0.05). Tissue plasminogen activator inhibitor-1 concentrations were raised in patients with acute myocardial infarction (45.1 (15) ng/ml) compared with volunteers (20.6 (16) ng/ml, p < 0.01). In patients with silent ischaemia tissue plasminogen activator inhibitor-1 concentrations were slightly but not significantly increased. Concentrations of cross-linked fibrin degradation products (D dimer) increased during unstable angina (2150 (350) ng/ml) and silent ischaemia (2270 (450) ng/ml) compared with the concentrations in volunteers (340 (80) ng/ml) and patients with acute myocardial infarction (310 (120) ng/ml; p < 0.01). The results suggest that thrombosis mediates the pathophysiological mechanisms of silent ischaemia and unstable angina.


The steady-state mosaic of disturbance and succession across an old-growth Central Amazon forest landscape.
Old-growth forest ecosystems comprise a mosaic of patches in different successional stages, with the fraction of the landscape in any particular state relatively constant over large temporal and spatial scales. The size distribution and return frequency of disturbance events, and subsequent recovery processes, determine to a large extent the spatial scale over which this old-growth steady state develops. Here, we characterize this mosaic for a Central Amazon forest by integrating field plot data, remote sensing disturbance probability distribution functions, and individual-based simulation modeling. Results demonstrate that a steady state of patches of varying successional age occurs over a relatively large spatial scale, with important implications for detecting temporal trends on plots that sample a small fraction of the landscape. Long highly significant stochastic runs averaging 1.0 Mg biomass⋅ha(-1)⋅y(-1) were often punctuated by episodic disturbance events, resulting in a sawtooth time series of hectare-scale tree biomass. To maximize the detection of temporal trends for this Central Amazon site (e.g., driven by CO2 fertilization), plots larger than 10 ha would provide the greatest sensitivity. A model-based analysis of fractional mortality across all gap sizes demonstrated that 9.1-16.9% of tree mortality was missing from plot-based approaches, underscoring the need to combine plot and remote-sensing methods for estimating net landscape carbon balance. Old-growth tropical forests can exhibit complex large-scale structure driven by disturbance and recovery cycles, with ecosystem and community attributes of hectare-scale plots exhibiting continuous dynamic departures from a steady-state condition.


Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.
Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.


La fièvre de Lassa : réponses immunes et pathogenèse.
Lassa fever is a hemorrhagic fever endemic to West Africa and caused by Lassa virus, an Old-World arenavirus. It may be fatal, but most patients recover from acute disease and some experience asymptomatic infection. The immune mechanisms associated with these different outcomes have not yet been fully elucidated, but considerable progress has recently been made, through the use of in vitro human models and non-human primates, the only relevant animal model that mimics the pathophysiology and immune responses induced in patients. We discuss here the roles of the various components of the innate and adaptive immune systems in Lassa virus infection and in the control of viral replication and pathogenesis.


A unique central tryptophan hydroxylase isoform.
Serotonin (5-hydroxytryptophan, 5-HT) is a neurotransmitter synthesized in the raphe nuclei of the brain stem and involved in the central control of food intake, sleep, and mood. Accordingly, dysfunction of the serotonin system has been implicated in the pathogenesis of psychiatric diseases. At the same time, serotonin is a peripheral hormone produced mainly by enterochromaffin cells in the intestine and stored in platelets, where it is involved in vasoconstriction, haemostasis, and the control of immune responses. Moreover, serotonin is a precursor for melatonin and is therefore synthesized in high amounts in the pineal gland. Tryptophan hydroxylase (TPH) catalyzes the rate limiting step in 5-HT synthesis. Until recently, only one gene encoding TPH was described for vertebrates. By gene targeting, we functionally ablated this gene in mice. To our surprise, the resulting animals, although being deficient for serotonin in the periphery and in the pineal gland, exhibited close to normal levels of 5-HT in the brain stem. This led us to the detection of a second TPH gene in the genome of humans, mice, and rats, called TPH2. This gene is predominantly expressed in the brain stem, while the classical TPH gene, now called TPH1, is expressed in the gut, pineal gland, spleen, and thymus. These findings clarify puzzling data, which have been collected over the last decades about partially purified TPH proteins with different characteristics and justify a new concept of the serotonin system. In fact, there are two serotonin systems in vertebrates, independently regulated and with distinct functions.


Cytotoxic T-lymphocyte epitope vaccination protects against human metapneumovirus infection and disease in mice.
Human metapneumovirus (hMPV) has emerged as an important human respiratory pathogen causing upper and lower respiratory tract infections in young children and older adults. In addition, hMPV infection is associated with asthma exacerbation in young children. Recent epidemiological evidence indicates that hMPV may cocirculate with human respiratory syncytial virus (hRSV) and mediate clinical disease similar to that seen with hRSV. Therefore, a vaccine for hMPV is highly desirable. In the present study, we used predictive bioinformatics, peptide immunization, and functional T-cell assays to define hMPV cytotoxic T-lymphocyte (CTL) epitopes recognized by mouse T cells restricted through several major histocompatibility complex class I alleles, including HLA-A*0201. We demonstrate that peptide immunization with hMPV CTL epitopes reduces viral load and immunopathology in the lungs of hMPV-challenged mice and enhances the expression of Th1-type cytokines (gamma interferon and interleukin-12 [IL-12]) in lungs and regional lymph nodes. In addition, we show that levels of Th2-type cytokines (IL-10 and IL-4) are significantly lower in hMPV CTL epitope-vaccinated mice challenged with hMPV. These results demonstrate for the first time the efficacy of an hMPV CTL epitope vaccine in the control of hMPV infection in a murine model.


Analysis of a combined tip-tilt and deformable mirror.
A deformable mirror mounted on a two-axis tilt platform can provide wavefront compensation at a single location in an adaptive optics system, resulting in a significant reduction in the number of optical components in the system and in a simplification of the alignment. However, the moment of inertia of a deformable mirror is significantly different from that of the monolithic mirror commonly mounted on a tilt platform. We report on what are to our knowledge the first experimental results of mounting a microelectromechanical deformable mirror onto a fast steering platform and the first observation that at low operating frequencies high-order deformation of the deformable mirror membrane was not recorded.


Analysis of aggrecan in human knee cartilage and synovial fluid indicates that aggrecanase (ADAMTS) activity is responsible for the catabolic turnover and loss of whole aggrecan whereas other protease activity is required for C-terminal processing in vivo.
Studies of aggrecan proteolysis in human joints have implicated both the aggrecanase [ADAMTS, a disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif] and matrix metalloproteinase (MMP) families. We have analysed the aggrecan core protein species present in vivo in both articular cartilage and synovial fluids from normal, acutely injured and osteoarthritic joints. Normal cartilage contains at least seven major G1 domain (the N-terminal globular domain of aggrecan)-bearing species, of which three (full-length core, G1-NITEGE(373) and G1-VDIPEN(341)) have been identified. The C-terminals of the others are unknown but digestion of fetal human aggrecan with MMP-3 and crude aggrecanase suggests that they are products of MMP-like activity in vivo. Normal synovial fluids contain at least 10 species, of which nine result from ADAMTS-dependent cleavage, and this cleavage occurs at all of the five known aggrecanase sites. Aggrecan fragments in the cartilage and synovial fluids of acutely injured joints are generally similar to normal, but all contain a markedly increased ratio of G1-NITEGE to G1-VDIPEN. Aggrecan from the cartilage of late-stage osteoarthritis patients is remarkably similar to normal, whereas the synovial fluid aggrecan is more fragmented than that from normal or injured knees. The analyses suggest that the role of the ADAMTS and these MMP-like activities in human cartilage are distinctly different. Excessive ADAMTS activity in vivo is destructive to cartilage matrix, since the bulk of the glycosaminoglycan (GAG)-bearing products are released from the tissue into the synovial fluid following cleavage of the Glu(373)-Ala(374) bond. In contrast, the MMP-like activity appears to be essentially non-destructive, since much of the GAG-bearing product is retained in the tissue following cleavages that are in the more C-terminal regions of the molecule.


Analysis of a Dictyostelium chemotaxis mutant with altered chemoattractant binding.
A Dictyostelium discoideum mutant defective in folate chemotaxis has been analysed using biochemical, behavioural, and genetic methods. A subset of the cell-surface folate binding sites appeared to be locked in a high-affinity state from which folate dissociated extremely slowly. Changes in cell area and motility induced by step increases in folate required 10- to 100-fold higher concentrations than in the wild type. Folate-stimulated cyclic GMP production was also altered. Chemotactic responses to cyclic AMP as well as cyclic AMP-stimulated cyclic GMP production were normal. The mutation responsible for the chemotaxis defect, termed folA1000, was localized to linkage group IV. The alterations in folate binding and sensitivity to folate co-localized with the folA1000 mutation. We conclude that the folA1000 mutation arrests the folate chemotaxis receptor in a high affinity state that can only poorly transduce folate binding into chemotactic responses.


Secular trends: a ten-year comparison of the amount and type of physical activity and inactivity of random samples of adolescents in the Czech Republic.
An optimal level of physical activity (PA) in adolescence influences the level of PA in adulthood. Although PA declines with age have been demonstrated repeatedly, few studies have been carried out on secular trends. The present study assessed levels, types and secular trends of PA and sedentary behaviour of a sample of adolescents in the Czech Republic. The study comprised two cross-sectional cohorts of adolescents ten years apart. The analysis compared data collected through a week-long monitoring of adolescents' PA in 1998-2000 and 2008-2010. Adolescents wore either Yamax SW-701 or Omron HJ-105 pedometer continuously for 7 days (at least 10 hours per day) excluding sleeping, hygiene and bathing. They also recorded their number of steps per day, the type and duration of PA and sedentary behaviour (in minutes) on record sheets. In total, 902 adolescents (410 boys; 492 girls) aged 14-18 were eligible for analysis. Overweight and obesity in Czech adolescents participating in this study increased from 5.5% (older cohort, 1998-2000) to 10.4% (younger cohort, 2008-2010). There were no inter-cohort significant changes in the total amount of sedentary behaviour in boys. However in girls, on weekdays, there was a significant increase in the total duration of sedentary behaviour of the younger cohort (2008-2010) compared with the older one (1998-2000). Studying and screen time (television and computer) were among the main sedentary behaviours in Czech adolescents. The types of sedentary behaviour also changed: watching TV (1998-2000) was replaced by time spent on computers (2008-2010).The Czech health-related criterion (achieving 11,000 steps per day) decreased only in boys from 68% (1998-2000) to 55% (2008-2010). Across both genders, 55%-75% of Czech adolescents met the health-related criterion of recommended steps per day, however less participants in the younger cohort (2008-2010) met this criterion than in the older cohort (1998-2000) ten years ago. Adolescents' PA levels for the monitored periods of 1998-2000 and 2008-2010 suggest a secular decrease in the weekly number of steps achieved by adolescent boys and girls. In the younger cohort (2008-2010), every tenth adolescent was either overweight or obese; roughly twice the rate when compared to the older cohort (1998-2000). Sedentary behaviour seems relatively stable across the two cohorts as the increased time that the younger cohort (2008-2010) spent on computers is compensated with an equally decreased time spent watching TV or studying. Across both cohorts about half to three quarters of the adolescents met the health-related criterion for achieved number of steps. The findings show a secular decrease in PA amongst adolescents. The significant interaction effects (cohort × age; and cohort × gender) that this study found suggested that secular trends in PA differ by age and gender.


Independent Left Ventricular Morphometric Atlases Show Consistent Relationships with Cardiovascular Risk Factors: A UK Biobank Study.
Left ventricular (LV) mass and volume are important indicators of clinical and pre-clinical disease processes. However, much of the shape information present in modern imaging examinations is currently ignored. Morphometric atlases enable precise quantification of shape and function, but there has been no objective comparison of different atlases in the same cohort. We compared two independent LV atlases using MRI scans of 4547 UK Biobank participants: (i) a volume atlas derived by automatic non-rigid registration of image volumes to a common template, and (ii) a surface atlas derived from manually drawn epicardial and endocardial surface contours. The strength of associations between atlas principal components and cardiovascular risk factors (smoking, diabetes, high blood pressure, high cholesterol and angina) were quantified with logistic regression models and five-fold cross validation, using area under the ROC curve (AUC) and Akaike Information Criterion (AIC) metrics. Both atlases exhibited similar principal components, showed similar relationships with risk factors, and had stronger associations (higher AUC and lower AIC) than a reference model based on LV mass and volume, for all risk factors (DeLong p < 0.05). Morphometric variations associated with each risk factor could be quantified and visualized and were similar between atlases. UK Biobank LV shape atlases are robust to construction method and show stronger relationships with cardiovascular risk factors than mass and volume.


Feline post-sterilization hyphema.
To determine incidence and risk factors of post-sterilization hyphema in shelter cats. Retrospective medical record review of 1204 cats and prospective screening of 195 cats. The study consisted of three parts: (a) Survey responses were collected from 20 veterinarians, who perform high-quality high-volume spay-neuter (HQHVSN) in both shelter and public clinic settings; (b) medical records of 1204 cats were analyzed retrospectively over a 14-month time period; and (c) ophthalmic examinations, including tonometry, were performed prospectively on 195 cats before and after sterilization surgery over 8 weeks. Nine of 20 surveyed veterinarians reported having witnessed hyphema in cats following sterilization surgery. Retrospective review of 1204 medical record and prospective screening of 195 cats showed that three juvenile (<1 year of age) male cats (<2 kg) developed hyphema within 1 hour following surgery (0.2% incidence). In all three affected cats, anesthesia was induced with tiletamine/zolazepam (3 of 523 cats induced with this drug combination; 0.6% incidence), and hyphema resolved within 20 hours. Mean intraocular pressures as measured by Icare® TonoVet were (mean ± standard deviation) 11.5 ± 3.8 mm Hg and 21.7 ± 4.6 mm Hg for juvenile (<1 year of age) and adult (>1 year of age) cats, respectively. Survey responses and three observed cases confirm the existence of feline post-sterilization hyphema with an estimated incidence of 0.2%. The underlying mechanism for this occurrence remains unknown.


Tumor safety and side effects of photobiomodulation therapy used for prevention and management of cancer treatment toxicities. A systematic review.
Photobiomodulation therapy (PBMT), also known as low-level laser therapy (LLLT), has been increasingly used for the treatment of toxicities related to cancer treatment. One of the challenges for the universal acceptance of PBMT use in cancer patients is whether or not there is a potential for the light to stimulate the growth of residual malignant cells that evaded oncologic treatment, increasing the risk for tumor recurrences and development of a second primary tumor. Current science suggests promising effects of PBMT in the prevention and treatment of breast cancer-related lymphedema and oral mucositis, among other cancer treatment toxicities. Nevertheless, this seems to be the first systematic review to analyze the safety of the use of PBMT for the management of cancer-related toxicities. Scopus, MEDLINE/PubMed, and Embase were searched electronically. A total of 27 articles met the search criteria. Selected studies included the use of PBMT for prevention and treatment of oral mucositis, lymphedema, radiodermatitis, and peripheral neuropathy. Most studies showed that no side effects were observed with the use of PBMT. The results of this systematic review, based on current literature, suggest that the use of PBMT in the prevention and management of cancer treatment toxicities does not lead to the development of tumor safety issues.


Neurohypophyseal hormones manipulation modulate social and anxiety-related behavior in zebrafish.
Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish (Danio rerio) allows higher throughput and ease in studying human brain disorders. This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists. Zebrafish were injected i.m. with increasing doses (0.001-40 ng/kg) of the neuropeptides. DesGly-NH(2)-d(CH(2))(5)-[D-Tyr(2),Thr(4)]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist. All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415. For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders.


A diagnostically useful histopathologic feature of endometrial polyp: the long axis of endometrial glands arranged parallel to surface epithelium.
We describe a histologic feature useful in the diagnosis of endometrial polyps, namely, the parallel arrangement of the endometrial glands' long axis to the surface epithelium (PGE). Polyps that are removed intact are usually easy to diagnose because of the polypoid appearance plus surface epithelium on all sides. In addition, there are thick-walled blood vessels and irregularly shaped glands. Rarely are all or even some of the characteristic features easy to identify in biopsies and curettage specimens. We evaluated 76 cases of grossly identifiable polyps from hysterectomy or polypectomy (working group) for various histologic features and tested the validity of those findings with another 75 specimens (test group), which had been diagnosed as polyps in another institute by separate investigators. The frequency of the various histologic features in the polyps varied depending on the menstrual state, shape, and histologic types of the polyps. PGE was found in 80% (40 of 50 polyps) of premenopausal women as the most common histologic feature, but it was less common in postmenopausal women (42%, 11 of 26) (P = 0.001). All functional polyps (100%, 19 of 19), many of hyperplastic polyp (65%, 20 of 31), and some fibrous polyps (38%, 8 of 21) showed the change. In premenopausal women, incidence of PGE was significantly different by the polyp's shape or histologic types (P < 0.05), but not in postmenopausal women. PGE was not identified in any of the 56 normal background endometria, even though the surface was often undulated. Almost identical findings were observed in the series from the test group, confirming the validity of this new finding. In summary, PGE, if present, is a useful histologic finding in facilitating the diagnosis of endometrial polyp in curettage specimens.


Na2CoSiO4 as a cathode material for sodium-ion batteries: structure, electrochemistry and diffusion pathways.
The importance of developing new low-cost and safe cathodes for large-scale sodium batteries has led to recent interest in silicate compounds. A novel cobalt orthosilicate, Na2CoSiO4, shows promise as a high voltage (3.3 V vs. Na/Na+) cathode material for sodium-ion batteries. Here, the synthesis and room temperature electrochemical performance of Na2CoSiO4 have been investigated with the compound found to yield a reversible capacity greater than 100 mA h g-1 at a rate of 5 mA g-1. Insights into the crystal structures of Na2CoSiO4 were obtained through refinement of structural models for its two polymorphs, Pn and Pbca. Atomistic modelling results indicate that intrinsic defect levels are not significant and that Na+ diffusion follows 3D pathways with low activation barriers, which suggest favourable electrode kinetics. The new findings presented here provide a platform on which future optimisation of Na2CoSiO4 as a cathode for Na-ion batteries can be based.


Vegetation controls on weathering intensity during the last deglacial transition in southeast Africa.
Tropical climate is rapidly changing, but the effects of these changes on the geosphere are unknown, despite a likelihood of climatically-induced changes on weathering and erosion. The lack of long, continuous paleo-records prevents an examination of terrestrial responses to climate change with sufficient detail to answer questions about how systems behaved in the past and may alter in the future. We use high-resolution records of pollen, clay mineralogy, and particle size from a drill core from Lake Malawi, southeast Africa, to examine atmosphere-biosphere-geosphere interactions during the last deglaciation (∼ 18-9 ka), a period of dramatic temperature and hydrologic changes. The results demonstrate that climatic controls on Lake Malawi vegetation are critically important to weathering processes and erosion patterns during the deglaciation. At 18 ka, afromontane forests dominated but were progressively replaced by tropical seasonal forest, as summer rainfall increased. Despite indication of decreased rainfall, drought-intolerant forest persisted through the Younger Dryas (YD) resulting from a shorter dry season. Following the YD, an intensified summer monsoon and increased rainfall seasonality were coeval with forest decline and expansion of drought-tolerant miombo woodland. Clay minerals closely track the vegetation record, with high ratios of kaolinite to smectite (K/S) indicating heavy leaching when forest predominates, despite variable rainfall. In the early Holocene, when rainfall and temperature increased (effective moisture remained low), open woodlands expansion resulted in decreased K/S, suggesting a reduction in chemical weathering intensity. Terrigenous sediment mass accumulation rates also increased, suggesting critical linkages among open vegetation and erosion during intervals of enhanced summer rainfall. This study shows a strong, direct influence of vegetation composition on weathering intensity in the tropics. As climate change will likely impact this interplay between the biosphere and geosphere, tropical landscape change could lead to deleterious effects on soil and water quality in regions with little infrastructure for mitigation.


Congenital Atlantoaxial Dislocation: Nature's Engineering Gone Wrong and Surgeon's Attempt to Rectify It.
The C1-2 joint is unique and is responsible for more than 50% of the neck rotation. The joints have an ergonomic design that allows maximum motion without getting dislocated. It provides six degrees of freedom, the maximum being axial rotation, and is a marvel of nature's engineering. The morphometry of lateral masses of C1 and C2 joints was analyzed to explain the possible movements despite minor variations. The normal morphometry was compared with the joints of individuals with congenital atlantoaxial dislocation. The structural flaws were assessed to understand the forces leading to dislocation in various planes. The surgical correction of such flaws and engineering involved has been discussed. The joints of patients with congenital atlantoaxial dislocation are deformed and the lateral masses are trapezoidal as compared to the cuboidal lateral masses of normal individuals. The orientation of joints decides the direction and rate of slip of C1 over C2. Surgical correction of the joints is possible by drilling them, aiding in reduction, and preventing redislocation. The construct needs to be as close to the C1-2 joints as possible. Studying the engineering in naturally occurring joints gives us a chance to understand the dynamics of the abnormal ones. Correcting the deformed joints to near-normal ones makes realignment possible in all planes and helps in understanding the best construct to fuse them. Mimicking the naturally occurring joints can help us in developing prosthesis for C1-2 arthroplasty.


Gaze control during interceptive actions with different spatiotemporal demands.
It is widely accepted that the sources of information used to guide interceptive actions depend on conflicting spatiotemporal task demands. However, there is a paucity of evidence that shows how information pick-up during interceptive actions is adapted to such conflicting constraints. The present study therefore examined the effects of systematic manipulations of spatiotemporal constraints on performance, timing and gaze in an in situ interceptive action. To this end, expert futsal goalkeepers faced penalty kicks taken from 10 m and 6 m. With the more lenient spatiotemporal constraints (i.e., kicks from 10 m), the goalkeepers saved more kicks, initiated their actions later, and looked longer toward ball relative to the penalty takers' body. Furthermore, analysis of gaze patterns showed that interindividual variations in information pick-up were related to the unfolding of the penalty taker's action, revealing a less variable, funnel-like gaze pattern toward the end of the action. These findings are interpreted to reflect that changes in spatiotemporal demands induce the differential use of information for the accurate control of interceptive actions. (PsycINFO Database Record


"Polar patch" proteases as glycopeptiligases.
The strategy of combined site directed mutagenesis and chemical modification with polar prosthetic groups was used to broaden substrate specificity of proteases resulting in the first successful formation of glycopeptides through the use of glucoamino acid acyl donors in yields of up to 90%.


Nitrous oxide emission from denitrification in stream and river networks.
Nitrous oxide (N(2)O) is a potent greenhouse gas that contributes to climate change and stratospheric ozone destruction. Anthropogenic nitrogen (N) loading to river networks is a potentially important source of N(2)O via microbial denitrification that converts N to N(2)O and dinitrogen (N(2)). The fraction of denitrified N that escapes as N(2)O rather than N(2) (i.e., the N(2)O yield) is an important determinant of how much N(2)O is produced by river networks, but little is known about the N(2)O yield in flowing waters. Here, we present the results of whole-stream (15)N-tracer additions conducted in 72 headwater streams draining multiple land-use types across the United States. We found that stream denitrification produces N(2)O at rates that increase with stream water nitrate (NO(3)(-)) concentrations, but that <1% of denitrified N is converted to N(2)O. Unlike some previous studies, we found no relationship between the N(2)O yield and stream water NO(3)(-). We suggest that increased stream NO(3)(-) loading stimulates denitrification and concomitant N(2)O production, but does not increase the N(2)O yield. In our study, most streams were sources of N(2)O to the atmosphere and the highest emission rates were observed in streams draining urban basins. Using a global river network model, we estimate that microbial N transformations (e.g., denitrification and nitrification) convert at least 0.68 Tg·y(-1) of anthropogenic N inputs to N(2)O in river networks, equivalent to 10% of the global anthropogenic N(2)O emission rate. This estimate of stream and river N(2)O emissions is three times greater than estimated by the Intergovernmental Panel on Climate Change.


[Use of glycerol trinitrate in an ointment for the management of chronic anal fissure at the National Hospital "Cayetano Heredia"].
The anal fissure is a linear tear in the anal canal mucosa. If healing fails, it evolves into a chronic anal fissure (CAF). This is one of the most frequent proctologic problems affecting younger patients, altering their social and work life. As it is disabling disease, it causes a socioeconomic problem and, hence, it is important to make a proper diagnosis and apply a rapid and efficient treatment.At present, there are different therapeutic options, both medical and surgical. Among the first, there are several options that relax the anal sphincter. One of the options which are most used is the 0.2% Glycerol Trinitrate (GTN) ointment, there being some randomized and controlled studies reporting 48% and 69% healing rates and other studies with comparable results against surgery.The objective was to know the results of the GTN ointment, so as to avoid surgery, and the probable permanent section of the internal anal sphincter. Topical Glycerol Trinitrate ointment 0.2% was used twice a day during two weeks. All patients diagnosed with CAF who met the inclusion criteria participated in this study for a one-year period, from February 2007 to January 2008. Two controls were carried out, one at the end of the treatment to verify healing and absence of symptoms, and the other after two months to check recidivism. There were 19 female patients (63.3%) and 11 male patients (36.7%). The average age was 34.87 years, with higher prevalence between 21 and 40 years (50%) and minor prevalence between 41 and 50 years (13.3%). The most frequent symptoms found were the association of anal pain with rectal bleeding in 66.6% of the patients, followed by isolated rectal bleeding and anal pain in 23.3% and 10% of cases, respectively. The most common localization of the CAF was the posterior midline in 63.3% of patients, followed by the anterior midline in 16.7% of patients, and by both midlines in 16.7% of cases. Four of the 30 patients included were lost. All the symptoms vanished in 73% (19)of the 26 remaining patients and symptoms persisted to a lower degree in 27% (7).Headache was an adverse effect in three patients. The control performed after 2 weeks of treatment evidenced partial and complete cicatrization of the fissure in 22 patients (84.6%) and persistence in 4 patients (15.4%). The final control performed after 2 months on the 18 patients who attended evidenced healing of the fissure in 16 (69.6%) and recidivism in 2 (8.7%). The following conclusion was drawn topical Glycerol Trinitrate 0.2% ointment, applied twice a day during two weeks, is effective in the treatment of chronic anal fissure, with a 69.9% success rate after two months of follow-up. Consequently, it must be considered as an alternate therapy in the treatment of CAF.


Applied Machine Learning for the Prediction of Growth of Abdominal Aortic Aneurysm in Humans.
Accurate prediction of abdominal aortic aneurysm (AAA) growth in an individual can allow personalised stratification of surveillance intervals and better inform the timing for surgery. The authors recently described the novel significant association between flow mediated dilatation (FMD) and future AAA growth. The feasibility of predicting future AAA growth was explored in individual patients using a set of benchmark machine learning techniques. The Oxford Abdominal Aortic Aneurysm Study (OxAAA) prospectively recruited AAA patients undergoing the routine NHS management pathway. In addition to the AAA diameter, FMD was systemically measured in these patients. A benchmark machine learning technique (non-linear Kernel support vector regression) was applied to predict future AAA growth in individual patients, using their baseline FMD and AAA diameter as input variables. Prospective growth data were recorded at 12 months (360 ± 49 days) in 94 patients. Of these, growth data were further recorded at 24 months (718 ± 81 days) in 79 patients. The average growth in AAA diameter was 3.4% at 12 months, and 2.8% per year at 24 months. The algorithm predicted the individual's AAA diameter to within 2 mm error in 85% and 71% of patients at 12 and 24 months. The data highlight the utility of FMD as a biomarker for AAA and the value of machine learning techniques for AAA research in the new era of precision medicine.


IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis.
Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown. Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.