Effectiveness of health checks conducted by nurses in primary care: final results of the OXCHECK study. Imperial Cancer Research Fund OXCHECK Study Group.
To determine the effectiveness of health checks, performed by nurses in primary care, in reducing risk factors for cardiovascular disease and cancer. Randomised controlled trial. Five urban general practices in Bedfordshire. 2205 men and women who were randomly allocated a first health check in 1989-90 and a re-examination in 1992-3 (the intervention group); 1916 men and women who were randomly allocated an initial health check in 1992-3 (the control group). All subjects were aged 35-64 at recruitment in 1989. Serum total cholesterol concentration, blood pressure, body mass index, and smoking prevalence (with biochemical validation of cessation); self reported dietary, exercise, and alcohol habits. Mean serum total cholesterol was 3.1% lower in the intervention group than controls (difference 0.19 mmol/l (95% confidence interval 0.12 to 0.26)); in women it was 4.5% lower (P < 0.0001) and in men 1.6% (P < 0.05), a significant difference between the sexes (P < 0.01). Self reported saturated fat intake was also significantly lower in the intervention group. Systolic and diastolic blood pressures and body mass index were respectively 1.9%, 1.9%, and 1.4% lower in the intervention group (P < 0.005 in all cases). There was a 3.9% (2.4 to 5.3) difference in the percentage of subjects with a cholesterol concentration > or = 8 mmol/l, but no significant differences in the number with diastolic blood pressure > or = 100 mm Hg or body mass index > or = 30 kg/m2. There was no significant difference between the two groups in prevalence of smoking or excessive alcohol use. Annual rechecks were no more effective than a single recheck at three years, but health checks led to a significant increase in visits to the nurse according to patients' degree of cardiovascular risk. The benefits of health checks were sustained over three years. The main effects were to promote dietary change and reduce cholesterol concentrations; small differences in blood pressure may have been attributable to accommodation to measurement. The benefits of systematic health promotion in primary care are real, but must be weighed against the costs in relation to other priorities.


Serelaxin Elicits Bronchodilation and Enhances β-Adrenoceptor-Mediated Airway Relaxation.
Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250-350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via epithelial-dependent and -independent mechanisms, likely via RXFP1 activation and generation of NO, prostaglandins and cAMP/cGMP. rhRLX also enhanced responsiveness to other dilators, suggesting its potential as an alternative or add-on therapy for severe asthma.


Weakening the ethical distinction between euthanasia, palliative opioid use and palliative sedation.
Opioid and sedative use are common 'active' practices in the provision of mainstream palliative care services, and are typically distinguished from euthanasia on the basis that they do not shorten survival time. Even supposing that they did, it is often argued that they are justified and distinguished from euthanasia via appeal to Aquinas' Doctrine of Double Effect. In this essay, I will appraise the empirical evidence regarding opioid/sedative use and survival time, and argue for a position of agnosticism. I will then argue that the Doctrine of Double Effect is a useful ethical tool but is ultimately not a sound ethical principle, and even if it were, it is unclear whether palliative opioid/sedative use satisfy its four criteria. Although this essay does not establish any definitive proofs, it aims to provide reasons to doubt-and therefore weaken-the often-claimed ethical distinction between euthanasia and palliative opioid/sedative use.


Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.
Mutation of the epidermal growth factor receptor (EGFR) results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling. Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992), one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics. Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.


Phylogenetic Revision of Savoryellaceae and Evidence for Its Ranking as a Subclass.
Morphology, phylogeny, and molecular clock analyses were carried out on Savoryellaceae in order to understand the placements of taxa in this family. Ascotaiwania and Neoascotaiwania formed a well-supported separate clade in the phylogeny of concatenated partial SSU, LSU, TEF, and RPB2 gene data. These two genera share similar morphological features, especially in their asexual morphs, indicating that they are congeneric. Hence, we synonymize Neoascotaiwania under Ascotaiwania. Ascotaiwania hughesii (and its asexual morph, Helicoon farinosum) and Monotosporella setosa grouped in a clade sister to Pleurotheciales and are excluded from Ascotaiwania which becomes monophyletic. A novel genus Helicoascotaiwania is introduced to accommodate Ascotaiwania hughesii and its asexual morph, Helicoon farinosum. A novel species, Savoryella yunnanensis is introduced from a freshwater habitat in Yunnan Province, China. Comprehensive descriptions and illustrations are provided for selected taxa in this family. In addition, we provide evolutionary divergence estimates for Savoryellomycetidae taxa and major marine based taxa to support our phylogenetic and morphological investigations. The taxonomic placement of these marine-based taxa is briefly discussed. Our results indicate that the most basal group of marine-based taxa are represented within Lulworthiales, which diverged from ancestral Sordariomycetes around 149 Mya (91-209) and Savoryellomycetidae around 213 Mya (198-303).


Distribution and disposition of trospectomycin sulfate in the in vivo rat, perfused rat liver, and cultured rat hepatocytes.
Trospectomycin sulfate is an experimental, aminocyclitol antibiotic. It has been shown in preclinical, chronic safety studies in the dog and rat to elicit a reversible, lysosomal phospholipidosis in liver. The present experiments were conducted to characterize the tissue distribution and disposition of 3H]trospectomycin sulfate in the male rat, perfused rat, perfused rat liver, and cultured rat hepatocytes. Following a 5 mg/kg iv dose to four rats, approximately 70% of the dose was recovered within 24 hr primarily in urine as unchanged drug, and the remainder was eliminated with a terminal phase half-life in blood and tissues of 3 days. Fecal excretion was relatively minor (16% of the dose recovered in feces in 7 days) until later timepoints, when it was the principal pathway of terminal phase elimination. The liver sequestered approximately 10% of the dose and had the highest tissue levels of drug at all times measured. Liver perfusion experiments indicated that trospectomycin accumulated in a hepatic depot compartment as parent drug by a first-order process which was nonsaturable up to a 1 mM concentration of drug. Biliary excretion of unchanged trospectomycin by the perfused liver was slow (approximately 3% of the dose in 2 hr) and occurred by both paracellular and transcellular mechanisms. The hepatic depot compartment appeared to be responsible for transcellular biliary excretion, and thus for the sustained fecal excretion observed in vivo. Subcellular distribution experiments indicated that at least 50% of the drug in the hepatic depot was sequestered in organelles having a broad density range. The existence of a trospectomycin depot compartment was also demonstrated in cultured hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


"Antral dysmotility". An unrecognized cause of chronic vomiting during infancy.
Ten infants who were less than nine months of age and had chronic nonbilious vomiting were evaluated for gastroesophageal reflux. Upper gastrointestinal series in all showed delayed gastric emptying, a funnel-shaped antrum, absent antral peristalsis, and gastroesophageal reflux. None had evidence of anatomic obstruction in the stomach or duodenum. Manometric studies of the esophagus revealed either normal (4 patients) or elevated (6 patients) lower esophageal sphincter pressures. One-hour esophageal pH probe tests were negative in seven of the ten infants. This obstruction to gastric emptying appears to represent a disorder of antral motility. Medical management, which consisted of small frequent feedings and postural therapy, was successful in six of the infants. The remaining four patients required pyloroplasty. All of the infants are now asymptomatic and gaining weight at either a normal or accelerated rate for their ages. Familiarity with this previously undescribed disorder should prevent the incorrect diagnosis of gastroesophageal reflux secondary to lower esophageal sphincter incompetence and the resulting inappropriate surgical reconstruction.


Weak compliance undermines the success of no-take zones in a large government-controlled marine protected area.
The effectiveness of marine protected areas depends largely on whether people comply with the rules. We quantified temporal changes in benthic composition, reef fish biomass, and fishing effort among marine park zones (including no-take areas) to assess levels of compliance following the 2005 rezoning of the government-controlled Karimunjawa National Park (KNP), Indonesia. Four years after the rezoning awareness of fishing regulations was high amongst local fishers, ranging from 79.5±7.9 (SE) % for spatial restrictions to 97.7±1.2% for bans on the use of poisons. Despite this high awareness and strong compliance with gear restrictions, compliance with spatial restrictions was weak. In the four years following the rezoning reef fish biomass declined across all zones within KNP, with >50% reduction within the no-take Core and Protection Zones. These declines were primarily driven by decreases in the biomass of groups targeted by local fishers; planktivores, herbivores, piscivores, and invertivores. These declines in fish biomass were not driven by changes in habitat quality; coral cover increased in all zones, possibly as a result of a shift in fishing gears from those which can damage reefs (i.e., nets) to those which cause little direct damage (i.e., handlines and spears). Direct observations of fishing activities in 2009 revealed there was limited variation in fishing effort between zones in which fishing was allowed or prohibited. The apparent willingness of the KNP communities to comply with gear restrictions, but not spatial restrictions is difficult to explain and highlights the complexities of the social and economic dynamics that influence the ecological success of marine protected areas. Clearly the increased and high awareness of fishery restrictions following the rezoning is a positive step. The challenge now is to understand and foster the conditions that may facilitate compliance with spatial restrictions within KNP and marine parks worldwide.


The molecular architecture of lamins in somatic cells.
The nuclear lamina is a fundamental constituent of metazoan nuclei. It is composed mainly of lamins, which are intermediate filament proteins that assemble into a filamentous meshwork, bridging the nuclear envelope and chromatin. Besides providing structural stability to the nucleus, the lamina is involved in many nuclear activities, including chromatin organization, transcription and replication. However, the structural organization of the nuclear lamina is poorly understood. Here we use cryo-electron tomography to obtain a detailed view of the organization of the lamin meshwork within the lamina. Data analysis of individual lamin filaments resolves a globular-decorated fibre appearance and shows that A- and B-type lamins assemble into tetrameric filaments of 3.5 nm thickness. Thus, lamins exhibit a structure that is remarkably different from the other canonical cytoskeletal elements. Our findings define the architecture of the nuclear lamin meshworks at molecular resolution, providing insights into their role in scaffolding the nuclear lamina.


Food sharing is linked to urinary oxytocin levels and bonding in related and unrelated wild chimpanzees.
Humans excel in cooperative exchanges between unrelated individuals. Although this trait is fundamental to the success of our species, its evolution and mechanisms are poorly understood. Other social mammals also build long-term cooperative relationships between non-kin, and recent evidence shows that oxytocin, a hormone involved in parent-offspring bonding, is likely to facilitate non-kin as well as kin bonds. In a population of wild chimpanzees, we measured urinary oxytocin levels following a rare cooperative event--food sharing. Subjects showed higher urinary oxytocin levels after single food-sharing events compared with other types of social feeding, irrespective of previous social bond levels. Also, urinary oxytocin levels following food sharing were higher than following grooming, another cooperative behaviour. Therefore, food sharing in chimpanzees may play a key role in social bonding under the influence of oxytocin. We propose that food-sharing events co-opt neurobiological mechanisms evolved to support mother-infant bonding during lactation bouts, and may act as facilitators of bonding and cooperation between unrelated individuals via the oxytocinergic system across social mammals.


Spreading the blame: The allocation of responsibility amongst multiple agents.
How do people assign responsibility to individuals in a group context? Participants played a repeated trial experimental game with three computer players, in which they counted triangles presented in complex diagrams. Three between-subject conditions differed in how the group outcome was computed from the individual players' answers. After each round, participants assigned responsibility for the outcome to each player. The results showed that participants' assignments varied between conditions, and were sensitive to the function that translated individual contributions into the group outcome. The predictions of different cognitive models of attribution were tested, and the Structural Model (Chockler & Halpern, 2004) predicted the data best.


Virulence of Bursaphelenchus xylophilus Isolated from Naturally Infested Pine Forests to Five Resistant Families of Pinus thunbergii.
Pine wilt disease is one of the most serious epidemic tree diseases in Japan, and resistant pine trees have been developed through a breeding program. To evaluate resistance of resistant families of Japanese black pine, Pinus thunbergii, to the pinewood nematode, Bursaphelenchus xylophilus, isolated from the field, and to determine whether differentiation of pathogenicity to resistant pine families appears in the nematode isolates, seedlings of five resistant pine families were inoculated with 25 nematode isolates. Disease incidence 18 weeks after inoculation was significantly different among nematode isolates and among pine families but there was no interaction effect between nematode isolate and pine family. This indicates that nematode isolates did not have differential host specificity to resistant families of P. thunbergii. Isolate Shimabara, a test isolate of the breeding program, showed the same degree of virulence as the highly virulent isolates frequently used in experiments. However, more virulent isolates than Shimabara were found among the isolates collected from natural pine forest. This indicated that B. xylophilus populations with higher virulence than Shimabara exist in the natural population. These findings are important in development of more efficient breeding procedures for resistant pine trees.


Radioprotective effects of Aegle marmelos (L.) Correa (Bael): a concise review.
The effective use of radiotherapy in cancer cure and palliation is compromised by the side-effects resulting from radiosensitivity of bordering normal tissues, which are invariably exposed to the cytotoxic effects of ionizing radiation during treatment. In this situation, use of radioprotective compounds that can protect normal tissues against radiation injury are of immense use. In addition to protecting normal tissue these compounds will also permit use of higher radiation doses to obtain better cancer control and possible cure. However, to date, no ideal radioprotectors are available as most synthetic compounds are toxic at their optimal concentrations and have produced little success in clinics. Radiation ill-effects are principally the result of generation of free radicals, and the antioxidant compounds that counter them are supposed to be of immense use in preventing them. In Ayurveda, the traditional Indian system of medicine, several plants have been observed to avert/ameliorate free radical-mediated ailments--an effect that has been documented--and such plants have recently been the focus of attention. Aegle marmelos (L.) Correa (Bael), commonly known as bael, has been used since antiquity for treating various ailments, some of which are now known to be the result of oxidative stress. In studies spanning nearly a decade, it has been observed that bael prevented radiation-induced ill-effects, and the results of these studies indicate that it has the potential to be an effective, nontoxic radioprotective agent. In this current review, for the first time, an attempt is made to summarize these observations and to discuss the plausible reasons responsible for bael's radioprotective effects.


PETAL LOSS is a boundary gene that inhibits growth between developing sepals in Arabidopsis thaliana.
Flower primordia are partitioned by boundaries during their early development. Such boundaries occur between whorls of organs, and also between organs within whorls. PETAL LOSS (PTL) is a trihelix transcription factor gene that is expressed in boundaries between sepal primordia in the outer whorl. Over-expression of PTL results in growth suppression suggesting that PTL normally inhibits growth between newly arising sepals. We have tested this by examining the consequences of loss of PTL function using confocal imaging. The size of the inter-sepal zone in stage 4 buds expands radially by 35-40% in ptl-1 mutants as a consequence of additional cell proliferation. There is no change in the size of PTL-expressing cells. PTL expression does not overlap with the sites of petal initiation identified using the DR5 auxin response reporter. The latter are closer to the centre of the flower. Thus the consequence of loss of PTL function on petal initiation is indirect, perhaps through interference with a mobile petal-initiation signal or movement of the PTL protein. CUP-SHAPED COTYLEDON (CUC) genes are also involved in defining inter-sepal boundaries. However, genetic studies combining ptl with loss of cuc1 function, and gain of CUC function in extra early petals-1 (miR164c) mutants, have revealed that CUC and PTL act differently. CUC suppresses growth of sepal tissues from the boundary region whereas PTL acts to keep the size of the boundary in check.


Psychiatric and behavioral comorbidities in epilepsy: A critical reappraisal.
Psychiatric and behavioral disorders are important aspects of epilepsy and have received increasing attention in the last several years. The literature upon which most of the field relies contains some biases that must be carefully examined and resolved in future studies. First, in the pediatric epilepsy literature, many reports find that children with epilepsy have high levels of behavioral and psychiatric disorders when compared to appropriate controls. Most of these studies rely on parent-proxy completed instruments to assess these behavioral endpoints. Parents' reports are not objective but reflect parents' reactions and emotions. Increasing evidence suggests inherent biases in proxy reports and highlights the need to assess children directly. Second, periictal phenomena may be mischaracterized as underlying mood disorders. Third, many studies report elevated levels of psychiatric morbidity before and after the diagnosis of epilepsy, suggesting an inherent relation between the two types of disorders. Psychogenic nonepileptic seizures, while widely recognized as posing a diagnostic dilemma in the clinic, may account for some of these research findings. Diagnostic errors between epilepsy and psychogenic nonepileptic seizures need careful consideration when evaluating studies demonstrating associations between psychiatric disorders and epilepsy or poorer seizure control in association with psychiatric disorders in people who have epilepsy. Mental health concerns are important for everyone. An accurate, undistorted understanding of the relation between mental health disorders and epilepsy is essential to ensure appropriate therapy and to avoid unnecessary and potentially harmful treatments and common misconceptions.


Controlling the size of hot injection made nanocrystals by manipulating the diffusion coefficient of the solute.
We investigate the relation between the chain length of ligands used and the size of the nanocrystals formed in the hot injection synthesis. With two different CdSe nanocrystal syntheses, we consistently find that longer chain carboxylic acids result in smaller nanocrystals with improved size dispersions. By combining a more in-depth experimental investigation with kinetic reaction simulations, we come to the conclusion that this size tuning is due to a change in the diffusion coefficient and the solubility of the solute. The relation between size tuning by the ligand chain length and the coordination of the solute by the ligands is further explored by expanding the study to amines and phosphine oxides. In line with the weak coordination of CdSe nanocrystals by amines, no influence of the chain length on the nanocrystals is found, whereas the size tuning brought about by phosphine oxides can be attributed to a solubility change. We conclude that the ligand chain length provides a practical handle to optimize the outcome of a hot injection synthesis in terms of size and size dispersion and can be used to probe the interaction between ligands and the actual solute.


Structural and biochemical studies of human galanin: NMR evidence for nascent helical structures in aqueous solution.
The 30-residue human neuropeptide, galanin, was shown to bind to rat insulinoma RINm5F cells and to inhibit glyceraldehyde-stimulated insulin secretion from these cells in a manner quantitatively similar to that of porcine galanin. Neither human nor porcine galanin stimulated Ca2+ mobilization in cultured human small cell lung carcinoma cells. Sedimentation equilibrium analysis of human galanin showed that it was strictly monomeric in aqueous solution, indicating that the peptide interacts with its receptor(s) as a monomer. The monomeric nature of the peptide makes it especially suitable for structural studies using NMR. Nuclear Overhauser enhancement spectroscopy experiments performed on galanin dissolved in aqueous solution (150 mM KCl, pH 4) at both 33 and 3 degrees C indicate that certain regions of the peptide are capable of adopting detectable levels of short-range structure in rapid equilibrium with random coil. At 33 degrees C, the short-range structures include a nascent helix spanning residues 3-11 which incorporates a hydrophobic core from residues 6-11. Residues 14-18 and 22-30 display sequential NH-NH and C beta H-NH connectivities, indicating that these regions of the peptide adopt nonrandom conformations by significantly populating the alpha-region of conformational space. However, no medium-range dipolar connectivities indicative of nascent helix or turn conformations were observed. At 3 degrees C, almost all residues significantly populate the alpha-region of conformational space, and the nascent helix between residues 3 and 11, with its hydrophobic core, is retained.(ABSTRACT TRUNCATED AT 250 WORDS)


Crystal structure of a eukaryotic phosphate transporter.
Phosphate is crucial for structural and metabolic needs, including nucleotide and lipid synthesis, signalling and chemical energy storage. Proton-coupled transporters of the major facilitator superfamily (MFS) are essential for phosphate uptake in plants and fungi, and also have a function in sensing external phosphate levels as transceptors. Here we report the 2.9 Å structure of a fungal (Piriformospora indica) high-affinity phosphate transporter, PiPT, in an inward-facing occluded state, with bound phosphate visible in the membrane-buried binding site. The structure indicates both proton and phosphate exit pathways and suggests a modified asymmetrical 'rocker-switch' mechanism of phosphate transport. PiPT is related to several human transporter families, most notably the organic cation and anion transporters of the solute carrier family (SLC22), which are implicated in cancer-drug resistance. We modelled representative cation and anion SLC22 transporters based on the PiPT structure to surmise the structural basis for substrate binding and charge selectivity in this important family. The PiPT structure demonstrates and expands on principles of substrate transport by the MFS transporters and illuminates principles of phosphate uptake in particular.


Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion.
Changes in the gut microbiota may underpin many human diseases, but the mechanisms that are responsible for altering microbial communities remain poorly understood. Antibiotic usage elevates the risk of contracting gastroenteritis caused by Salmonella enterica serovars, increases the duration for which patients shed the pathogen in their faeces, and may on occasion produce a bacteriologic and symptomatic relapse. These antibiotic-induced changes in the gut microbiota can be studied in mice, in which the disruption of a balanced microbial community by treatment with the antibiotic streptomycin leads to an expansion of S. enterica serovars in the large bowel. However, the mechanisms by which streptomycin treatment drives an expansion of S. enterica serovars are not fully resolved. Here we show that host-mediated oxidation of galactose and glucose promotes post-antibiotic expansion of S. enterica serovar Typhimurium (S. Typhimurium). By elevating expression of the gene encoding inducible nitric oxide synthase (iNOS) in the caecal mucosa, streptomycin treatment increased post-antibiotic availability of the oxidation products galactarate and glucarate in the murine caecum. S. Typhimurium used galactarate and glucarate within the gut lumen of streptomycin pre-treated mice, and genetic ablation of the respective catabolic pathways reduced S. Typhimurium competitiveness. Our results identify host-mediated oxidation of carbohydrates in the gut as a mechanism for post-antibiotic pathogen expansion.


Demographic plasticity facilitates ecological and economic resilience in a commercially important reef fish.
Variation in life-history characteristics is evident within and across animal populations. Such variation is mediated by environmental gradients and reflects metabolic constraints or trade-offs that enhance reproductive outputs. While generalizations of life-history relationships across species provide a framework for predicting vulnerability to overexploitation, deciphering patterns of intraspecific variation may also enable recognition of peculiar features of populations that facilitate ecological resilience. This study combines age-based biological data from geographically disparate populations of bluespine unicornfish (Naso unicornis)-the most commercially valuable reef-associated species in the insular Indo-Pacific-to explore the magnitude and drivers of variation in life span and examine the mechanisms enabling peculiar mortality schedules. Longevity and mortality schedules were investigated across eleven locations encompassing a range of latitudes and exploitation levels. The presence of different growth types was examined using back-calculated growth histories from otoliths. Growth-type-dependent mortality (mortality rates associated with particular growth trajectories) was corroborated using population models that incorporated size-dependent competition. We found a threefold geographic variation in life span that was strongly linked to temperature, but not to anthropogenic pressure or ocean productivity. All populations consistently displayed a two-phase mortality schedule, with higher than expected natural mortality rates in earlier stages of post-settlement life. Reconstructed growth histories and population models demonstrated that variable growth types within populations can yield this peculiar biphasic mortality schedule, where fast growers enjoy early reproductive outputs at the expense of greater mortality, and benefits for slow growers derive from extended reproductive outputs over a greater number of annual cycles. This promotes population resilience because individuals can take advantage of cycles of environmental change operating at both short- and long-term scales. Our results highlight a prevailing, fundamental misperception when comparing the life histories of long-lived tropical ectotherms: the seemingly incongruent combination of extended life spans with high mortality rates was enabled by coexistence of variable growth types in a population. Thus, a demographic profile incorporating contrasting growth and mortality strategies obscures the demographic effects of harvest across space or time in N. unicornis and possibly other ectotherms with the combination of longevity and asymptotic growth.


FGF signalling restricts haematopoietic stem cell specification via modulation of the BMP pathway.
Haematopoietic stem cells (HSCs) are produced during embryogenesis from the floor of the dorsal aorta. The localization of HSCs is dependent on the presence of instructive signals on the ventral side of the vessel. The nature of the extrinsic molecular signals that control the aortic haematopoietic niche is currently poorly understood. Here we demonstrate a novel requirement for FGF signalling in the specification of aortic haemogenic endothelium. Our results demonstrate that FGF signalling normally acts to repress BMP activity in the subaortic mesenchyme through transcriptional inhibition of bmp4, as well as through activation of two BMP antagonists, noggin2 and gremlin1a. Taken together, these findings demonstrate a key role for FGF signalling in establishment of the developmental HSC niche via its regulation of BMP activity in the subaortic mesenchyme. These results should help inform strategies to recapitulate the development of HSCs in vitro from pluripotent precursors.


Begomoviruses Associated with Bean Golden Mosaic Disease in Nicaragua.
Begomovirus spp. cause substantial losses in bean crops in tropical and subtropical regions of the Americas. The predominant Begomovirus sp. in Central America associated with golden mosaic symptoms in bean is Bean golden yellow mosaic virus (BGYMV). However, Calopogonium golden mosaic virus was previously found to infect bean crops in the northern region of Costa Rica. The objective of this research was to identify Begomovirus spp. that infect bean plants in different geographical regions of Nicaragua. In all, 126 samples of young bean leaves with symptoms of golden mosaic were collected from eight different regions of Nicaragua. Using DNA hybridization with specific probes, 120 samples tested positive for BGYMV, 14 samples tested positive for Squash yellow mild mottle virus, and 7 samples tested positive for Calopogonium golden mosaic virus. Sequence analysis of polymerase chain reaction-amplified products from three samples (MA-9 Managua, BE-8 Rivas, and SO-9 Granada) also indicated that the symptoms of golden mosaic in bean are associated with viral sequences from three different Begomovirus spp. Management of bean golden mosaic disease must take into account that BGYMV is the predominant virus (95% of the samples) and that 12% of the samples exhibited possible mixed infections or recombination events in the south and central geographical regions of Nicaragua.


Results of a pilot test of a brief computer-assisted tailored HIV prevention intervention for use with a range of demographic and risk groups.
There is a need for brief HIV prevention interventions that can be disseminated and implemented widely. This article reports the results of a small randomized field experiment that compared the relative effects of a brief two-session counselor-delivered computer-tailored intervention and a control condition. The intervention is designed for use with African-American, non-Hispanic white and Hispanic males and females who may be at risk of HIV through unprotected sex, selling sex, male to male sex, injecting drug use or use of stimulants. Participants (n = 120) were recruited using a quota sampling approach and randomized using block randomization, which resulted in ten male and ten female participants of each racial/ethnic group (i.e. African-American, non-Hispanic white and Hispanic) being assigned to either the intervention or a control arm. In logistic regression analyses using a generalized estimating equations approach, at 3-month followup, participants in the intervention arm were more likely than participants in the control arm to report condom use at last sex (Odds ratio [OR] = 4.75; 95 % Confidence interval [CI] = 1.70-13.26; p = 0.003). The findings suggest that a brief tailored intervention may increase condom use. Larger studies with longer followups are needed to determine if these results can be replicated.


The effects of recombinant human thrombomodulin on endotoxin-induced multiple-system organ failure in rats.
Activation of the coagulation system is postulated to play an important role in the pathogenesis of endotoxin-induced tissue injury. Thrombomodulin (TM) is an endothelial cell membrane glycoprotein receptor for thrombin. Once bound to TM, thrombin loses its procoagulant activity, which results in decreased clotting. In addition, the binding of thrombin to TM activates the endogenous anticoagulant pathway through protein C. We studied the effect of recombinant human TM (rh-TM) on endotoxin-induced multiple-system organ failure (MSOF) in Sprague-Dawley rats weighing 400 to 450 g: 2 mg/kg of rh-TM was injected (T1/2 = 4.5 h) 30 min prior to intravenous injection of 20 mg/kg of Escherichia coli endotoxin. The study presented here consisted of three separate experiments. Experiment 1: 24-h survival study. Experiment 2: multiple-system organ microthrombi study in which 125I-human fibrinogen was injected 30 min prior to an endotoxin or saline injection and tissue microthrombi formation was assessed by measuring the percentage of organ radioactivity (lung, heart, liver, and kidney) against total injected radioactivity (microthrombi index, MI) 2.25 h after an endotoxin or saline injection. Experiment 3: endotoxin-induced MSOF study in which 125I-rat albumin was injected 5 h after an endotoxin or saline injection, and endotoxin-induced organ injury was evaluated by measuring tissue wet-to-dry ratios (W/D) and tissue-to-plasma 125I-rat albumin concentration ratios (T/P) 8 h after the endotoxin or saline injection. Blood contamination in samples from Experiments 2 and 3 was corrected by using 131I-rat albumin measurements. Pretreatment with rh-TM improved the survival from 12 h through 23 h as compared with that of the endotoxin control group (p < 0.05). However, at 24 h, after essentially all injected rh-TM had been eliminated, there was no difference in survival. Significant reductions in MI, W/D, and T/P in the organs sampled were observed in the rh-TM pretreated groups (p < 0.05). In conclusion, rh-TM improved short-term but not overall survival and decreased MSOF in endotoxemic rats.


Length of stay and mortality in neurocritically ill patients: impact of a specialized neurocritical care team.
To determine predictors of in-hospital and long-term mortality and length of stay in patients admitted to the neurosciences critical care unit. Retrospective analysis of a prospectively collected database. Neurosciences critical care unit of a large academic tertiary care hospital. Adult patients (n = 2381) admitted to our neurosciences critical care unit from January 1997 to April 2000. Introduction of a specialized neurocritical care team. Data obtained from the database included demographics, admission source, length of stay, neurosciences critical care unit and hospital disposition, admission Acute Physiology and Chronic Health Evaluation (APACHE) III score, and principal and secondary diagnoses. The introduction of a neurocritical care team in September 1998 was also collected, as was death at 1 yr after admission. Univariate analysis was carried out using Student's t-test, Mann-Whitney U test, or chi-square test (significance, p < .05). A logistic regression model was used to create a prediction model for in-hospital and long-term mortality. A general linear model was used to determine predictors of length of stay (after log transformation). Independent predictors of in-hospital mortality included APACHE III (odds ratio, 1.07 [1.06-1.08]) and admission from another intensive care unit (odds ratio, 2.9 [1.4-6.2]). The presence of a neurocritical care team was an independent predictor of decreased mortality (odds ratio, 0.7 [0.5-1.0], p = .044). Admission after the neurocritical care team was implemented was associated with reduced length of stay in both the neurosciences critical care unit (4.2 +/- 4.0 vs. 3.7 +/- 3.4, p < .001) and the hospital (9.9 +/- 8.0 vs. 8.4 +/- 6.9, p < .0001). There was no difference in readmission rates to the intensive care unit or discharge disposition to home before and after the neurocritical care team was established. The availability of the neurocritical care team was not associated with significant changes in long-term mortality. Factors independently associated with long-term mortality included female gender, admission from another intensive care unit, APACHE III score, and being moderately disabled before admission. Introduction of a neurocritical care team, including a full-time neurointensivist who coordinated care, was associated with significantly reduced in-hospital mortality and length of stay without changes in readmission rates or long-term mortality.


A critical role for adiponectin-mediated development of endometrial luminal epithelial cells during the peri-implantation period of pregnancy.
Adiponectin is one of the adipokines in the collagen superfamily. It is secreted primarily by white adipocytes and influences reproductive processes including ovarian and uterine functions. Adiponectin regulates energy homeostasis, insulin sensitivity, and is anti-inflammatory in various tissues. Its receptors (ADIPOR1 and ADIPOR2) are widely expressed in mammalian tissues, including porcine conceptuses and endometrial during the estrous cycle and peri-implantation period of pregnancy. However, regulatory effects of adiponectin on endometrial epithelial cells are unknown. Therefore, we investigated the effects of parity on expression of ADIPOR1 and ADIPOR2 and the effects of adiponectin in the porcine endometrium during early pregnancy. Results of this study revealed robust expression of ADIPOR1 and ADIPOR2 in uterine luminal (LE) and glandular (GE) epithelia during early pregnancy and expression decreased as with increasing parity. For porcine luminal epithelial (pLE) cells, adiponectin enhanced proliferation, and increased phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38, and P90RSK in a time-dependent manner. Moreover, the abundance of adiponectin-activated signaling molecules were suppressed by pharmacological inhibitors including wortmannin, U0126, SP600125, and SB203580, respectively, in pLE cells. Furthermore, inhibition of each targeted signal transduction molecule influenced proliferation of adiponectin-stimulated pLE cells. In addition, adiponectin inhibited tunicamycin-induced endoplasmic reticulum (ER)-stress through effects on ER stress regulated proteins in pLE cells. Collectively, these results suggest that adiponectin affects development of porcine uterine epithelia and reproductive performance through modulation of PI3K/AKT and MAPK cell signaling pathways.


Oportunidades program participation and body mass index, blood pressure, and self-reported health in Mexican adults.
Governments around the world are seeking to address the increasing prevalence of obesity and hypertension. Our objective was to evaluate the effect of an incentive-based development program (Oportunidades, formerly Progresa) on body mass index (BMI), blood pressure, and self-reported health. An intervention group of low-income (below the 20th percentile nationally), rural, Mexican adults (aged 30-65 years) (n = 5280) received program benefits (cash transfers contingent on positive changes in health behavior such as regular health checkups) for 3.5 to 5.0 years. They were compared with a newly recruited control group of adults (n = 1063) who had not yet begun receiving benefits. Analyses were adjusted for almost 50 social and economic covariates. Age- and sex-adjusted BMI was lower in adults from intervention communities than in those from control communities (26.57 kg/m(2) vs 27.16 kg/m(2), P < .001), as was the prevalence of obesity (20.28% vs 25.31%, P < .001) and overweight (59.24% vs 63.04%, P = .03); these results were attenuated after covariates were included. Adults in intervention communities had a lower combined prevalence of uncontrolled hypertension (33.80% vs 34.52%, P = .008) when adjusting for all covariates. Mean systolic (beta = -2.60, P < .001) and diastolic (beta = -2.84, P < .001) blood pressures were significantly lower in the intervention communities after all covariates were included, and self-reported health outcomes were better. Participation in Oportunidades, a large-scale cash-transfer program, was associated with lower prevalence of obesity and hypertension and better self-reported health in adults in rural Mexico.


Torque Loss After Miniscrew Placement: An In-Vitro Study Followed by a Clinical Trial.
To evaluate torque loss a week after insertion, both in an in vivo and an in vitro experimental setup were designed. In the in vivo setup a total of 29 miniscrews were placed in 20 patients who underwent orthodontic treatment. Maximum insertion torque (MIT) was evaluated at insertion time (T1). A week later, insertion torque was measured again by applying a quarter turn (T2); no load was applied on the screw during the first week. In the in vitro setup a total of 20 miniscrews were placed in pig rib bone samples. MIT was evaluated at insertion time (T1). Bone samples were kept in saline solution and controlled environment for a week during which the solution was refreshed every day. Afterwards, torque was measured again by applying a quarter turn (T2). The comparison of MIT over time was done calculating the percentage difference of the torque values between pre- and post-treatment and using the parametric two independent samples t-test or the non-parametric Mann-Whitney test. After a week unloaded miniscrews showed a mean loss of rotational torque of 36.3% and 40.9% in in vitro and in in vivo conditions, respectively. No statistical differences were found between the two different setups. Torque loss was observed after the first week in both study models; in vitro experimental setup provided a reliable study model for studying torque variation during the first week after insertion.


Leadership for safety: industrial experience.
The importance of leadership for effective safety management has been the focus of research attention in industry for a number of years, especially in energy and manufacturing sectors. In contrast, very little research into leadership and safety has been carried out in medical settings. A selective review of the industrial safety literature for leadership research with possible application in health care was undertaken. Emerging findings show the importance of participative, transformational styles for safety performance at all levels of management. Transactional styles with attention to monitoring and reinforcement of workers' safety behaviours have been shown to be effective at the supervisory level. Middle managers need to be involved in safety and foster open communication, while ensuring compliance with safety systems. They should allow supervisors a degree of autonomy for safety initiatives. Senior managers have a prime influence on the organisation's safety culture. They need to continuously demonstrate a visible commitment to safety, best indicated by the time they devote to safety matters.


Quantitation of neuropeptides in Cpe(fat)/Cpe(fat) mice using differential isotopic tags and mass spectrometry.
Neuroendocrine peptides play important roles as intercellular messengers. We previously developed a technique to isolate and identify a large number of neuroendocrine peptides from Cpe(fat)/Cpe(fat) mice (Che, F.; et al. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 9971-6); these mice lack carboxypeptidase E activity and this defect causes an accumulation of neuropeptide intermediates that contain C-terminal Lys or Arg residues (Naggert, J. K.; et al. Nat. Genet. 1995, 10, 135-42). In the present study, we have developed a differential isotopic-labeling technique that can be used to quantitate changes in neuropeptide levels in Cpe(fat)/Cpe(fat) mouse tissues. Samples are treated with either the H6 or the D6 form of acetic anhydride, peptides that contain C-terminal basic amino acids are isolated by affinity chromatography on anhydrotrypsin agarose, and the isolated peptides are analyzed by mass spectrometry. Measurement of the regulation of pituitary peptides in response to dehydration showed a decrease in vasopressin. The general method described in this report should be widely applicable to a large number of neuroendocrine peptides, known and novel, in a variety of regulatory paradigms.


Cleansing my abuse: A reparative response model of perpetrating abusive supervisor behavior.
Research on abusive supervision has predominantly focused on the consequences for victims while overlooking how leaders respond to their own abusive behavior. Drawing from the literature on moral cleansing, we posit that supervisors who engage in abusive behavior may paradoxically engage in more constructive leadership behaviors subsequently as a result of feeling guilty and perceiving loss of moral credits. Results from two experience sampling studies show that, within leaders on a daily basis, perpetrating abusive supervisor behavior led to an increase in experienced guilt and perceived loss of moral credits, which in turn motivated leaders to engage in more constructive person-oriented (consideration) and task-oriented (initiating structure) leadership behaviors. In addition, leader moral attentiveness and moral courage strengthen these indirect effects by amplifying leaders' awareness of their immoral behavior and their willingness and determination to make reparations for such behavior. Our research contributes to the theoretical understanding of leaders' responses toward their own abusive supervisor behavior and provides insights into how and when destructive leadership behaviors may, paradoxically, trigger more constructive behaviors. (PsycINFO Database Record


The Influence of Isoflurane Anaesthesia on the Rat Grimace Scale.
Over 234,000 rats were used in regulated procedures in the UK in 2014, many of which may have resulted in some degree of pain. When using animals in research, there is an ethical and legal responsibility to alleviate or at least reduce pain to an absolute minimum. To do this, we must be able to effectively assess pain in an accurate and timely manner. The Rat Grimace Scale (RGS) is a pain assessment tool, which is suggested to be both accurate and rapid in pain assessment. Many procedures involve the use of general anaesthesia. To date, the effects of anaesthesia on the RGS have not been assessed, limiting its potential utility for assessing pain following anaesthesia. Forty-eight Lister hooded rats were used in this study (24 in part A and 24 in a separate part B). Rats were randomly assigned to one of two treatment groups in part A; short duration isoflurane exposure, short duration control exposure (air) and one of two treatment groups in part B; surgical duration isoflurane exposure or surgical duration control exposure (oxygen). Rats were placed into an anaesthetic induction chamber and isoflurane, or control gas piped into the chamber for either 4 (short duration exposure) or 12 minutes (surgical duration exposure). Following recovery, photographs of the rats' faces were taken and then scored blindly using the RGS. Short duration isoflurane anaesthesia had no effect on RGS scores. However, when rats are anaesthetised for a longer duration, akin to a simple routine surgical procedure, the RGS score increases significantly and this increase remains on repeated exposure to this duration of anaesthesia over a 4-day period. This should be accounted for when using the RGS to assess pain in rats in the immediate time period following procedures involving the use of isoflurane anaesthesia.


Physical fitness and incidence of hypertension in healthy normotensive men and women.
We measured physical fitness, assessed by maximal treadmill testing in 4,820 men and 1,219 women aged 20 to 65 years. Participants had no history of cardiovascular disease and were normotensive at baseline. We followed up these persons for one to 12 years (median, four years) for the development of hypertension. Multiple logistic risk analysis was used to estimate the independent contribution of physical fitness to risk of becoming hypertensive. After adjustment for sex, age, follow-up interval, baseline blood pressure, and baseline body-mass index, persons with low levels of physical fitness (72% of the group) had a relative risk of 1.52 for the development of hypertension when compared with highly fit persons. Risk of hypertension developing also increased substantially with increased baseline blood pressure.


ACOG committee opinion no. 528: Adoption.
Obstetrician–gynecologists may find themselves at the center of adoption issues because of their expertise in the assessment and management of infertility, pregnancy, and childbirth. The lack of clarity about both ethical issues and legal consequences may create challenges for physicians. Therefore, the Committee on Ethics of the American College of Obstetricians and Gynecologists discusses ethical issues, proposes safeguards,and makes recommendations regarding the role of the physician in adoption.


Adverse reaction; patent blue turning patient blue.
The authors report a severe anaphylactic reaction to Patent Blue V dye used in sentinel node biopsy for lymphatic mapping during breast cancer surgery to stage the axilla. Patent Blue dye is the most widely used in the UK; however, adverse reactions have been reported with the blue dye previously. This case highlights that reactions may not always be immediately evident and to be vigilant in all patients that have undergone procedures using blue dye. If the patients are not responding appropriately particularly during an anaesthetic, one must always think of a possible adverse reaction to the dye. All surgical patients should give consent for adverse reactions to patent blue dye preoperatively. Alternative agents such as methylene blue are considered.


[A case of arteriovenous malformation successfully treated with functional mapping of the language area by PET activation study].
The authors report a case of temporal AVM safely treated by mapping the language area with PET activation study. The patient was a 50-year-old woman with temporal epilepsy as her chief complaint. MRI and angiography revealed a right temporal AVM. Before surgical treatment, we assessed the dominant hemisphere with PET activation study. We performed PET scanning while the patient was playing "capping" (called "Shiritori" in Japanese), from which we subtracted PET images performed when she was in a resting state, and then we superimposed those images upon MRIs. The blood flow increased in the left frontal operculum (Broca's area), the left caudal head, the left putamen and the right cerebellar hemisphere. We were thus able to determine that her left hemisphere was dominant, and that it was safe to undertake embolization and operation for the AVM. Postoperative course was uneventful and higher cortical functions were preserved perfectly. In cases of cerebral AVMs, unusual dominancy of cerebral hemispheres is often encountered, and so, preoperative evaluation of the relation of AVM to the eloquent cortex is essential. In our study, blood flow increased in some areas other than the language area, but they were considered to be areas related to phonation, and we think that we were able to map the language area. Though this method is still in its preliminary stage, we think it gives us useful information for surgical treatment of cerebral AVMs.


Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients.
Although cytomegalovirus (CMV) specific cell-mediated immunity (CMI) has been suggested as a predictive marker for CMV infection, proper CMI monitoring strategy in CMV-seropositive recipients and optimal method are not defined. The aim of this study was to evaluate two interferon gamma release assays during early post-transplant period as a predictor of the development of CMV infection in CMV-seropositive patients. A total of 124 CMV-seropositive recipients who received kidney transplantation from CMV-seropositive donor were prospectively examined. At pre-transplant and post-transplant 1 and 3 months, CMV-CMIs were tested using QuantiFERON-CMV assay (QF-CMV) and CMV specific T cell ELISPOT against CMV pp65 and IE-1 antigens (pp65-ELISPOT, IE-1-ELISPOT). CMV DNAemia occurred in 16 (12.9%) patients within 3 months after transplant. Post-transplant pp65 or IE-1 ELISPOT response, but not QF-CMV, was significantly associated with CMV DNAemia. The pp65 ELISPOT (cut-off; 30 spots/200,000 cells) and IE-1 ELISPOT (10 spots/200,000 cells) at post-transplant 1 month predicted the risk of post-transplant CMV DNAemia (P = 0.019). Negative predictive values (NPV) for protection from CMV DNAemia in case of positive ELISPOT results were 94.5% (95% CI: 86.9-97.8%) and 97.6% (95% CI: 86.3-99.6%) in pp65-ELISPOT and IE-1-ELISPOT assays, respectively. These results suggest that the variability may exist between CMV ELISPOT assays and QF-CMV, and CMV ELISPOT at post-transplant 1 month can identify the risk of CMV DNAemia in seropositive kidney transplant recipients.


Simultaneous detection of FISH signals and bromo-deoxyuridine incorporation in fixed tissue cultured cells.
FISH (Fluorescence in situ hybridization) is a powerful technique that detects and localises specific DNA sequences on metaphase chromosomes, interphase nuclei or chromatin fibres. When coupled to BrdU (5-Bromo 2-deoxy-uridine) labeling of newly replicated DNA, the replication properties of different DNA sequences can be analysed. However, the technique for the detection of BrdU incorporation is time consuming, and relies on acidic pH buffer treatments, that prevent use of pH sensitive fluorochromes such as FITC (Fluoro-isothiocianate) during FISH. In this work, we describe a simplified protocol that allows the simultaneous detection of FISH signals and BrdU incorporation. Since the technique does not involve paraformaldehyde for cell fixation, or formamide for denaturation of the target DNA and in post-hybridisation washes, it represents a safer alternative to classical FISH techniques.


Spironolactone ameliorates the cardiovascular toxicity induced by concomitant trastuzumab and thoracic radiotherapy.
We aimed to evaluate impact of spironolactone (S) on cardiovascular toxicity of concomitant use of radiotherapy (RT) and trastuzumab (T). S, an aldosterone receptor antagonist, is known to ameliorate the cardiac damage. S ameliorates anthracycline -induced cardiotoxicity, there is no data regarding to effect of S on both T and radiation-induced cardiotoxicity. Eighty rats were divided into eight groups: group (G) 1 was defined as control group. G2, G3 and G4 were RT, S and T groups respectively. G5, G6, G7 and G8 were RT + T, T + S, RT + S and RT + T + S groups respectively. Rats were sacrificed at 6th hour; 21st and 100th days after RT. Heart and thoracic aorta samples were taken for microscopical examination. Cardiac inflammation and fibrosis scores and; TGF-β expression were not significantly different within study groups at 6th hour and 21st days of RT. By 100th days of RT fibrosis scores and TGF-β expression in cardiac samples were significantly different between study groups (p values were 0.004 and 0.002 respectively). Pair-wise comparisons revealed that both cardiac fibrosis scores and TGF-β expression levels were higher in G5 when compared to G8 (p values were 0.046 and 0.028 respectively). Moreover the TGF-β expression was higher in G5 when compared to G2 (p = 0.046). We could not demonstrate any significant differences with respect to inflammation, fibrosis and TGF-β expression in thoracic aorta samples between study groups. Although S had a protective effect on cardiac tissue it had no protective effect on thoracic aorta when administered with RT + T.


Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management.
Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR or MPL mutation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival. Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are "triple-negative." None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). According to the revised 2016 World Health Organization (WHO) classification and diagnostic criteria, "prefibrotic" PMF (pre-PMF) is distinguished from "overtly fibrotic" PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two. Risk stratification: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109 /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109 /L and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), 5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3" and ≥4 adverse factors defines low, intermediate-1, intermediate-2 and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9 and 1.3 years, respectively. Most recently, DIPSS-plus-independent adverse prognostic relevance has been demonstrated for certain mutations including ASXL1 and SRSF2 whereas patients with type 1/like CALR mutations, compared to their counterparts with other driver mutations, displayed significantly better survival. Risk-adapted therapy: Observation alone is a reasonable treatment strategy for asymptomatic low or intermediate-1 DIPSS-plus risk disease, especially in the absence of high-risk mutations. All other patients with high or intermediate-2 risk disease, or those harboring high-risk mutations such as ASXL1 or SRSF2, should be considered for stem cell transplant, which is currently the only treatment modality with the potential to favorably modify the natural history of the disease. Non-transplant candidates should be encouraged to participate in clinical trials, since the value of conventional drug therapy, including the use of JAK2 inhibitors, is limited to symptoms palliation and reduction in spleen size. Specifically, JAK2 inhibitors have not been shown to induce complete clinical or cytogenetic remissions or significantly affect JAK2/CALR/MPL mutant allele burden. Splenectomy is considered for drug-refractory splenomegaly. Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension and extremity bone pain. Am. J. Hematol. 91:1262-1271, 2016. © 2016 Wiley Periodicals, Inc.


The detection and analysis of chitinase activity from the yeast form of Candida albicans.
Chitinase activity was detected in the supernatant fraction of a high-speed centrifugation preparation of broken Candida albicans yeast cells. The enzyme showed peak activity during the rapid budding phase of growth and was found to parallel the chitin synthase activity. The optimum conditions for the hydrolysis of chitin, regenerated from acetylation of chitosan, were determined. Analysis of the kinetics of the enzyme-substrate interaction and a measurement of their binding suggests that an equilibrium binding situation exists and that the kinetics follow a Langmuir isotherm interaction.


A 1-week intradermal dose-sparing regimen for rabies post-exposure prophylaxis (RESIST-2): an observational cohort study.
The international health authorities are backing an effort to eliminate canine-mediated rabies in humans by 2030. This effort will require improving access to adequate and timely rabies post-exposure prophylaxis as compliance is low with WHO-recommended regimens (given in four to five visits over 1 month). Access could be substantially improved by an abridged regimen to reduce doses, direct and indirect costs, and improve vaccine equity by better sharing of available vaccine. We aimed to compare rabies virus neutralising antibody titres before and after the fourth visit to determine whether that session was needed or the current regimen could be abridged. In this observational cohort study, we measured rabies virus neutralising antibody titres using rapid fluorescent focus inhibition tests in 116 people bitten by dogs with laboratory-confirmed rabies and 20 control individuals. Percentages of circulating plasmablasts were determined by flow cytometry. All individuals had been referred to the rabies prevention clinic at Institut Pasteur in Cambodia and received two intradermal injections of post-exposure prophylaxis on days 0, 3, 7, and 28 (Thai Red Cross regimen) with or without equine rabies immunoglobulin, as per 2010 WHO recommendations. All individuals had rabies virus neutralising antibody titres considered protective (≥0·5 IU/mL) and plasmablast activation on day 28 before the last injection. The median rabies virus neutralising antibody concentration in the group of individuals bitten by rabies virus-positive dogs was 1·08 IU/mL (IQR 0·37-3·09) on day 7, 26·86 (22·68-49·50) on day 28, and 26·74 (11·78-49·06) on day 42. No significant differences were observed in titres between days 28 and 42, after titres reached a plateau. These titres were reached notwithstanding equine rabies immunoglobulin use, age, sex, nutrition status as indicated by upper-arm circumference in children or BMI in adults, or dog infection status. Titres or plasmablast percentages did not increase between the day of the last injection and 2 weeks later. All patients were alive 1 year after post-exposure prophylaxis. The fourth vaccine session on day 28 provides no additional benefit. Rabies post-exposure prophylaxis can be abridged to a two-dose, three-session, 1 week regimen to improve post-exposure prophylaxis coverage and equity at no risk to patients. Institut Pasteur.


Applying a system approach to forecast the total hepatitis C virus-infected population size: model validation using US data.
Hepatitis C virus (HCV) infection is associated with chronic progressive liver disease. Its global epidemiology is still not well ascertained and its impact will be confronted with a higher burden in the next decade. The goal of this study was to develop a tool that can be used to predict the future prevalence of the disease in different countries and, more importantly, to understand the cause and effect relationship between the key assumptions and future trends. A system approach was used to build a simulation model where each population was modeled with the appropriate inflows and outflows. Sensitivity analysis was used to identify the key drivers of future prevalence. The total HCV-infected population in the US was estimated to decline 24% from 3.15 million in 2005 to 2.47 million in 2021, while disease burden will increase as the remaining infected population ages. During the same period, the mortality rate was forecasted to increase from 2.1 to 3.1%. The diagnosed population was 50% of the total infections, while less than 2% of the total infections were treated. We have created a framework to evaluate the HCV-infected populations in countries around the world. This model may help assess the impact of policies to meet the challenges predicted by the evolution of HCV infection and disease. This prediction tool may help to target new public health strategies.


The relationship among platelet-associated IgG, platelet lifespan, and reticuloendothelial cell function.
Platelet-associated IgG (PAIgG) has been reported to be elevated in nonthrombocytopenic patients who have a normal platelet lifespan. This has been interpreted as indicating that PAIgG is a nonspecific finding in these patients and not a determinant of platelet survival. It is important to recognize that the reticuloendothelial (RE) system plays an important role in the clearance of antibody-sensitized cells. In this study, we related the level of PAIgG and the platelet lifespan to the RE function in patients with: (A) idiopathic thrombocytopenic purpura (ITP), and (B) five patients with elevated levels of PAIgG yet normal or near-normal platelet counts. RE function was assessed by measuring the clearance of autologous chromium-labeled red cells sensitized with a precise amount of alloantibody (2,000-3,600 molecules of IgG/cell). Eight patients with immune thrombocytopenia had significantly shortened platelet survivals (less than 2-113 hr). In contrast, the five patients with elevated PAIgG, yet normal or near-normal platelet counts, all had normal autologous platelet survivals (186-222 hr). These patients also had significantly impaired clearance of IgG-sensitized red cells, with an average of 85% of the infused red cells remaining in the circulation at 60 min (normal 42% +/- 14%, n = 10). In this study, every patient with elevated PAIgG and normal RE function had a shortened platelet lifespan. Those patients with elevated PAIgG and impaired RE function did not invariably have a shortened platelet lifespan. The observation that the PAIgG is elevated in some patients whose platelet survival is normal does not indicate that PAIgG is not biologically relevant. It indicates that these patients may have RE blockade and do not clear IgG-sensitized cells.


Morphine-induced alterations in antibody levels: receptor and immune mechanisms.
We have previously shown that an acute administration of morphine (10 mg/kg, i.v.) decreases IgG, but not IgM, antibody levels to antigen administered before morphine. Further, decreases in IgG were blocked by previous administration of naltrexone, indicating that receptor binding is critical to the decreased antibody levels. These studies investigated potential receptor and immune mechanisms for these effects. To investigate potential receptor mechanisms, the stereoselectivity and location of receptor binding was determined. The results of these experiments suggest morphine must bind stereoselectively to central sites to decrease antibody levels after antigen administration. To investigate potential immune mechanisms for these changes, antibody secreting cells (ASC) for keyhole limpet hemocyanin-specific IgG and IgM were enumerated. Morphine decreased ASC for IgG but increased ASC for IgM. Two pathways for the genetic switch from IgM to IgG production were investigated. One pathway requires interferon-gamma to stimulate IgM-secreting cells to switch to IgG2a-secreting cells. Another pathway requires interleukin-4 to stimulate IgM-secreting cells to switch to IgG1- secreting cells. IgG1 and IgG2a levels were measured to determine if these pathways were differentially affected and only IgG2a levels were decreased. Further, these decreases were accompanied by decreased IFN-gamma levels but not by altered numbers of splenocytes. These data indicate that morphine may alter the ability of ASC to switch from IgM to IgG2a production, possibly by reducing the availability of IFN-gamma.


The Evolution of an Elective in Health Disparities and Advocacy: Description of Instructional Strategies and Program Evaluation.
Health disparities remain pervasive in the United States. Training future physicians to address health disparities requires attention to both systemic and provider causes of disparities, but comprehensive curricula are lacking. Albert Einstein College of Medicine in Bronx, New York, offers a 13-session health disparities elective to first-year medical students. The curriculum covers three main content areas: background, provider contributions to health disparities, and systemic contributions to health disparities (i.e., social determinants of health). Teaching methods included didactic and multimedia presentations, reflective discussions, and skill-building seminars (e.g., addressing subconscious assumptions and advocacy training).The authors evaluated the course in 2010-2013 by comparing students' summary scores for knowledge, attitudes, and self-reported confidence on pre- and postintervention tests. They investigated associations between students' sociodemographic characteristics and changes in summary scores. Scores increased significantly in each domain: Mean knowledge scores increased from 63.6 (± 10.0), out of 100, to 76.4 (± 12.8); mean attitudes scores increased from 16.7 (± 1.9), out of 20, to 18.2 (± 1.1); mean confidence scores increased from 10.7 (± 1.5), out of 16, to 14.4 (± 1.7). Younger students (< 24) had greater changes in confidence than older students. Other sociodemographic characteristics were not associated with changes in any domain. Exposure to health disparities instruction is important for medical students. The authors' experience provides insights for incorporating such material into the compulsory curriculum. Future evaluation of outcomes from similar curricula should include measures of clinical behaviors (e.g., through clinical examinations).


Particle-hole symmetry and the nu=5/2 quantum Hall state.
We discuss the implications of approximate particle-hole symmetry in a half-filled Landau level in which a paired quantum Hall state forms. We note that the Pfaffian state is not particle-hole symmetric. Therefore, in the limit of vanishing Landau-level mixing, in which particle-hole transformation is an exact symmetry, the Pfaffian spontaneously breaks this symmetry. There is a particle-hole conjugate state, which we call the anti-Pfaffian, which is degenerate with the Pfaffian in this limit. We observe that strong Landau-level mixing should favor the Pfaffian, but it is an open problem which state is favored for the moderate Landau-level mixing which is present in experiments. We discuss the bulk and edge physics of the anti-Pfaffian. We analyze a simplified model in which transitions between analogs of the two states can be studied in detail. Finally, we discuss experimental implications.


Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules.
Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein.


Integral bias in the cognitive processing of emotionally linked pictures.
It is well established that human cognitive processes are subject to systematic biases associated with particular emotional states. But how do these cognitive biases arise? This question was addressed by means of a pictorial Stroop task which allowed the development of such a bias to be assessed. In each of two experiments, spider-phobic participants were significantly impaired at naming the colours of phobia-related pictures relative to those of control pictures. Investigation of the magnitude of this effect for participants of different ages allowed two contrasting hypotheses concerning the development of such biases to be compared. The integral bias hypothesis asserts that the effects of emotion on cognition reflect integral links between emotional states and cognitive mechanisms, links that are not arbitrary but instead are fixed constituents of our mental architecture. In contrast, the inferred bias hypothesis asserts that these effects arise as a consequence of the gradual establishment of associations between particular emotional states and particular patterns of cognitive behaviour. It was found that the magnitude of the observed bias remained approximately constant irrespective either of the ages of participants or of the directly estimated durations of their phobias. This fixed relation provides strong support for the integral bias explanation of the cognitive effects of an emotional disturbance. Finally, the evolutionary context in which integral links between emotion and cognition may arise is discussed.


Regulatory links between imprinted genes: evolutionary predictions and consequences.
Genomic imprinting is essential for development and growth and plays diverse roles in physiology and behaviour. Imprinted genes have traditionally been studied in isolation or in clusters with respect to cis-acting modes of gene regulation, both from a mechanistic and evolutionary point of view. Recent studies in mammals, however, reveal that imprinted genes are often co-regulated and are part of a gene network involved in the control of cellular proliferation and differentiation. Moreover, a subset of imprinted genes acts in trans on the expression of other imprinted genes. Numerous studies have modulated levels of imprinted gene expression to explore phenotypic and gene regulatory consequences. Increasingly, the applied genome-wide approaches highlight how perturbation of one imprinted gene may affect other maternally or paternally expressed genes. Here, we discuss these novel findings and consider evolutionary theories that offer a rationale for such intricate interactions among imprinted genes. An evolutionary view of these trans-regulatory effects provides a novel interpretation of the logic of gene networks within species and has implications for the origin of reproductive isolation between species.


Combination of a graphene SERS substrate and magnetic solid phase micro-extraction used for the rapid detection of trace illegal additives.
Surface enhanced Raman scattering (SERS) is an ultra-sensitive spectroscopy technique, which can provide rich structural information for a great number of molecules, while solid phase micro-extraction (SPME) is an efficient method for sample pretreatment in analytical chemistry, particularly in a micro-system. In the present report, a silver-loaded and graphene-based magnetic composite (Fe3O4@GO@Ag) was fabricated for use as both a SERS-active substrate and SPME material. The π-π stacking and fluorescence quenching abilities of GO make the composite a perfect candidate for SERS in analyzing real-world samples. Therefore, through combining the magnetic nanoparticles with a SPME device, we have developed a pretreatment method named as disperse magnetic solid phase micro-extraction (Dis-MSPME). In comparison to traditional SPME, the proposed Dis-MSPME realized solid phase micro-extraction from a dispersive system and largely improved the extraction efficiency. Furthermore, by combining the advantages of both Dis-MSPME and SERS we have proposed a new detection method called Dis-MSPME-SERS. Finally, as an example, the illegal additive chloramphenicol (CAP) was successfully detected in aqueous solution with low LOQ and LOD values (1.0 × 10-8 and 1.0 × 10-10 M, respectively), which was finalized within 10 min based on the proposed Dis-MSPME-SERS method. Therefore, a simpler, more efficient and sensitive approach to realize enrichment, magnetic separation and detection, all-in-one, for the detection of illegal additives has been reported, which will be promising towards the detection of trace amounts of substance in micro-systems.


Assessing the need for a dietitian in radiation oncology.
Nutritional care is an integral component of quality cancer treatment. Patients undergoing cancer therapy are at risk for developing a variety of side effects that impact their intake, absorption, and nutritional status. The issue becomes compounded in newly diagnosed patients who have preexisting poor nutritional status, comorbid diseases, mechanical obstruction, and metabolic abnormalities. Standards related to the role of dietitians are well defined in the literature and by the Joint Commission. The quality improvement project illustrated in this article clearly demonstrated the need for a dietitian in the radiation oncology clinic by using the Patient-Generated Subjective Global Assessment.


Energy Expenditure During Acute Periods of Sitting, Standing, and Walking.
Identifying strategies to increase energy expenditure (EE) may help combat the harmful effects of sedentary behavior. This study examined EE during sitting, standing, and walking. Participants (N = 74) were randomized to 2 of the following activities: sitting using a laptop computer (SIT-C), sitting watching television (SIT-T), standing watching television (STAND), and walking at a self-selected pace ≤3.0 (mph) (WALK). Each activity lasted 15 minutes with a 3-minute transition period between activities. The experimental conditions were: SIT-C to STAND (N = 18), SIT-T to WALK (N = 18), STAND to SIT-C (N = 20), and WALK to SIT-T (N = 18). EE was measured using indirect calorimetry. Based on the first activity performed, EE during WALK (55.92 ± 14.19 kcal) was significantly greater than SIT-C (19.63 ± 6.90 kcal), SIT-T (18.66 ± 4.01 kcal), and STAND (21.92 ± 5.08 kcal) (P < .001). Cumulative EE in SIT-T to WALK (74.50 ± 17.88 kcal) and WALK to SIT-T (82.72 ± 21.70 kcal) was significantly greater than EE in SIT-C to STAND (45.38 ± 14.78 kcal) and STAND to SIT-C (45.64 ± 9.69 kcal) (P < .001). Substituting periods of sitting or standing with walking significantly increases EE, but substituting periods of sitting with standing may not affect EE. Thus, the potential benefits of standing as opposed to sitting need further investigation beyond the role of EE.


Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study.
The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.


Foot and ankle characteristics associated with falls in adults with established rheumatoid arthritis: a cross-sectional study.
People with rheumatoid arthritis (RA) have an increased risk of falls. The foot is a common site of pathology in RA and foot problems are reported in up to 90% of patients with established disease. The aim of this study was to determine whether foot and ankle characteristics are associated with falls in people with RA. Adults with RA were recruited from rheumatology outpatient clinics in Auckland, New Zealand. Participants reported whether they had fallen in the preceding year, and the number of falls. Clinical characteristics, common fall risk factors, and foot and ankle variables were measured. Univariate parametric and non-parametric analysis compared fallers and non-fallers on all variables to determine significant differences. Logistic regression analysis identified variables independently associated with falls. Two hundred and one participants were prospectively recruited. At least one fall in the preceding 12-months was reported by 119 (59%) participants. Univariate analysis showed that fallers had significantly longer mean disease duration, more co-morbid conditions, an increase in lower limb tender joints, higher midfoot peak plantar pressures and were more likely to have a history of vascular disease than non-fallers. Fallers also reported greater difficulty with activities of daily living, increased fear of falling and greater self-reported foot impairment. Logistic regression analysis revealed that increased midfoot peak plantar pressures (odds ratio (OR) 1.12 [for each 20 kPa increase], 95% confidence interval (CI) 1.00-1.25), self-reported foot impairment (OR 1.17 [for each three point increase], 95% CI 1.05-1.31) and history of vascular disease (OR 3.22, 95% CI 1.17-8.88) were independently associated with a fall in the preceding 12 months. Elevated midfoot peak plantar pressures, self-reported foot impairment and vascular disease are associated with falls in people with RA. Assessment of foot deformity, foot function and self-reported foot impairment may be of benefit when considering falls prevention strategies in people with RA. Australia New Zealand Clinical Trial Registry (trial ACTRN12612000597897).


Characterization of post-translational modifications of histone H2B-variants isolated from Arabidopsis thaliana.
Eukaryotic DNA is structurally packed into chromatin by the basic histone proteins H2A, H2B, H3, and H4. There is increasing evidence that incorporation and post-translational modifications of histone variants have a fundamental role in gene regulation. While modifications of H3 and H4 histones are now well-established, considerably less is known about H2B modifications. Here, we present the first detailed characterization of H2B-variants isolated from the model plant Arabidopsis thaliana. We combined reversed-phase chromatography with tandem mass spectrometry to identify post-translational modifications of the H2B-variants HTB1, HTB2, HTB4, HTB9, and HTB11, isolated from total chromatin and euchromatin-enriched fractions. The HTB9-variant has acetylation sites at lysines 6, 11, 27, 32, 38, and 39, while Lys-145 can be ubiquitinated. Analogous modifications and an additional methylation of Lys-3 were identified for HTB11. HTB2 shows similar acetylation and ubiquitination sites and an additional methylation at Lys-11. Furthermore, the N-terminal alanine residues of HTB9 and HTB11 were found to be mono-, di-, or trimethylated or unmodified. No methylation of arginine residues was detected. The data suggest that most of these modification sites are only partially occupied. Our study significantly expands the map of covalent Arabidopsis histone modifications and is the first step to unraveling the histone code in higher plants.


Atlas encoding by randomized forests for efficient label propagation.
We propose a method for multi-atlas label propagation based on encoding the individual atlases by randomized classification forests. Most current approaches perform a non-linear registration between all atlases and the target image, followed by a sophisticated fusion scheme. While these approaches can achieve high accuracy, in general they do so at high computational cost. This negatively affects the scalability to large databases and experimentation. To tackle this issue, we propose to use a small and deep classification forest to encode each atlas individually in reference to an aligned probabilistic atlas, resulting in an Atlas Forest (AF). At test time, each AF yields a probabilistic label estimate, and fusion is done by averaging. Our scheme performs only one registration per target image, achieves good results with a simple fusion scheme, and allows for efficient experimentation. In contrast to standard forest schemes, incorporation of new scans is possible without retraining, and target-specific selection of atlases remains possible. The evaluation on three different databases shows accuracy at the level of the state of the art, at a significantly lower runtime.


Bevacizumab alone or in combination with irinotecan in recurrent WHO grade II and grade III gliomas.
The repertoire of salvage regimens for patients with WHO grade II and III gliomas recurring or progressing after surgery, radiotherapy and temozolomide chemotherapy is limited. Based on promising response and progression-free survival (PFS) data in recurrent glioblastoma, the use of bevacizumab (BEV) has been extended to recurrent grade II/III gliomas. We retrospectively assessed the safety and efficacy of BEV alone or combined with irinotecan in 39 patients with recurrent grade II/III gliomas. Both BEV monotherapy and its combination with irinotecan were well tolerated. Response rates were 26% as monotherapy and 33% in combination using Macdonald and RANO criteria. The median PFS was 4.2 months and the PFS rate at 6 months 29% for BEV alone, and 4.7 months and 42% for the combination. The median overall survival was 14.8 months for BEV monotherapy and 8.1 months for the combination. Outcome after failure of BEV was better when patients continued BEV beyond progression. BEV has limited activity in recurrent grade II/III gliomas. The additional value of irinotecan remains questionable. Prospective studies with BEV-free control groups are required to better define the role of BEV among the limited options in patients with recurrent grade II/III gliomas.


Acute and chronic effects of propionyl-L-carnitine on the hemodynamics, exercise capacity, and hormones in patients with congestive heart failure.
Carnitine is an important cofactor in the intermediary metabolism of the heart, and carnitine deficiency is associated with congestive heart failure. We therefore studied the effects of acute (IV bolus, 30 mg/kg body weight) and chronic administration (1.5 mg/d for 1 month) of propionyl-L-carnitine on hemodynamics, hormone levels, ventricular function, exercise capacity, and peak oxygen consumption in 30 patients with chronic congestive heart failure (NYHA II-III, mean EF 29.5 +/- 7%) in a phase II, parallel, single-blind, randomized, and placebo-controlled study. Acute administration of propionyl-L-carnitine caused a significant reduction in pulmonary artery and pulmonary wedge pressures at both day 1 (P < 0.001) and day 30 (P < 0.05) of the study but no other hemodynamics changes. Hormone levels did not change following acute administration of the drug. Chronic administration of propionyl-L-carnitine increased peak oxygen consumption by 45% (from 16.0 +/- 3 to 23.5 +/- 2 mL/kg/min, P +/- 0.001), exercise time by 21% (from 8.1 +/- 0.5 to 9.8 +/- 0.4 minutes, P < 0.01), and peak exercise heart rate by 12% (P < 0.01). These changes were concomitant with a reduction of pulmonary artery pressure. In the treated group, there was a slight, but significant (P < 0.01), reduction in left ventricular dimensions. Hemodynamics and hormones measured after 1 month of oral therapy remained unchanged, except for a fall in pulmonary artery pressures, with a nonsignificant trend towards a fall in filling pressures and plasma norepinephrine. The chronic changes in the propionyl-L-carnitine group were seen at 15 days of treatment, and no further changes in these parameters were seen at 1 month. We conclude that propionyl-L-carnitine increases exercise capacity and reduces ventricular size in patients with congestive heart failure. The drug has no significant effects on hemodynamics or neurohormone levels. The use of a single-blind design reduces the impact of the positive finding on exercise capacity.


SINBAD: a neocortical mechanism for discovering environmental variables and regularities hidden in sensory input.
We propose that a top priority of the cerebral cortex must be the discovery and explicit representation of the environmental variables that contribute as major factors to environmental regularities. Any neural representation in which such variables are represented only implicitly (thus requiring extra computing to use them) will make the regularities more complex and therefore more difficult, if not impossible, to learn. The task of discovering such important environmental variables is not an easy one since their existence is only indirectly suggested by the sensory input patterns the cortex receives--these variables are "hidden". We present a candidate computational strategy for (i) discovering regularity-simplifying environmental variables, (ii) learning the regularities, and (iii) using regularities in perceptual and decision-making tasks. The SINBAD computational model discovers useful environmental variables through a search for different, but nevertheless highly correlated, functions of any kind over nonoverlapping subsets of the known variables, this being indicative of some important environmental variable that is responsible for the correlation. We suggest that such a search is performed in the neocortex by the dendritic trees of individual pyramidal cells. According to the SINBAD model, the basic function of each pyramidal cell is to (i) discover and represent one of the regularity-simplifying environmental variables and (ii) learn to infer the state of its variable from the states of other variables, represented by other pyramidal cells. A network of such cells--each cell just attending to representation of its variable--can function as a sophisticated and useful inferential model of the outside world.


Transmission characteristics of finite periodic dielectric waveguides.
Transmission properties of the periodic dielectric waveguide (PDWG) formed by aligning a sequence of dielectric cylinders in air are investigated theoretically. Unlike photonic crystal waveguides (PCWs), light confinement in a PDWG is due to total internal reflection. Besides, the dispersion relation of the guided modes is strongly influenced by the dielectric periodicity along the waveguide. The band structure for the guided modes is calculated using a finite-difference time-domain (FDTD) method. The first band is used for guiding light, which makes PDWG single mode. Transmission is calculated using the multiple scattering method for various S shaped PDWGs, each containing two opposite bends. When PDWG operates in appropriate frequency ranges, high transmission (above 90%) is observed, even if the radius of curvature of the bends is reduced to three wavelengths. This feature indicates that the guiding ability of PDWG can be made better than the conventional waveguide when used in an optical circuit. In addition, PDWG has the advantage that it can be bent to any arbitrary shape while still preserves the high transmission, avoiding the geometric restriction that PCWs are subject to.


[Intra-domiciliary capture of Panstrongylus rufotuberculatus (Champion, 1899) (Hemiptera, Reduviidae, Triatominae) in Piura, Peru].
Panstrongylus rufotuberculatus is widely distributed in Central and South America. In Peru, it has been found in Tumbes, Piura, and Cuzco. The authors report the presence of P. rufotuberculatus in Chirinos-La Pareja, Suyo district, Ayabaca Province, Piura Region, Peru. Twenty-eight specimens were collected in two of 15 dwellings: three 2nd instar, four 3rd instar, two 4th instar, and eight 5th instar nymphs, three male and eight female, in an intra-domiciliary colony of guinea pigs (Cavia porcellus, raised indoors as a source of diet protein) and beds and bedroom walls. None of the fecal samples were naturally infected with Trypanosoma cruzi. This is the first report of synanthropic presence of P. rufotuberculatus in the region. The finding emphasizes the need for careful entomological and epidemiological surveillance of this and other triatomine species in the Region.