Stability of discrete memory states to stochastic fluctuations in neuronal systems.
Noise can degrade memories by causing transitions from one memory state to another. For any biological memory system to be useful, the time scale of such noise-induced transitions must be much longer than the required duration for memory retention. Using biophysically-realistic modeling, we consider two types of memory in the brain: short-term memories maintained by reverberating neuronal activity for a few seconds, and long-term memories maintained by a molecular switch for years. Both systems require persistence of (neuronal or molecular) activity self-sustained by an autocatalytic process and, we argue, that both have limited memory lifetimes because of significant fluctuations. We will first discuss a strongly recurrent cortical network model endowed with feedback loops, for short-term memory. Fluctuations are due to highly irregular spike firing, a salient characteristic of cortical neurons. Then, we will analyze a model for long-term memory, based on an autophosphorylation mechanism of calcium/calmodulin-dependent protein kinase II (CaMKII) molecules. There, fluctuations arise from the fact that there are only a small number of CaMKII molecules at each postsynaptic density (putative synaptic memory unit). Our results are twofold. First, we demonstrate analytically and computationally the exponential dependence of stability on the number of neurons in a self-excitatory network, and on the number of CaMKII proteins in a molecular switch. Second, for each of the two systems, we implement graded memory consisting of a group of bistable switches. For the neuronal network we report interesting ramping temporal dynamics as a result of sequentially switching an increasing number of discrete, bistable, units. The general observation of an exponential increase in memory stability with the system size leads to a trade-off between the robustness of memories (which increases with the size of each bistable unit) and the total amount of information storage (which decreases with increasing unit size), which may be optimized in the brain through biological evolution.


Affinity purification of human DNA repair/transcription factor TFIIH using epitope-tagged xeroderma pigmentosum B protein.
TFIIH is a high molecular weight complex with a remarkable dual function in nucleotide excision repair and initiation of RNA polymerase II transcription. Mutations in the largest subunits, the XPB and XPD helicases, are associated with three inherited disorders: xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy. To facilitate the purification and biochemical characterization of this intricate complex, we generated a cell line stably expressing tagged XPB, allowing the immunopurification of the XPB protein and associated factors. Addition of two tags, a N-terminal hexameric histidine stretch and a C-terminal hemagglutinin epitope, to this highly conserved protein did not interfere with its functioning in repair and transcription. The hemagglutinin epitope allowed efficient TFIIH immunopurification to homogeneity from a fractionated whole cell extract in essentially one step. We conclude that the predominant active form of TFIIH is composed of nine subunits and that there is one molecule of XPB per TFIIH complex. The affinity-purified complex exhibits all expected TFIIH activities: DNA-dependent ATPase, helicase, C-terminal domain kinase, and participation in in vitro and in vivo nucleotide excision repair and in vitro transcription. The affinity purification procedure described here is fast and simple, does not require extensive chromatographic procedures, and yields highly purified, active TFIIH.


Cochlear function in Prestin knockout mice.
Gross-potential recordings in mice lacking the Prestin gene indicate that compound action potential (CAP) thresholds are shifted by approximately 45 dB at 5 kHz and by approximately 60 dB at 33 kHz. However, in order to conclude that outer hair cell (OHC) electromotility is associated with the cochlear amplifier, frequency selectivity must be evaluated and the integrity of the OHC's forward transducer ascertained. The present report demonstrates no frequency selectivity in CAP tuning curves recorded in homozygotes. In addition, CAP input-output functions indicate that responses in knockout mice approach those in controls at high levels where the amplifier has little influence. Although the cochlear microphonic in knockout mice remains approximately 12 dB below that in wild-type mice even at the highest levels, this deficit is thought to reflect hair cell losses in mice lacking prestin. A change in OHC forward transduction is not implied because knockout mice display non-linear responses similar to those in controls. For example, homozygotes exhibit a bipolar summating potential (SP) with positive responses at high frequencies; negative responses at low frequencies. Measurement of intermodulation distortion also shows that the cubic difference tone, 2f(1)-f(2), is approximately 20 dB down from the primaries in both homozygotes and their controls. Because OHCs are the sole generators of the negative SP and because 2f(1)-f(2) is also thought to originate in OHC transduction, these data support the idea that forward transduction is not degraded in OHCs lacking prestin. Finally, application of AM1-43, which initially enters hair cells through their transducer channels, produces fluorescence in wild-type and knockout mice indicating transducer channel activity in both inner and outer hair cells.


A group-enhanced sprint interval training program for amateur athletes.
Sprint interval training (SIT) can elicit improvements in aerobic and anaerobic capacity. While variations in SIT protocols have been investigated, the influence of social processes cannot be overlooked. As research supports the use of groups to influence individual cognitions and behaviours, the current project assessed the effectiveness of a group-based intervention with participants conducting SIT. Specifically, 53 amateur athletes (age, 21.9 ± 2.9 years; 53% females) took part in a 4-week training program (3 sessions per week, 30-s "all-out" efforts with 4 min active recovery, repeated 4-6 times per session), and were assigned to "true group", aggregate, or individual conditions. Results indicated no significant differences between groups for the physiological measures. With regards to training improvements from baseline for all participants- regardless of condition - significant main effects for time were identified for maximal oxygen uptake (2.5-2.8 mL·kg(-1)·min(-1), p < 0.001, η(2) = 0.03), time-trial performance (14-32 s, p < 0.001, η(2) = 0.37), and anaerobic power (1.1-1.7 k·h(-1), p < 0.001, η(2) = 0.66). With regards to the psychological measures, significant main effects between groups were found for motivation (p = 0.033, η(2) = 0.13), task self-efficacy (p = 0.018, η(2) = 0.15), and scheduling self-efficacy (p = 0.003, η(2) = 0.22). The true group experienced greater improvements in motivation than the individual condition, but the aggregate and individual conditions demonstrated greater increases in task and scheduling self-efficacy. Though the SIT paradigm employed induced training improvements similar to previous work, the group intervention was not able to further these improvements.


Optimizing experimental parameters for the projection requirement in HAADF-STEM tomography.
Tomographic reconstruction algorithms offer a means by which a tilt-series of transmission images can be combined to yield a three dimensional model of the specimen. Conventional reconstruction algorithms assume that the measured signal is a linear projection of some property, typically the density, of the material. Here we report the use of multislice simulations to investigate the extent to which this assumption is met in HAADF-STEM imaging. The use of simulations allows for a systematic survey of a range of materials and microscope parameters to inform optimal experimental design. Using this approach it is demonstrated that the imaging of amorphous materials is in good agreement with the projection assumption in most cases. Images of crystalline specimens taken along zone-axes are found to be poorly suited for conventional linear reconstruction algorithms due to channelling effects which produce enhanced intensities compared with off-axis images, and poor compliance with the projection requirement. Off-axis images are found to be suitable for reconstruction, though they do not strictly meet the linearity requirement in most cases. It is demonstrated that microscope parameters can be selected to yield improved compliance with the projection requirement.


Unmet need and fertility decline: a comparative perspective on prospects in sub-Saharan Africa.
This study assesses how changes in unmet need for family planning have contributed to contemporary fertility declines, and the implications of this historical record for further fertility decline, especially in sub-Saharan Africa. We examine joint trends at the national level in fertility, unintended fertility, and unmet need. We bring unintended fertility into the analysis because the underlying rationale for reducing unmet need is to avert unintended pregnancies and births. The association over time between unmet need and fertility is investigated using survey data from 45 countries in Africa, Asia, and Latin America and the Caribbean from the mid-1970s to the present. The empirical analysis finds that reduction in unmet need, especially unmet need for limiting, is strongly associated with fertility decline in Latin America and the Caribbean and in Asia and North Africa. Fertility decline in sub-Saharan Africa is weakly associated with trends in unmet need (and satisfaction of demand). We propose that the stark regional difference is due to measurement problems and to the fundamentally different character of fertility decline in sub-Saharan Africa, itself reflective of basic differences in pretransition reproductive regimes.


Inhibition of Endothelial SCUBE2 (Signal Peptide-CUB-EGF Domain-Containing Protein 2), a Novel VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) Coreceptor, Suppresses Tumor Angiogenesis.
SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), expressed on the endothelial cell surface, functions as a novel coreceptor for VEGFR2 (vascular endothelial growth factor receptor 2) and enhances VEGF-induced signaling in adult angiogenesis. However, whether SCUBE2 plays a role in pathological angiogenesis and whether anti-SCUBE2 antibody is an effective strategy for blocking tumor angiogenesis remain unknown. The aim of this study was to investigate the pathological role and targeting therapy of SCUBE2 in tumor vasculature. Immunohistochemistry revealed that SCUBE2 is highly expressed in endothelial cells of numerous carcinomas. Genetic endothelial cell knockout of SCUBE2 and pharmacological inhibition with the anti-SCUBE2 monoclonal antibody SP.B1 significantly reduced xenograft tumor growth, decreased tumor vascular density, increased apoptosis, and decreased the proliferation of tumor cells. Mechanistic studies revealed that SP.B1 binds to SCUBE2 and induces its internalization for lysosomal degradation, thereby reducing its cell surface level and inhibiting the binding of and downstream signaling of VEGF, including VEGFR2 phosphorylation and AKT/MAPK (mitogen-activated protein kinase) activation. Importantly, dual combination therapy with anti-SCUBE2 monoclonal antibody and anti-VEGF antibody or chemotherapy was more effective than single-agent therapy. Endothelial cell surface SCUBE2 is a VEGFR2 coreceptor essential for pathological tumor angiogenesis, and anti-SCUBE2 monoclonal antibody acting as an internalization inducer may provide a potent combination therapy for tumor angiogenesis.


Large 14C excursion in 5480 BC indicates an abnormal sun in the mid-Holocene.
Radiocarbon content in tree rings can be an excellent proxy of the past incoming cosmic ray intensities to Earth. Although such past cosmic ray variations have been studied by measurements of 14C contents in tree rings with ≥10-y time resolution for the Holocene, there are few annual 14C data. There is a little understanding about annual 14C variations in the past, with the exception of a few periods including the AD 774-775 14C excursion where annual measurements have been performed. Here, we report the result of 14C measurements using the bristlecone pine tree rings for the period from 5490 BC to 5411 BC with 1- to 2-y resolution, and a finding of an extraordinarily large 14C increase (20‰) from 5481 BC to 5471 BC (the 5480 BC event). The 14C increase rate of this event is much larger than that of the normal grand solar minima. We propose the possible causes of this event are an unknown phase of grand solar minimum, or a combination of successive solar proton events and a normal grand solar minimum.


A Bacteroides ruminicola 1,4-beta-D-endoglucanase is encoded in two reading frames.
Escherichia coli transformed with a plasmid containing a Bacteroides ruminicola endoglucanase (carboxymethyl cellulase [CMCase]) gene produced three immunologically cross-reacting CMCases which had molecular weights of 40,500, 84,000, and 88,000, while B. ruminicola produced CMCases with molecular weights of 82,000 and 88,000. The two B. ruminicola enzymes (purified from culture supernatants) had different N-terminal amino acid sequences, but each enzyme was encoded by the same gene (three independent clones had the same DNA sequence). The 88,000-molecular-weight CMCase (88K CMCase) gene appeared to contain two open reading frames which overlapped for 18 bp and were -1 out of frame, and each open reading frame contained several stop codons near the overlap region. The two 88K CMCase open reading frames had enough DNA to produce a protein of 106K, but the mobility of the enzyme in sodium dodecyl sulfate gels gave a value which was 20% lower. On the basis of the -1 frame shift and the large deviation in theoretical versus actual size, it appears that an unusual event (e.g., ribosomal hopping or RNA splicing) is involved in either the translation or the transcription of the 88K B. ruminicola CMCase gene. The 82K CMCase was completely encoded in the second reading frame, and its size was in agreement with the DNA sequence.


Features of the Streptomyces hygroscopicus HtpG reveal how partial geldanamycin resistance can arise with mutation to the ATP binding pocket of a eukaryotic Hsp90.
Much attention is focused on the benzoquinone ansamycins as anticancer agents, with several derivatives of the natural product geldanamycin (GdA) now in clinical trials. These drugs are selective inhibitors of Hsp90, a molecular chaperone vital for many of the activities that drive cancer progression. Mutational changes to their interaction site, the extremely conserved ATP binding site of Hsp90, would mostly be predicted to inactivate the chaperone. As a result, drug resistance should not arise readily this way. Nevertheless, Streptomyces hygroscopicus, the actinomycete that produces GdA, has evolved an Hsp90 family protein (HtpG) that lacks GdA binding. It is altered in certain of the highly conserved amino acids making contacts to this antibiotic in crystal structures of GdA bound to eukaryotic forms of Hsp90. Two of these amino acid changes, located on one side of the nucleotide-binding cleft, weakened GdA/Hsp90 binding and conferred partial GdA resistance when inserted into the endogenous Hsp90 of yeast cells. Crystal structures revealed their main effect to be a weakening of interactions with the C-12 methoxy group of the GdA ansamycin ring. This is the first study to demonstrate that partial GdA resistance is possible by mutation within the ATP binding pocket of Hsp90.


beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.
In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta-amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.


MAGNETIC CORE SHELL STRUCTURES: from 0D to 1D assembling.
Material research and development studies are focused on different techniques of bringing out nanomaterials with desired characteristics and properties. From the point of view of materials development, nowadays scientists are strongly focused on obtaining materials with predefined characteristics and properties. The morphology control seems to be a determinant factor and increasing attention is devoted to this aspect. At this moment it is possible to engineer the material's features by using different methods and materials combination for both medical and industrial applications. In the applications of chemistry and synthesis, biology, mechanics, optics solar cells and microelectronics tailoring the adjustable parameters of stoichiometry, chemical structure, shape and segregation are evaluated and opens new fields. Because of the magnetic features of nanoparticles and durable particle size, less than 100 nm, this study is aiming to describe their uses in practical applications. That's why the whole hydrodynamic magnetic core shell topic will be reviewed on this paper. Additionally, the properties acting in general sight in solid-state physics are utilized for material selection and for defining issue connecting the core, shell structure and their producing properties. Here, in the study of core/shell nanoparticle various physical and chemical synthesis routes and the effect of electrospun method are briefly discussed. Starting from a real void of the scientific literature, the existent data related to the 1D magnetic electrospun materials are reviewed. The perspectives in the medical, environmental or energetic sector is great and bring some real advantages related to the 0D core@shell structures because both mechanical and biological properties are dependent on the morphology of the materials.


Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol.
We report the outcome for children and young people with Down syndrome-associated acute lymphoblastic leukaemia (DS-ALL) treated on a contemporary protocol. Compared with non-DS ALL, patients with DS-ALL had an inferior event-free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment-related mortality - was primarily responsible for the worse outcomes for DS-ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group.


Additions to the hydroids (Cnidaria, Hydrozoa) of the Bay of Fundy, northeastern North America, with a checklist of species reported from the region.
Two new species of hydroids, Eudendrium bleakneyi and Halecium praeparvum, are described from the Bay of Fundy. Fourteen others, Tubularia acadiae Petersen, 1990, Coryne pusilla Gaertner, 1774, Sarsia lovenii (M. Sars, 1846), Zanclea implexa (Alder, 1856), Corydendrium dispar Kramp, 1935, Rhizogeton fusiformis L. Agassiz, 1862, Bougainvillia muscus (Allman, 1863), Rhizorhagium roseum M. Sars, in G.O. Sars, 1874, Hydractinia symbiolongicarpus Buss & Yund, 1989, Eudendrium vaginatum Allman, 1863, Tiaropsis multicirrata (M. Sars, 1835), Obelia bidentata S.F. Clark, 1875, Halecium marsupiale Bergh, 1887, and Sertularella gigantea Hincks, 1874, are reported, with collection data, for the first time from the bay. All but Coryne pusilla, Rhizorhagium roseum, Eudendrium vaginatum, and Sertularella gigantea are also new to Atlantic Canada, while Zanclea implexa, Corydendrium dispar, and Halecium marsupiale are reported for the first time in the western North Atlantic. Two of those species, Hydractinia symbiolongicarpus and Obelia bidentata, are disjunct in distribution, with core populations occurring in warmer waters to the south of Cape Cod, Massachusetts. Both were discovered in Minas Basin, a hydrographically distinct embayment where surface water temperatures are much warmer during summer than in the perpetually cold lower Bay of Fundy. Rhizorhagium roseum and the subfamily Rhizorhagiinae are transferred from family Bougainvilliidae Lütken, 1850 to Pandeidae Haeckel, 1879. An annotated checklist of hydroids from the Fundy region, based on previously published reports and on new records of species, is added as an appendix. Included in the checklist are 43 species of anthoathecates and 75 species of leptothecates, referable to 30 families and 56 genera. Families with the most species were Sertulariidae (23), Haleciidae (13), Eudendriidae (11), and Obeliidae (10). Biogeographically, the aggregate hydroid fauna of the bay conforms with that occurring in other parts of the Western Atlantic Boreal Region. Halecium permodicum is proposed as a replacement name for Halecium minor Fraser, 1935, an invalid junior homonym of H. minor Pictet, 1893.


Experimental acute thrombotic stroke in baboons.
To study the effects of antithrombotic therapy in experimental stroke, we have characterized a baboon model of acute cerebrovascular thrombosis. In this model an inflatable silastic balloon cuff has been implanted by transorbital approach around the right middle cerebral artery (MCA), proximal to the take-off of the lenticulostriate arteries (LSA). Inflation of the balloon for 3 hours in six animals produced a stereotypic sustained stroke syndrome characterized by contralateral hemiparesis. An infarction volume of 3.2 +/- 1.5 cm3 in the ipsilateral corpus striatum was documented by computerized tomographic (CT) scanning at 10 days following stroke induction and 3.9 +/- 1.9 cm3 (n = 4) at 14 days by morphometric neuropathologic determinations of brain specimens fixed in situ by pressure-perfusion with 10% buffered formalin. Immediate pressure-perfusion fixation following deflation of the balloon was performed in 16 additional animals given Evans blue dye intravenously prior to the 3 hour MCA balloon occlusion. Light microscopy and transmission electron microscopy consistently confirmed the presence of thrombotic material occluding microcirculatory branches of the right LSA in the region of Evans blue stain, but not those of the contralateral corpus striatum. When autologous 111In-platelets were infused intravenously in four animals from the above group prior to the transient 3 hour occlusion of the right MCA, gamma scintillation camera imaging of each perfused-fixed whole brain demonstrated the presence of a single residual focus of 111In-platelet activity involving only the Evans blue-stained right corpus striatum. Focal right hemispheric activity was equivalent to 0.55 +/- 0.49 ml of whole blood, and the occlusion score derived from histologic examination of the microcirculation of the Evans blue-stained corpus striatum averaged 34.8 +/- 2.8. Similar 111In-platelet imaging and histologic scoring experiments carried out in four animals pretreated with the antithrombotic combination heparin and ticlopidine showed marked reduction of both 111In-platelet activity (0.01 +/- 0.03 ml vs. 0.55 +/- 0.49 ml; p less than 0.01) and thrombotic occlusion of the microcirculation (10.8 +/- 7.4 units vs. 34.8 +/- 2.8 units; p less than 0.01) in the right corpus striatum following 3 hours of MCA occlusion. In separate control experiments 111In-labeled autologous platelets were infused after the 3 hour period of right MCA occlusion and subsequent balloon deflation in two animals; no focus of 111In-platelet activity was demonstrated in fixed whole brain.(ABSTRACT TRUNCATED AT 400 WORDS)


Emissions of nitrous oxide and ammonia from a sandy soil following surface application and incorporation of cauliflower leaf residues.
Vegetable production systems are often characterized by excessive nitrogen (N) fertilization and the incorporation of large amounts of post-harvest crop residues. This makes them particularly prone to ammonia (NH3) and nitrous oxide (N2O) emissions. Yet, urgently needed management strategies that can reduce these harmful emissions are missing, because underlying processes are not fully understood. The present study therefore focuses on the effects of residue placement on NH3 and N2O emissions. For this, cauliflower leaf residues (286 kg N/ha) were either applied as surface mulch (mulch) or mixed with the topsoil (mix) and in situ NH3 and N2O emissions were investigated. The experiment took place on a sandy soil in Northeastern Germany during summer 2012. Residue application created a high peak in N2O emissions during the first 2 weeks, irrespective of residue placement. There was no significant difference in the emission sums over the experimental period (65 days) between the mix (5·8 ± 0·68 kg N2O-N/ha) and the mulch (9·7 ± 1·53 kg N2O-N/ha) treatment. This was also the case for NH3 emissions, which exhibited a lower initial peak followed by a prolonged decline. Measured emission sums were 4·1 ± 0·33 (mix) and 5·1 ± 0·73 (mulch) kg NH3-N/ha. It was concluded that substantial NH3 and N2O emissions can occur after high input of available organic carbon and N even in a coarse-textured soil with low water-holding capacity. Other than expected, surface-application does not enhance NH3 emissions at the expense of N2O emissions compared with residue mixing into the soil, at least under the conditions of the present study.


[Oral health status of elderly women from the Brazilian Federal District].
Data from Brazilian researches that evaluated oral health of elderly people show a worrisome situation. The purpose of this study was to estimate the frequency of edentulism, analyze both the use and need profiles of prosthesis, calculate the DMFT index and check the condition of periodontal elderly residents in the Federal District. One hundred and forty women aged 60 years or above were examined. The condition of each prosthesis was evaluated to detect the presence of functional or aesthetic damage. Then, clinical examination was carried out to detect the number of decayed, missing or filled teeth in order to calculate the DMFT index. The periodontal examination included the index of visible plaque, bleeding index, measurement of clinical probing depth, measurement of clinical attachment level and teeth mobility. The results showed poor oral conditions of the patients. The rate of edentulism was high, the DMFT index was elevated (29.8) with a predominance of the extracted component (87.1%) and periodontal condition was considered severe. From these data we can conclude that the oral condition of elderly represented in this study is precarious and reflects the need for health promotion and rehabilitation programs for this segment of the population.


Determinants of the use of breast cancer screening among women workers in urban Mexico.
This case-control study aimed to determine critical factors influencing the use of clinical breast examination and mammography among women workers in Monterrey, Mexico. We determined case and control status from survey results. Cases were defined in accordance with the guidelines of the Official Mexican Standard as lack of at least one clinical breast examination during the past year by surveyed women. For women older than 40 years, cases were further defined as lack of at least one mammogram in the previous 2 years and, for women older than 50, lack of a mammogram in the previous year. Controls were defined as adherence by surveyed women to these guidelines. Participants (N = 306 clerks aged 18-60) provided information about their practices, knowledge, and perceptions regarding breast cancer screening. Factors identified by odds ratio analysis as significantly different between cases and controls were analyzed by multivariate logistic regression. Survey participants' knowledge about the utility of breast self-examination (odds ratio, 6.0; 95% confidence interval, 1.0-33.9), perception that the health care system has enough equipment and personnel for clinical breast examination (odds ratio, 4.7; 95% confidence interval, 1.7-13.2), and perception that they have enough time to wait for and receive clinical breast examinations (odds ratio, 2.5; 95% confidence interval, 1.1-5.8) significantly predisposed women to use screening services independent of years of formal education, number of pregnancies, number of living children, hours worked per week, and monthly family income. Perception of organizational and structural factors played a significant role in screening use. Our findings have implications for the general population, provider practices, community interventions, and future development of strategies to increase use of screening services in similar locales.


MCP-1-induced protein attenuates endotoxin-induced myocardial dysfunction by suppressing cardiac NF-кB activation via inhibition of IкB kinase activation.
Myocardial contractile dysfunction is a major consequence of septic shock, which is mainly mediated by nuclear factor-kappa B (NF-кB)-dependent production of inflammatory mediators in the heart. A novel zinc-finger protein, MCP-1-induced protein (MCPIP), is thought to have NF-кB inhibitory activity in certain cell cultures, but its pathophysiological consequence in vivo remains undefined. This study aims to clarify whether the anti-inflammatory potency of MCPIP contribute to amelioration of septic myocardial inflammation and dysfunction in vivo. Transgenic mice (TG) with cardiac-specific expression of MCPIP and their littermate wild-type (WT) controls were challenged with Escherichia coli LPS (10mg/kg ip) and myocardial function was assessed 18 h later using echocardiography. LPS administration markedly deteriorated myocardial contractile function evidenced by reduction of the percentage of left ventricular fractional shortening, which was significantly attenuated by myocardial expression of MCPIP. MCPIP TG mice exhibited a markedly reduced myocardial inflammatory cytokines, less of iNOS expression and peroxynitrite formation, decreased caspase-3/7 activities and apoptotic cell death compared with LPS-treated WT mice. Activation of cardiac NF-кB observed in LPS-challenged WT mice was suppressed by the presence of MCPIP, as evidenced by decreased phosphorylation of IкB kinase (IKKα/β), reduced degradation of the cytosolic IкBα, and decreased nuclear translocation of NF-кB p65 subunit and its target DNA-binding activity. These results suggest that MCPIP has therapeutic values to protect heart from inflammatory pathologies, possibly through inhibition of IкB kinase complex, leading to blockade of NF-кB activation, and subsequently, attenuation of the proinflammatory state and nitrosative stress in the myocardium.


Cardiovascular disease risk factor knowledge in young adults and 10-year change in risk factors: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
This study's objective was assessment of cardiovascular disease (CVD) risk factor knowledge in young adults, its association with 10-year changes in risk factor levels, and variables related to risk factor knowledge. A total of 4,193 healthy persons (55% female, 48% Black; mean age=30 years) from four urban US communities were queried about risk factor knowledge in 1990-1991 and were reexamined in 2000-2001. Of six risk factors considered (hypertension, hyperlipidemia, smoking, overweight, sedentary lifestyle, and unhealthy diet), participants mentioned a mean of two; more than 65% were not aware of any risk factors, and less than 35% recognized being overweight as a risk factor. After adjustment, variables associated with mentioning more than two CVD risk factors versus one or fewer were Black race (OR=0.52, 95% confidence interval (CI): 0.44, 0.61), having a high school education or less (OR=0.88, 95% CI: 0.80, 0.95), having one or two (vs. zero) risk factors (OR=1.27, 95% CI: 1.05, 1.53), and having three or more (vs. zero) risk factors (OR=1.79, 95% CI: 1.35, 2.38). More knowledge was marginally associated with less increase in body mass index 10 years later (p=0.06) but was unrelated to other risk factor changes. Knowledge of CVD risk factors was very low in these young adults but increased with the presence of risk factors. Knowledge alone did not predict 10-year changes in risk factors.


The Edgecombe County (NC) High Blood Pressure Control Program: II. Barriers to the use of medical care among hypertensives.
As the initial step in a five-year project to improve control of high blood pressure in Edgecombe County, North Carolina, a survey was conducted in 1980 to determine the prevalence of hypertension and to identify factors which might constitute barriers to the use of medical care by hypertensives. This report summarizes the findings for the 539 hypertensives identified through the baseline survey. In general, Black hypertensives reported more access problems than Whites. Within race, however, males and females differed very little on selected measures of potential access to medical care. Among women, lower scores on potential access were strongly associated with being untreated, whereas for men, concerns about the safety of anti-hypertensive drug therapy were associated with being unaware. On a summary measure of the actual use of medical care in response to symptoms, both male and female treated hypertensives scored higher than their untreated counterparts. The implications of these and other findings for community-based blood pressure control activities are discussed.


Prevalence And Spending Associated With Patients Who Have A Behavioral Health Disorder And Other Conditions.
People with multiple medical conditions are a growing and increasingly costly segment of the U.S. Despite the co-occurrence of physical and behavioral health comorbidities, the US health care system tends to treat these conditions separately rather than holistically. To identify opportunities for population health improvement, we examined the treated prevalence of and health care spending on behavioral health disorders, by the number of coexisting physical disorders, among noninstitutionalized adults. The vast majority (85 percent) of spending was attributed to treatment of the physical comorbidities. Only 15 percent was attributed to treatments of the behavioral disorders; of these, a primary diagnosis of depression was most common, seen in 57 percent of the sample. These findings suggest the potential to improve outcomes and reduce spending by applying collaborative care models more broadly. Policies should promote payment and delivery reforms that advance the integration of behavioral health and primary care.


Patient-specific spinal stiffness in AIS: a preoperative and noninvasive method.
The clinical tests currently used to assess spinal biomechanics preoperatively are unable to assess true mechanical spinal stiffness. They rely on spinal displacement without considering the force required to deform a patient's spine. We propose a preoperative method for noninvasively quantifying the three-dimensional patient-specific stiffness of the spines of adolescent idiopathic scoliosis patients. The technique combines a novel clinical test with numerical optimization of a finite element model of the patient's spine. A pilot study conducted on five patients showed that the model was able to provide accurate 3D reconstruction of the spine's midline and predict the spine's stiffness for each patient in flexion, bending, and rotation. Statistically significant variation of spinal stiffness was observed between the patients. This result confirms that spinal biomechanics is patient-specific, which should be taken into consideration to individualize surgical treatment.


BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY.
A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual re-assessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The Bayesian data augmentation approach is used to sample both the missing data and model parameters from their posterior full conditional distributions. We evaluate the performance of the DA-CRM through extensive simulation studies, and also compare it with other existing methods. The results show that the proposed design satisfactorily resolves the issues related to late-onset toxicities and possesses desirable operating characteristics: treating patients more safely, and also selecting the maximum tolerated dose with a higher probability. The new DA-CRM is illustrated with two phase I cancer clinical trials.


First Report of Mango Malformation Disease Caused by Fusarium mangiferae in Spain.
Mango (Mangifera indica L.) malformation disease (MMD) is one of the most important diseases affecting this crop worldwide, which causes severe economic losses because of the reduction of productivity. Symptoms of MMD in Spain were observed for the first time in April of 2006 in three mango orchards in the Axarquia Region (southern Spain). Symptoms included an abnormal development of vegetative shoots with shortened internodes and dwarfed leaves and hypertrophied short and thickened panicles. In the years of 2006, 2009, and 2010, isolates of Fusarium were obtained from vegetative shoots and floral tissue of symptomatic mango trees from 21 different orchards of cvs. Keitt, Kent, Osteen, Tommy Atkins, and a variety of minor commercial cultivars, all showing typical symptoms of MMD. Different Fusarium-like strains were isolated from infected tissues. Colonies from single-spored isolates possessed dark purple-to-salmon-colored mycelium when grown on potato dextrose agar medium. On fresh carnation leaf agar medium, mycelium contained aerial conidiophores possessing three- to five-celled macroconidia and abundant microconidia in false heads from mono- and polyphialides; while cream-orange-colored sporodochia were produced on the surface of the medium, typical for Fusarium mangiferae. The identification of 37 isolates was confirmed as F. mangiferae by species-specific PCR analysis with the primer pair 1-3 F/R that amplified a 608-bp DNA fragment from all Spanish isolates as well as a representative Israeli control strain, Fus 34, also designated as MRC7560 (2). Pathogenicity using four representative isolates, UMAF F02, UMAF F10, UMAF F17, and UMAF F38 of F. mangiferae from Spain as well as isolate MRC7560, was tested on 2-year-old healthy mango seedlings cv. Keitt by inoculating 15 buds from three different trees with a 20-μl conidial suspension (5 × 107 conidia per ml) per isolate (1). This experiment was conducted twice with two independent sets of plants and at different times (March and November 2010). Typical mango malformation symptoms were detected after bud break in March 2011, 5 and 12 months after inoculation. Symptoms were observed for 60% of the inoculated buds with the four F. mangiferae Spanish isolates and 75% with the MRC7560 control strain, but not with water-inoculated control plants. Recovered isolates from the infected floral and vegetative malformed buds were identical morphologically to those inoculated, and the specific 608-bp fragment described for F. mangiferae was amplified with specific-PCR, thus fulfilling Koch's postulates. To our knowledge, this is the first report of mango malformation disease caused by F. mangiferae in Spain and Europe. References: (1) S. Freeman et al. Phytopathology 89:456, 1999. (2) Q. I. Zheng and R. C. Ploetz. Plant Pathol. 51:208, 2002.


A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia.
Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified a kindred with FIP with short telomeres who did not carry a mutation in known FIP genes TERT or hTR . We performed targeted sequencing of other telomere-related genes to identify the genetic basis of FIP in this kindred. The proband was a 69 year-old man with dyspnea, restrictive pulmonary function test results, and reticular changes on high-resolution CT scan. An older male sibling had died from IPF. The proband had markedly shortened telomeres in peripheral blood and undetectably short telomeres in alveolar epithelial cells. Polymerase chain reaction-based sequencing of NOP10 , TINF2 , NHP2 , and DKC1 revealed that both affected siblings shared a novel A to G 1213 transition in DKC1 near the hTR binding domain that is predicted to encode a Thr405Ala amino acid substitution. hTR levels were decreased out of proportion to DKC1 expression in the T405A DKC1 proband, suggesting this mutation destabilizes hTR and impairs telomerase function. This DKC1 variant represents the third telomere-related gene identified as a genetic cause of FIP. Further investigation into the mechanism by which dyskerin contributes to the development of lung fibrosis is warranted.


Antiarrhythmic potential of mesenchymal stem cell is modulated by hypoxic environment.
The purpose of this study was to evaluate the antiarrhythmic potential of mesenchymal stem cells (MSC) under a different environment. Little is known about how environmental status affects antiarrhythmic potential of MSCs. To investigate the effect of paracrine factors secreted from MSCs under different circumstances on arrhythmogenicity in rats with myocardial infarction, we injected paracrine media (PM) secreted under hypoxic, normoxic conditions (hypoxic PM and normoxic PM), and MSC into the border zone of infarcted myocardium in rats. We found that the injection of hypoxic PM, but not normoxic PM, markedly restored conduction velocities, suppressed focal activity, and prevented sudden arrhythmic deaths in rats. Underlying this electrophysiological alteration was a decrease in fibrosis, restoration of connexin 43, alleviation of Ca(2+) overload, and recovery of Ca(2+)-regulatory ion channels and proteins, all of which is supported by proteomic data showing that several paracrine factors including basic fibroblast growth factor, insulinlike growth factor 1, hepatocyte growth factor, and EF-hand domain-containing 2 are potential mediators. When compared with PM, MSC injection did not reduce or prevent arrhythmogenicity, suggesting that the antiarrhythmic or proarrhythmic potential of MSC is mainly dependent on paracrine factors. A hypoxic or normoxic environment surrounding MSC affects the type and properties of the growth factors or cytokines, and these secreted molecules determine the characteristics of the electro-anatomical substrate of the surrounding myocardium.


Ultrastructure of myoepithelial cells as a target cell in sialoadenitis of submandibular glands of lupus-prone female NZBxNZWF1 mice.
The changes of myoepithelial cells of sialoadenitis in submandibular glands in lupus-prone female NZB x NZWF1 (B/WF1) mice, a model for human secondary Sjögren's syndrome (sSS), were examined ultrastructurally. Inflammatory foci consisting of mainly lymphoid cells (lymphocytes and plasma cells) in the interlobular interstitium began to develop from 18 weeks of ages, and those were found within acini from the age of 25 weeks. These were paralleled with the production of anti-double-stranded deoxyribonucleic acid and anti-Ro/SS-A antibodies with age. Infiltrated lymphoid cells consisted of CD4+ T cells and Ig+ (or IgG2a+) cells. Electron microscopy revealed destruction of myoepithelial cells with lysis of basement membranes contacted with either lymphocytes or plasma cells. These led to the destruction (degeneration and necrosis) of the epithelium in striated and intercalated ducts and acinar epithelium. Further destruction of those cells occurred by the invasion of lymphocytes into the epithelial layers. Small numbers of apoptotic myoepithelium and duct epithelium from the age of 25 to 36 weeks and an increase of those cells in survived mice at 44 weeks of age were observed. The present study suggests that the myoepithelium may be one of the target cells and that the destruction of myoepithelial cells by infiltrated lymphoid cells may precede the destruction of acinar ducts and epithelium in sialoadenitis in sSS.


Regulation of solute carriers oct2 and OAT1/3 in the kidney: a phylogenetic, ontogenetic, and cell dynamic perspective.
Over the course of more than 500 million years, the kidneys have undergone a remarkable evolution from primitive nephric tubes to intricate filtration-reabsorption systems that maintain homeostasis and remove metabolic end products from the body. The evolutionarily conserved solute carriers organic cation transporter 2 (OCT2) and organic anion transporters 1 and 3 (OAT1/3) coordinate the active secretion of a broad range of endogenous and exogenous substances, many of which accumulate in the blood of patients with kidney failure despite dialysis. Harnessing OCT2 and OAT1/3 through functional preservation or regeneration could alleviate the progression of kidney disease. Additionally, it would improve current in vitro test models that lose their expression in culture. With this review, we explore OCT2 and OAT1/3 regulation from different perspectives: phylogenetic, ontogenetic, and cell dynamic. Our aim is to identify possible molecular targets both to help prevent or compensate for the loss of transport activity in patients with kidney disease and to enable endogenous OCT2 and OAT1/3 induction in vitro in order to develop better models for drug development.


Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1.
Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidney, liver and heart. A potent spiroquinoxalinamine derivative named liproxstatin-1 is discovered by high-throughput screening, which is able to suppress ferroptosis via lipid peroxide scavenging in vivo. Thus, molecular simulations, density functional theory (DFT) and variational transition-state theory with a small-curvature tunneling (SCT) coefficient are utilized to elucidate the detailed mechanisms of inactivation of a lipid peroxide radical by liproxstatin-1. H-atom abstracted from liproxstatin-1 by a CH3OO˙ radical occurs preferentially at the aromatic amine site (1'-NH) under thermodynamic and frontier molecular orbital analysis. The value of a calculated rate constant at 300 K is up to 6.38 × 103 M-1 S-1, indicating that the quantum tunneling effect is responsible for making a free radical trapping reaction more efficient by liproxstatin-1. The production of a liproxstatin-1 radical is easily regenerated to the active reduced form by ubiquinol in the body to avoid secondary damage by free radicals. A benzene ring and the higher HOMO energy are beneficial to enhance the lipid radical scavenging activity based on the structure-activity relationship study. Overall, the present results provide theoretical insights into the exploration of novel ferroptosis inhibitors.


Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect.
We studied quinidine block of Kv1.4DeltaN, a K(+) channel lacking N-type inactivation, expressed in Xenopus ooctyes. Initially, quinidine intracellularly blocked the open channel so rapidly it overlapped with activation. This rapid open channel block was reduced (non-additively) by interventions that slow C-type inactivation: [K(+)](o) elevation and an extracellular lysine to tyrosine mutation (K532Y). These manipulations reduced the affinity of rapid open channel block ~10-fold, but left the effective electrical distance unchanged at ~0.15. Following rapid open channel block, there were time-dependent quinidine effects: the rate of inactivation during a single depolarisation was increased, and repetitive pulsing showed use dependence. The rate of recovery from the time-dependent aspect of quinidine block was similar to recovery from normal C-type inactivation. Manipulations that prevented the channel from entering the C-type inactivated state (i.e. high [K(+)](o) or the K532Y mutation) prevented the development of the time-dependent quinidine-induced inactivation. The concentration dependence of the rapid block and the time-dependent quinidine-induced inactivation were similar, but the time-dependent component was strongly voltage sensitive, with an effective electrical distance of 2. Clearly, this cannot reflect the permeation of quinidine through the electric field, but must be the result of some other voltage-sensitive change in the channel. We propose that quinidine promotes the entry of the channel into a C-type inactivated state in a time- and voltage-dependent manner. We developed a mathematical model based on these results to test the hypothesis that, following rapid open channel block, quinidine promotes development of the C-type inactivated state through a voltage-dependent conformational change.


Cause-specific mortality trends in The Netherlands, 1875-1992: a formal analysis of the epidemiologic transition.
The objective of this study is to produce a detailed yet robust description of the epidemiologic transition in The Netherlands. National mortality data on sex, age, cause of death and calendar year (1875-1992) were extracted from official publications. For the entire period, 27 causes of death could be distinguished, while 65 causes (nested within the 27) could be studied from 1901 onwards. Cluster analysis was used to determine groups of causes of death with similar trend curves over a period of time with respect to age- and sex-standardized mortality rates. With respect to the 27 causes, three important clusters were found: (1) infectious diseases which declined rapidly in the late 19th century (e.g. typhoid fever), (2) infectious diseases which showed a less precipitous decline (e.g. respiratory tuberculosis), and (3) non-infectious diseases which showed an increasing trend during most of the period 1875-1992 (e.g. cancer). The 65 causes provided more detail. Seven important clusters were found: four consisted mainly of infectious diseases, including a new cluster that declined rapidly after the Second World War (WW2) (e.g. acute bronchitis/influenza) and a new cluster showing an increasing trend in the 1920s and 1930s before declining in the years thereafter (e.g. appendicitis). Three clusters mainly contained non-infectious diseases, including a new one that declined from 1900 onwards (e.g. cancer of the stomach) and a new one that increased until WW2 but declined thereafter (e.g. chronic rheumatic heart disease). The results suggest that the conventional interpretation of the epidemiologic transition, which assumes a uniform decline of infectious diseases and a uniform increase of non-infectious diseases, needs to be modified.


Quantitative determination of salvinorin A, a natural hallucinogen with abuse liability, in Internet-available Salvia divinorum and endemic species of Salvia in Taiwan.
In recent years, recreational use of Salvia divinorum (Lamiaceae), a herbal drug that contains a hallucinogenic ingredient, salvinorin A, has become a new phenomenon among young drug users. In Taiwan, as in many other countries, dry leaves of S. divinorum and its related concentrated extract products are available via the Internet. Besides S. divinorum, there are many endemic Salvia species whose salvinorin A content is yet unknown. To understand the abuse liability of these products, the aim of this study was to assess the concentration of salvinorin A in endemic Salvia species and Internet-available salvinorin A-related products. Samples of S. divinorum were purchased via the Internet and samples of eight endemic species of Salvia were collected in Taiwan, including S. arisanensis Hayata, S. coccinea Juss. ex Murr, S. hayatana Makino ex Hayata, S. japonica Thumb. ex Murr, S. nipponica Miq. Var. formosana (Hayata) Kudo, S. scapiformis Hance, S. tashiroi Hayata. Icon. PI. Formosan, and S. keitaoensis Hayata. The content of salvinorin A was determined by high performance liquid chromatography (HPLC). Salvinorin A was extracted from the dry leaves of S. divinorum and endemic species of Salvia with methanol and analyzed on a C-18 column by isocratic elution with a mobile phase of acetonitrile-water. Salvinorin A was detected in S. divinorum, but not in the endemic Salvia species of Taiwan. Therefore, endemic species of Salvia in Taiwan may not possess hallucinogenic potential. However, the potential harm from S. divinorum available via the Internet should be thoroughly assessed in Taiwan, and control measures similar to those implemented in many other countries should be considered.


Concepts in biocompatibility testing of dental restorative materials.
Due to the diversity of adverse biological effects which might be caused by dental restorative materials, biocompatibility assessment cannot rely on a single test but has to be based on a planned and structured approach (concept). First, the possible harm evoked by the material, the known data, and suitable biological and other test methods available must be taken into consideration. Modern regulatory concepts require for this purpose the services of experts to propose the appropriate set of required tests for a given material. The use of standards is generally emphasized because of better comparability of the data. Other tests may be chosen if more appropriate. Modern scientific concepts of biocompatibility testing are based on the need for rapid and cost-effective test methods, avoiding animal tests whenever possible. While formerly in vitro experiments did not take into account the special clinical situation in which the material would be used, modern concepts try to simulate important parameters of the in vivo situation as closely as possible. This may be achieved, for example, by including suitable barriers between the material and the target cells, by constructing appropriate target cells, and by choosing clinically relevant markers for measuring the biological effects caused by the material. There are indications so far that through this approach the number of animal tests can be reduced. The use of these methods may also lead to a better understanding of the mechanisms behind the biological reactions (mechanistic approach) in describing the biocompatibility of dental restorative materials.


Suggestions on surgical treatment during coronavirus disease 2019 (COVID-19) pandemic.
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus, is now generating a global epidemic, leading to a severe public health emergency. Until April 12, 2020 around 1,700,954 confirmed cases and 105,633 deaths have been reported all over the world. The World Health Organization (WHO) has declared COVID-19 as a Public Health Emergency of International Concern. Under this circumstance, surgical activities should be carefully evaluated to avoid excessive occupation of limited medical resources, and to reduce the possibility of hospital infection. China has achieved an inspiring achievement on epidemic control. Here, we reviewed available studies on surgical activities during the outbreak, in combination with our current experience, with the aim of providing feasible suggestions on surgical issues during the COVID-19 pandemic.


Age differences in functional network reconfiguration with working memory training.
Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task-related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default-mode network for younger adults, it enhanced efficiency within a task-specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default-mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between-network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age-related trajectories in functional network reorganization with WM training.


Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer.
Our objective was to determine the maximum tolerated dose (MTD) of sequential raltitrexed (Tomudex) and 5-fluorouracil (5-FU) by bolus administration every 3 weeks in patients with advanced colorectal cancer (aCRC) and appendiceal adenocarcinoma. This phase I dose-escalation study was carried out in three stages: (1) 5-FU fixed at 900 mg/m, raltitrexed escalated from 0.5 to 3.0 mg/m, (2) raltitrexed fixed at 3.0 mg/m, 5-FU escalated from 900 mg/m until dose-limiting toxicity (DLT) and (3) 5-FU fixed at the dose level below DLT, raltitrexed escalated from 3.0 mg/m until MTD. Seventy-one patients with measurable disease were enrolled. No DLTs were observed during stage 1 of treatment. At a fixed dose of raltitrexed 3.0 mg/m, DLT developed when 5-FU was increased to 1350 mg/m (stage 2). When 5-FU was fixed at 1200 mg/m and raltitrexed was increased to 6.0 mg/m (stage 3), DLT was dose limiting. The recommended doses for further study are 5.5 mg/m ralitrexed and 1200 mg/m 5-FU. Of the 69 patients evaluated for efficacy, one had a complete response (8.0 months) and five had partial responses (5.1-11.6 months). Thirty patients had stable disease for 5 or more cycles of therapy (mean time to progression: 3.6 months). Median survival was 11.7 months. We conclude that raltitrexed can be combined with bolus 5-FU, at raltitrexed doses that are higher than the recommended single-agent dose of 3.0 mg/m, with manageable toxicity. This combination shows encouraging activity, and survival appears promising in the pre-treated aCRC patient population. Further clinical trials are warranted.


Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management).
Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific self-management, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guideline-oriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NT-proBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care.


Problem Gambling in a Sample of Older Adult Casino Gamblers.
As older adults continue to make up a greater proportion of the Canadian population, it becomes more important to understand the implications that their leisure activities have for their physical and mental health. Gambling, in particular, is a form of leisure that is becoming more widely available and has important implications for the mental health and financial well-being of older adults. This study examines a large sample (2103) of casino-going Ontarian adults over the age of 55 and identifies those features of their gambling participation that are associated with problem gambling. Logistic regression analysis is used to analyze the data. Focusing on types of gambling participated in and motivations for visiting the casino, this study finds that several forms of gambling and motivations to gamble are associated with greater risk of problem gambling. It also finds that some motivations are associated with lower risk of problem gambling. The findings of this study have implications related to gambling availability within an aging population.


DNA barcoding at riverscape scales: assessing biodiversity among fishes of the genus Cottus (Teleostei) in northern Rocky Mountain streams.
There is growing interest in broad-scale biodiversity assessments that can serve as benchmarks for identifying ecological change. Genetic tools have been used for such assessments for decades, but spatial sampling considerations have largely been ignored. Here, we demonstrate how intensive sampling efforts across a large geographical scale can influence identification of taxonomic units. We used sequences of mtDNA cytochrome c oxidase subunit 1 and cytochrome b, analysed with maximum parsimony networks, maximum-likelihood trees and genetic distance thresholds, as indicators of biodiversity and species identity among the taxonomically challenging fishes of the genus Cottus in the northern Rocky Mountains, USA. Analyses of concatenated sequences from fish collected in all major watersheds of this area revealed eight groups with species-level differences that were also geographically circumscribed. Only two of these groups, however, were assigned to recognized species, and these two assignments resulted in intraspecific genetic variation (>2.0%) regarded as atypical for individual species. An incomplete inventory of individuals from throughout the geographical ranges of many species represented in public databases, as well as sample misidentification and a poorly developed taxonomy, may have hampered species assignment and discovery. We suspect that genetic assessments based on spatially robust sampling designs will reveal previously unrecognized biodiversity in many other taxa.


Angiotensin converting enzyme 1 in the median preoptic nucleus contributes to chronic intermittent hypoxia hypertension.
Obstructive sleep apnea is associated with hypertension and cardiovascular disease. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in sleep apnea patients and is associated with increased sympathetic nerve activity and a sustained diurnal increase in blood pressure. The renin angiotensin system has been associated with hypertension seen in chronic intermittent hypoxia. Angiotensin converting enzyme 1, which cleaves angiotensin I to the active counterpart angiotensin II, is present within the central nervous system and has been shown to be regulated by AP-1 transcription factors, such as ΔFosB. Our previous study suggested that this transcriptional regulation in the median preoptic nucleus contributes to the sustained blood pressure seen following chronic intermittent hypoxia. Viral mediated delivery of a short hairpin RNA against angiotensin converting enzyme 1 in the median preoptic nucleus was used along with radio-telemetry measurements of blood pressure to test this hypothesis. FosB immunohistochemistry was utilized in order to assess the effects of angiotensin converting enzyme 1 knockdown on the activity of nuclei downstream from median preoptic nucleus. Angiotensin converting enzyme 1 knockdown within median preoptic nucleus significantly attenuated the sustained hypertension seen in chronic intermittent hypoxia. Angiotensin converting enzyme 1 seems to be partly responsible for regulating downstream regions involved in sympathetic and blood pressure control, such as the paraventricular nucleus and the rostral ventrolateral medulla. The data suggest that angiotensin converting enzyme 1 within median preoptic nucleus plays a critical role in the sustained hypertension seen in chronic intermittent hypoxia.


Magnetic resonance imaging of monocytes labeled with ultrasmall superparamagnetic particles of iron oxide using magnetoelectroporation in an animal model of multiple sclerosis.
AbstractInfiltrated monocytes play a crucial role in the demyelination process during multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS). Still, methods to monitor their infiltration pattern over time are lacking. In this study, magnetoelectroporation (MEP) was used to label rat monocytes with the superparamagnetic iron oxide particles Sinerem, Endorem, and Supravist. Supravist-labeled monocytes were injected in rats that we induced with experimental autoimmune encephalomyelitis, a model for MS. Imaging at 4.7 and 9.4 T revealed multiple foci of decreased signal intensity predominantly located in the cerebellum. Immunohistochemical evaluation confirmed the presence of intracellular iron in infiltrated cells, indicating the suitability of MEP to specifically follow labeled monocytes in vivo in this disease model. This technique may be further optimized and potentially used in MS patients to assess monocyte migration into the brain and to monitor the efficacy of therapeutic agents aimed at blocking cellular migration into the CNS.


ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice.
Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre (Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.


Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma.
It has been postulated that gastroesophageal reflux plays a role in the etiology of head and neck squamous cell carcinomas (HNSCC) and contributes to complications after surgery or during radiotherapy. Antacid medications are commonly used in patients with HNSCC for the management of acid reflux; however, their relationship with outcomes has not been well studied. Associations between histamine receptor-2 antagonists (H2RA) and proton pump inhibitors (PPI) use and treatment outcomes were determined in 596 patients with previously untreated HNSCC enrolled in our SPORE epidemiology program from 2003 to 2008 (median follow-up 55 months). Comprehensive clinical information was entered prospectively in our database. Risk strata were created on the basis of possible confounding prognostic variables (age, demographics, socioeconomics, tumor stage, primary site, smoking status, HPV16 status, and treatment modality); correlations within risk strata were analyzed in a multivariable model. Patients taking antacid medications had significantly better overall survival (OS; PPI alone: P < 0.001; H2RA alone, P = 0.0479; both PPI + H2RA, P = 0.0133). Using multivariable Cox models and adjusting for significant prognostic covariates, both PPIs and H2RAs used were significant prognostic factors for OS, but only H2RAs use for recurrence-free survival in HPV16-positive oropharyngeal patients. We found significant associations between the use of H2RAs and PPIs, alone or in combination, and various clinical characteristics. The findings in this large cohort study indicate that routine use of antacid medications may have significant therapeutic benefit in patients with HNSCC. The reasons for this association remain an active area of investigation and could lead to identification of new treatment and prevention approaches with agents that have minimal toxicities.


Transjugular percutaneous endovascular treatment of dysfunctional hemodialysis access.
To evaluate the feasibility and the outcomes of transjugular percutaneous endovascular treatment of dysfunctional hemodialysis access in patients with chronic kidney disease. A total of 50 transjugular treatments in 38 patients with arteriovenous fistulas or arteriovenous grafts from September 2011 to May 2015 were included in this study. Medical records and angiographies were retrospectively reviewed. Success rate, patency rate, procedure time, and complications including internal jugular vein stenosis were evaluated. A total of 50 sessions of transjugular treatments were performed in 38 patients. There were 31 native arteriovenous fistulas including 10 immature cases and 19 arteriovenous grafts. Among the 50 cases, technical success was achieved in 45 and clinical success was achieved in 44; 37 cases (74%) with multiple stenotic sites were treated by the transjugular approach without placement of cross-sheaths. The mean time from puncture of the internal jugular vein to first fistulography was 10 min, and the mean total procedure time was 64 min. The primary patency rate at 6 months was 77%, while the secondary patency rate at 6 months was 97%. Perforation occurred in two cases during conventional percutaneous transluminal angioplasty after failure of the transjugular approach. One dissection occurred during the transjugular approach. There was no newly developed internal jugular vein stenosis during a mean follow-up period of 19.3 months. For the treatment of dysfunctional or immature hemodialysis access, the transjugular approach is a feasible and effective option that avoids injury to the graft or draining vein, especially in immature fistulas.


Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives.
Chronic pulmonary aspergillosis (CPA) complicates conditions including tuberculosis, chronic obstructive pulmonary disease and sarcoidosis, and is associated with high morbidity and mortality. Surgical cure should be considered where feasible; however, many patients are unsuitable for surgery due to extensive disease or poor respiratory function. Azoles are the only oral drug with anti-Aspergillus activity and itraconazole and voriconazole are considered as first-line drugs. A randomized controlled trial demonstrated improvement or stability in three-quarters of patients given 6 months of itraconazole, but a quarter relapsed on stopping therapy. Long-term treatment may therefore be required in some cases. Itraconazole, voriconazole and posaconazole require therapeutic drug monitoring. No published data are yet available for isavuconazole. Adverse drug effects of azoles are common, including peripheral neuropathy, heart failure, elevated liver enzymes, QTc prolongation and sun sensitivity. Many serious drug-drug interactions occur, including major interactions with rifamycins, simvastatin, warfarin, clopidogrel, immunosuppressant drugs like sirolimus. Furthermore, drug resistance occurs, including cross-resistance to all azoles, but the true prevalence is not yet determined. Intravenous therapy is possible with echinocandins or amphotericin B, but long-term use is challenging. Hemoptysis complicates CPA and can be fatal. Tranexamic acid should be given acutely to reduce bleeding. Bronchial artery embolization can stop acute bleeds. In some circumstances, emergency surgery may be necessary to resect the source of the bleed. Current CPA treatments can be beneficial but have many drawbacks. New oral anti-Aspergillus agents are needed, along with optimization of currently available treatments.


Multi-parameter based coagulant dosing control.
The required coagulant dosage is strongly related to the quality of raw water or wastewater. Online sensors for most quality parameters are now readily available to treatment facilities, yet remain rarely used in treatment process control. This paper presents the evaluation of an advanced coagulant dosing control system based on online measurements in full-scale processes. The popular multivariate analytical method, partial least square regression, was used to build up the relationship between the coagulant dose and wastewater quality. The system was tested in two wastewater treatment plants (WWTPs) in Norway. Coagulant savings up to 30% in Norwegian plants were observed with feed forward calibrations. The considerable savings reduce sludge production, leading to further cost saving on sludge treatment. This paper presents the method, function and experiences of the full-scale implementation of the system in different WWTPs.


Serotonin and anxiety: current models.
Evidence for the importance of the serotonin system in anxiety disorders has increased substantially in recent years. Although preclinical research has provided an important source of hypotheses, clinical work on the value of selective serotonin reuptake inhibitors (SSRIs) in these conditions has been particularly persuasive. In this paper, a number of models of serotonin in the anxiety disorders are reviewed, and the clinical advantages of the SSRIs in anxiety disorders are emphasized. Models of serotonin in anxiety disorders include: 1) a 'see-saw model'; 2) an 'amygdala model'; and 3) a 'basal ganglia model'. While any simplistic schema in this complex area must fail, these various models have some heuristic value for the clinician. From a clinical perspective, the availability of the SSRIs has proved a significant step forward in the treatment of the anxiety disorders such as panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder (social phobia); certainly these agents offer several advantages over previously existing pharmacotherapeutic alternatives such as the benzodiazepines and tricyclic antidepressants.


Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson's disease.
Nigrostriatal degeneration, the pathological hallmark of Parkinson's disease (PD), is mirrored by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. MPTP-treated animals show the common behavioral, motor, and pathological features of human disease. We demonstrated previously that adoptive transfer of Copaxone (Cop-1) immune cells protected the nigrostriatal dopaminergic pathway in MPTP-intoxicated mice. Herein, we evaluated this protection by quantitative proton magnetic resonance spectroscopic imaging (1H MRSI). 1H MRSI performed in MPTP-treated mice demonstrated that N-acetyl aspartate (NAA) was significantly diminished in the substantia nigra pars compacta (SNpc) and striatum, regions most affected in human disease. When the same regions were coregistered with immunohistochemical stains for tyrosine hydroxylase, numbers of neuronal bodies and termini were similarly diminished. MPTP-intoxicated animals that received Cop-1 immune cells showed NAA levels, in the SNpc and striatum, nearly equivalent to PBS-treated animals. Moreover, adoptive transfer of immune cells from ovalbumin-immunized to MPTP-treated mice failed to alter NAA levels or protect dopaminergic neurons and their projections. These results demonstrate that 1H MRSI can evaluate dopaminergic degeneration and its protection by Cop-1 immunization strategies. Most importantly, the results provide a monitoring system to assess therapeutic outcomes for PD.


Intercellular Extensions Are Induced by the Alphavirus Structural Proteins and Mediate Virus Transmission.
Alphaviruses are highly organized enveloped RNA viruses with an internal nucleocapsid surrounded by a membrane containing the E2 and E1 transmembrane proteins. Alphavirus budding takes place at the plasma membrane and requires the interaction of the cytoplasmic domain of E2 with the capsid protein. Here we used WT alphaviruses and Sindbis virus in which E2 was fused to a fluorescent protein to characterize virus exit from host cells. Our results show that alphavirus infection induced striking modifications of the host cell cytoskeleton and resulted in the formation of stable intercellular extensions that emanated exclusively from the infected cell. The intercellular extensions were long (> 10 μM), contained actin and tubulin, and formed flattened contacts with neighboring cells, but did not mediate membrane or cytoplasmic continuity between cells. Receptor down-regulation studies indicated that formation of stable extensions did not require the virus receptor, and that extensions promoted cell-to-cell virus transmission to receptor-depleted cells. Virus mutant experiments demonstrated that formation of extensions required the E2-capsid interaction but not active particle budding, while intercellular transmission of infection required the production of fusion-active virus particles. Protein expression studies showed that even in the absence of virus infection, the viral structural proteins alone induced intercellular extensions, and that these extensions were preferentially targeted to non-expressing cells. Together, our results identify a mechanism for alphavirus cell-to-cell transmission and define the key viral protein interactions that it requires.


Duelling Ontologies: Might Vitalism Offer Balance and Value?
This article is part of a project investigating chiropractors' beliefs on the role of vitalism in their philosophical and practice approaches and how that might contribute to addressing current epidemics of non-communicable diseases. It aims to present atomism, reductionism, materialism and mechanism as fundamental ontologies in biomedicine and to examine what role these might play in its struggle to deal with these epidemics; to present vitalism as a fundamental ontology existing in chiropractic along with these ontologies of biomedicine; and to discuss how imbalances in the use of these ontologies and practices stemming from them might be contributing to difficulties in addressing these epidemics. The use of more balanced approaches by chiropractors involving not only mechanistic biomedical ontologies but also an increased focus on vitalism might offer value in addressing these epidemics and should be investigated.


The tethered aminohydroxylation (TA) reaction.
Since Sharpless' discovery of the asymmetric aminohydroxylation (AA) reaction, a major challenge for chemists has been to find ways of controlling the regio- and stereochemical outcome of this important reaction. Detailed herein is a review of our novel approach towards gaining reliable and predictable regio- and stereocontrol through the use of a tethered carbamate to promote an intramolecular AA reaction, along with a description of the mechanism proposed for this new methodology.


Single room occupancy (SRO) hotels as mental health risk environments among impoverished women: the intersection of policy, drug use, trauma, and urban space.
Due to the significantly high levels of comorbid substance use and mental health diagnosis among urban poor populations, examining the intersection of drug policy and place requires a consideration of the role of housing in drug user mental health. In San Francisco, geographic boundedness and progressive health and housing polices have coalesced to make single room occupancy hotels (SROs) a key urban built environment used to house poor populations with co-occurring drug use and mental health issues. Unstably housed women who use illicit drugs have high rates of lifetime and current trauma, which manifests in disproportionately high rates of post-traumatic stress disorder (PTSD), anxiety, and depression when compared to stably housed women. We report data from a qualitative interview study (n=30) and four years of ethnography conducted with housing policy makers and unstably housed women who use drugs and live in SROs. Women in the study lived in a range of SRO built environments, from publicly funded, newly built SROs to privately owned, dilapidated buildings, which presented a rich opportunity for ethnographic comparison. Applying Rhodes et al.'s framework of socio-structural vulnerability, we explore how SROs can operate as "mental health risk environments" in which macro-structural factors (housing policies shaping the built environment) interact with meso-level factors (social relations within SROs) and micro-level, behavioral coping strategies to impact women's mental health. The degree to which SRO built environments were "trauma-sensitive" at the macro level significantly influenced women's mental health at meso- and micro-levels. Women who were living in SROs which exacerbated fear and anxiety attempted, with limited success, to deploy strategies on the meso- and micro-level to manage their mental health symptoms. Study findings underscore the importance of housing polices which consider substance use in the context of current and cumulative trauma experiences in order to improve quality of life and mental health for unstably housed women.


Association Between Randall's Plaque Stone Anchors and Renal Papillary Pits.
Renal papillary pits are commonly encountered during ureteroscopy. The mechanism by which such pits arise is unclear. One hypothesis is that pits represent sites where stones overgrowing Randall's plaque (RP) were dislodged. We sought to examine this theory by using digital ureteroscopy and stone μCT. Patients undergoing endoscopic stone removal had procedures recorded and stones analyzed by using μCT. Stones with evidence of Randall's plaque anchors (RPAs) were identified in a blinded fashion. Surgical videos were reviewed independently by two urologists. Twenty-eight patients had μCT-confirmed stones with RPA. Among them, 93% were recurrent stone formers and 75% had had prior stone procedures. Metabolic abnormalities were present in 87%, with 79% classified as idiopathic calcium oxalate stone formers. A mean of 7.6 stones with RPA were identified per procedure. In each case, papillary pits were visualized before any stone manipulation and in several cases the active dislodgement of an attached stone led to immediate identification of an underlying pit. Such stones routinely demonstrated an RPA on μCT. The average depth of RPA was 302 ± 172 μm, consistent with the corresponding shallow pits visualized on the papillary surface. Stones overgrowing RP are capable of pulling away a piece of papilla when dislodged, resulting in a visible papillary pit. This process manifests as an RPA on the undersurface of the stone and a papillary pit on the corresponding area of attachment. Identification of pits may help identify patients who form stones primarily by the RP mechanism.


Contraction-independent effects of catecholamines on glucose transport in isolated rat cardiomyocytes.
The effects of catecholamines on glucose transport were studied in noncontracting isolated rat cardiomyocytes. alpha-Adrenergic treatment (phenylephrine, or norepinephrine + propranolol) led to an approximately fourfold stimulation of glucose transport in basal cells (no insulin). The effect of phenylephrine was suppressed by the alpha 2-antagonist yohimbine or the beta-antagonist propranolol. The beta-adrenergic agonist isoproterenol partially counteracted the action of phenylephrine (but not that of insulin). Phenylephrine increased glucose transport in two phases with apparent half times of 3.2 and 13.0 min, respectively. Correspondingly, different EC50 values were found after 10 and 45 min on phenylephrine addition (5.0 +/- 1.9 vs. 31.6 +/- 9.6 microM, respectively). Maximal stimulation by phenylephrine was at least partially additive to that of insulin and of other stimulators of glucose transport (e.g., H2O2, vanadate, lithium). Phenylephrine significantly increased the level of cell surface glucose carriers GLUT-1 (1.54-fold) and GLUT-4 (1.78-fold), as assessed by using the specific photolabel 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]- 1,3-bis(D-mannos-4-yloxy)propyl-2-amine. In conclusion, catecholamines stimulate cardiomyocyte glucose transport through alpha 1-adrenergic receptors independently or downstream of a contraction-evoked stimulus. This effect is at least partially explained by a recruitment of glucose transporters to the cell surface. The mechanism(s) and/or signals involved differ from those triggered by insulin and insulinomimetic agents.


Alkylpurine-DNA-N-glycosylase excision of 7-(hydroxymethyl)-1,N6-ethenoadenine, a glycidaldehyde-derived DNA adduct.
Glycidaldehyde (GDA) is a bifunctional alkylating agent that has been shown to be mutagenic in vitro and carcinogenic in rodents. However, the molecular mechanism by which it exerts these effects is not established. GDA is capable of forming exocyclic hydroxymethyl-substituted etheno adducts on base residues in vitro. One of them, 7-(hydroxymethyl)-1,N6-ethenoadenine (7-hm-epsilonA), was identified as the principal adduct in mouse skin treated with GDA or a glycidyl ether. In this work, using defined oligonucleotides containing a site-specific 7-hm-epsilonA, the human and mouse alkylpurine-DNA-N-glycosylases (APNGs), responsible for the removal of the analogous 1,N6-ethenoadenine (epsilonA) adduct, are shown to recognize and excise 7-hm-epsilonA. Such an activity can be significantly modulated by both 5' neighboring and opposite sequence contexts. The efficiency of human or mouse APNG for excision of 7-hm-epsilonA is about half that, or similar to the excision of epsilonA, respectively. When human or mouse cell-free extracts were tested, however, the extent of 7-hm-epsilonA excision is dramatically lower than that for epsilonA, suggesting that, in the crude extracts, the APNG activities toward these two adducts are differentially affected. Using cell-free extracts from APNG deficient mice, this enzyme is shown to be the primary glycosylase excising 7-hm-epsilonA. A structural approach, using molecular modeling, was employed to examine how the structure of the 7-hm-epsilonA adduct affects DNA conformation, as compared to the epsilonA adduct. These novel substrate specificities could have both biological and structural implications.


Shade Promotes Phototropism through Phytochrome B-Controlled Auxin Production.
Phototropism is an asymmetric growth response enabling plants to optimally position their organs. In flowering plants, the phototropin (phot) blue light receptors are essential to detect light gradients. In etiolated seedlings, the phototropic response is enhanced by the red/far-red (R/FR)-sensing phytochromes (phy) with a predominant function of phyA. In this study, we analyzed the influence of the phytochromes on phototropism in green (de-etiolated) Arabidopsis seedlings. Our experiments in the laboratory and outdoors revealed that, in open environments (high R/FR ratio), phyB inhibits phototropism. In contrast, under foliar shade, where access to direct sunlight becomes important, the phototropic response was strong. phyB modulates phototropism, depending on the R/FR ratio, by controlling the activity of three basic-helix-loop-helix (bHLH) transcription factors of the PHYTOCHROME INTERACTING FACTORs (PIFs) family. Promotion of phototropism depends on PIF-mediated induction of several members of the YUCCA gene family, leading to auxin production in the cotyledons. Our study identifies PIFs and YUCCAs as novel molecular players promoting phototropism in photoautotrophic, but not etiolated, seedlings. Moreover, our findings reveal fundamental differences in the phytochrome-phototropism crosstalk in etiolated versus green seedlings. We propose that in natural conditions where the light environment is not homogeneous, the uncovered phytochrome-phototropin co-action is important for plants to adapt their growth strategy to optimize photosynthetic light capture.


Viral infections in travellers from tropical Africa.
Examination of sera from 86 travellers to Britain from tropical Africa disclosed evidence of past infection with 10 identifiable viruses, of which the most important were O'nyong-nyong, dengue, chikungunya, and Ntaya. The findings indicate that infection with O'nyong-nyong may be acquired sporadically in Nigeria, Ghana, and Sierra Leone, where it has not previously been identified. Chikungunya infection had not been recorded in West Africa other than Nigeria and Senegal. Patients from Sierra Leone and contiguous Liberia had antibodies to this infection. An outbread of dengue fever in the Seychelles in early 1977 was confirmed. Ntaya virus, though known in Uganda, Cameroon, and Zaire, appears also to be transmitted in Kenya, Nigeria, and Zambia. Clinical studies indicated that chikungunya infection may present with alimentary features, possibly with jaundice. The clinical features of Ntaya infection may include kizarre neurological manifestations in addition to fever. The absence of Lassa antibodies among these travellers suggested that this infection is not a common hazard among such persons.


Initiatives for education, training, and dissemination of morbidity assessment and reporting in a multiinstitutional international context: Insights from the EMBRACE studies on cervical cancer.
In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.


Studying human nociceptors: from fundamentals to clinic.
Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.