Reprocessing filtering facepiece respirators in primary care using medical autoclave: prospective, bench-to-bedside, single-centre study.
There are widespread shortages of personal protective equipment as a result of the COVID-19 pandemic. Reprocessing filtering facepiece particle (FFP)-type respirators may provide an alternative solution in keeping healthcare professionals safe. Prospective, bench-to-bedside. A primary care-based study using FFP-2 respirators without exhalation valve (3M Aura 1862+ (20 samples), Maco Pharma ZZM002 (14 samples)), FFP-2 respirators with valve (3M Aura 9322+ (six samples) and San Huei 2920V (16 samples)) and valved FFP type 3 respirators (Safe Worker 1016 (10 samples)). All masks were reprocessed using a medical autoclave (17 min at 121°C with 34 min total cycle time) and subsequently tested up to three times whether these respirators retained their integrity (seal check and pressure drop) and ability to filter small particles (0.3-5.0 µm) in the laboratory using a particle penetration test. We tested 33 respirators and 66 samples for filter capacity. All FFP-2 respirators retained their shape, whereas half of the decontaminated FFP-3 respirators showed deformities and failed the seal check. The filtering capacity of the 3M Aura 1862 was best retained after one, two and three decontamination cycles (0.3 µm: 99.3%±0.3% (new) vs 97.0±1.3, 94.2±1.3% or 94.4±1.6; p<0.001). Of the other FFP-2 respirators, the San Huei 2920 V had 95.5%±0.7% at baseline vs 92.3%±1.7% vs 90.0±0.7 after one-time and two-time decontaminations, respectively (p<0.001). The tested FFP-3 respirator (Safe Worker 1016) had a filter capacity of 96.5%±0.7% at baseline and 60.3%±5.7% after one-time decontamination (p<0.001). Breathing and pressure resistance tests indicated no relevant pressure changes between respirators that were used once, twice or thrice. This small single-centre study shows that selected FFP-2 respirators may be reprocessed for use in primary care, as the tested masks retain their shape, ability to retain particles and breathing comfort after decontamination using a medical autoclave.


Vascular function and atherosclerosis progression after 1 y of flavonoid intake in statin-treated postmenopausal women with type 2 diabetes: a double-blind randomized controlled trial.
In healthy participants, short-term flavan-3-ol and isoflavone intakes improve vascular function; however, the potential combined benefit of these compounds on atherosclerosis progression remains unclear for those at elevated risk of cardiovascular disease. The objective was to examine whether combined isoflavone and flavan-3-ol intake alters vascular function in postmenopausal women with type 2 diabetes mellitus (T2DM). A double-blind, parallel-design, placebo-controlled 1-y trial was conducted in postmenopausal T2DM patients randomly assigned to a split dose of 27 g flavonoid-enriched chocolate/d [850 mg flavan-3-ols (90 mg epicatechin) + 100 mg isoflavones (aglycone equivalents)/d] or matched placebo. Intima-media thickness of the common carotid artery (CCA-IMT), pulse wave velocity (PWV), augmentation index, blood pressure (BP), and vascular biomarkers were assessed. A total of 93 patients completed the trial. Overall, the flavonoid intervention did not significantly change CCA-IMT, augmentation index, or BP, but pulse pressure variability improved (flavonoid: -0.11 ± 0.07 mm Hg/min; placebo: 0.10 ± 0.11 mm Hg/min; P = 0.04). In a subgroup with PWV data, net improvements were observed [flavonoid (n = 18): -0.07 ± 0.38 m/s; placebo (n = 17): 0.68 ± 0.25 m/s; P = 0.01], which equated to a 10% CV risk reduction. Equol producers (n = 17) had larger reductions in diastolic BP, mean arterial pressure, and PWV (-2.24 ± 1.31 mm Hg, -1.24 ± 1.30 mm Hg, and -0.68 ± 0.40 m/s, respectively; P < 0.01) compared with non-equol producers (n = 30). Although the 1-y intervention did not change CCA-IMT or BP, clinically relevant improvements in arterial stiffness were observed; equol producers were particularly responsive. Flavonoids may augment existing therapeutic strategies to reduce cardiovascular disease risk in postmenopausal T2DM patients, and longer studies are needed to examine the effects on atherosclerosis progression. This trial was registered at clinicaltrials.gov as NCT00677599.


The effectiveness of blood tests in detecting secondary osteoporosis or mimicking conditions in postmenopausal women.
The National Service Framework for Older People requires a reduction in the number of falls that result in serious injury. Those most at risk need to be identified, investigated in line with the Royal College of Physicians Clinical Guidelines and receive appropriate treatment. This report looks at the results of investigation of postmenopausal women diagnosed as having osteoporosis in primary care by forearm Dexa scanner (DTX200) and questions whether the investigations suggested within the National Service Framework are justifiable. Scans were performed on 699 postmenopausal women aged 54 or over resulting in a new diagnosis of osteoporosis in 173 women. Complete blood tests were performed in 107 of the newly diagnosed patients. Only three of these patients (2.8%) had blood test results that revealed a potential secondary cause. The rates of positive findings are low; further research is needed to see if they are justified in postmenopausal women.


Differential effects of dietary fatty acids on the regulation of CYP2E1 and protein kinase C in human hepatoma HepG2 cells.
We investigated the effects of different fatty acids (FAs) or with different degrees of unsaturation on cytochrome P450 2E1 (CYP2E1) induction and protein kinase C (PKC) activity in human hepatoma HepG2 cells. As the degree of unsaturation increased, the cell survival rate decreased for FAs with 18 carbons, but linolenic acid (LNA) or docosahexaenoic acid (DHA) groups were similar even through they have different degrees of unsaturation. Treatment with palmitic acid (PA), oleic acid (OA), linoleic acid (LA), LNA, and DHA resulted in respective cellular FA concentrations of C16:0 (43.1%), C18:1 (18.5%), C18:2 (7.4%), LNA (2.85%), and C22:6 (3.13%), which was highest for the FA that was used as the treatment, indicating that their incorporation within the cell is directly proportional to treatment. After 2 hours of cultivation, the lipid peroxide (LPO) in the DHA group increased 600% compared with control, and was much higher than in the groups treated with the other FAs, with LNA > LA > OA > PA. CYP2E1 induction increased with greater effect as the degree of unsaturation of OA, LA, and DHA increased. PA did not affect PKC activity, but DHA treatment increased PKC activity the most. The effects of LNA and LA were similar, but less than that of DHA, and that of OA was lower still, indicating that activity of PKC is proportional to the degree of unsaturation, and not the configuration of the FA. Increased plasma membrane concentrations of n-3 FA, such as DHA, might exert regulatory effects on PKC by increasing membrane fluidity, causing changes in CYP2E1, elevating levels of LPO, or producing oxidative stress.


Receptor tyrosine kinase signaling: a view from quantitative proteomics.
Growth factor receptor signaling via receptor tyrosine kinases (RTKs) is one of the basic cellular communication principals found in all metazoans. Extracellular signals are transferred via membrane spanning receptors into the cytoplasm, reversible tyrosine phosphorylation being the hallmark of all RTKs. In recent years proteomic approaches have yielded detailed descriptions of cellular signaling events. Quantitative proteomics is able to characterize the exact position and strength of post-translational modifications (PTMs) providing essential information for understanding the molecular basis of signal transduction. Numerous new post-translational modification sites have been identified by quantitative mass spectrometry-based proteomics. In addition, plentiful new players in signal transduction have been identified underlining the complexity and the modular architecture of most signaling networks. In this review, we outline the principles of signal transduction via RTKs and highlight some of the new insights obtained from proteomic approaches such as protein microarrays and quantitative mass spectrometry.


XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.
X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis. Here, we describe a role for XIAP in copper metabolism. We find that XIAP levels are greatly reduced by intracellular copper accumulation in Wilson's disease and other copper toxicosis disorders and in cells cultured under high copper conditions. Elevated copper levels result in a profound, reversible conformational change in XIAP due to the direct binding of copper to XIAP, which accelerates its degradation and significantly decreases its ability to inhibit caspase-3. This results in a lowering of the apoptotic threshold, sensitizing the cell to apoptosis. These data provide an unsuspected link between copper homeostasis and the regulation of cell death through XIAP and may contribute to the pathophysiology of copper toxicosis disorders.


Mitochondrial tRNA mutations and disease.
Mitochondrial (mt-) tRNA (MTT) gene mutations are an important cause of human morbidity and are associated with a wide range of pathology, from isolated organ-specific diseases such as myopathy or hearing loss, through to multisystem disorders with encephalopathy, gastrointestinal dysmotility, and life-threatening cardiomyopathy. Our understanding of how MTT mutations cause disease remains poor and progress has been hampered by the complex interaction of genotype with phenotype that can result in patients who harbor the same mutation exhibiting starkly contrasting phenotypes, whereas other (genetically heterogeneous) patients manifest clinically identical syndromes. A further complexity is the highly polymorphic nature of mitochondrial DNA (mtDNA), which must temper any reflex assumptions of pathogenicity for novel MTT substitutions. Nevertheless significant progress is being made and we shall review the methods employed to identify and characterize MTT mutations as pathogenic. Also important is our understanding of the molecular processes involved and we shall discuss the data available on two of the most studied MTT mutations (m.8344A > G and m.3243A > G) as well as other potential pathogenic mechanisms. Knowledge of factors influencing the inheritance of MTT mutations, and therefore the likelihood of disease transmission, is of particular importance to female patients. At present, the factors determining transmission remain elusive, but we shall examine several possible mechanisms and discuss the evidence for each. Finally, a number of different yeast and mouse models are currently used to investigate mitochondrial disease and we will assess the importance of and difficulties associated with each model as well as the future of possible therapies for patients with mitochondrial disease.


Immunohistochemical description of nitric oxide synthase isoforms in human clitoris.
Our aim was to identify and localize nitric oxide synthase isoforms in the human clitoris in support of the hypothesis that nitric oxide mediates erectile function in this organ. Nitric oxide synthase immunohistochemistry studies specific for neuronal, inducible and endothelial isoforms of the enzyme were performed on human clitoral tissue obtained from 4 patients (3 with female pseudohermaphroditism and 1 with true hermaphroditism) at feminizing genitoplasty and from 1 phenotypically normal woman at autopsy. Neuronal nitric oxide synthase immunoreactivity was detected in nerve bundles and fibers coursing within the glans clitoris and corpora cavernosa of the clitoris, predominating in the latter tissue. Specific inducible nitric oxide synthase immunoreactivity was not identified. Endothelial nitric oxide synthase immunoreactivity was detected in vascular and sinusoidal endothelium of these tissues with a predominance in the glans clitoris. The presence and anatomical localizations of nitric oxide synthase isoforms in the human clitoris indicate that nitric oxide is generated in this organ. These data suggest that nitric oxide may be involved in the erectile physiology of the clitoris as a modulator of clitoral smooth muscle activity. Functional studies are required to support this hypothesis.


A comparison of nicotine and cocaine self-administration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion.
Beagle dogs pressed a lever under a 15-response fixed-ratio schedule of i.v. nicotine or cocaine infusion or water presentation. A 4-min time-out period followed each fixed-ratio trial and each daily session ended after 16 successive fixed-ratio trials. Both nicotine and cocaine were self-administered above saline levels, with the maximum number of infusions occurring at a dose of 30 micrograms/kg of nicotine and 100 micrograms/kg of cocaine. Rates of responding first increased, reaching a maximum at 10 to 30 micrograms/kg/infusion and then decreased, as the dose of nicotine or cocaine was varied between 3 and 300 micrograms/kg/infusion. The rate of responding and number of infusions obtained per session were higher under the schedule of cocaine self-administration than under the schedule of nicotine self-administration. Presession treatment with the nicotinic antagonist, mecamylamine (1.0 mg/kg i.v.), for seven consecutive sessions, decreased nicotine-maintained responding to levels not unlike those seen when saline was substituted for drug. Neither cocaine- nor water-maintained responding was affected by presession treatment with mecamylamine. A second group of beagle dogs pressed a lever under a schedule of i.v. nicotine (50-400 micrograms/kg/infusion) or cocaine (200-1600 micrograms/kg/infusion) infusion in which the fixed-ratio requirement was increased daily (i.e., a progressive-ratio schedule). The maximum fixed-ratio value at which responding was maintained first increased as the dose per infusion increased and then, at the highest dose, either remained the same or decreased. Cocaine maintained considerably higher fixed-ratio values than did nicotine, but maximum fixed-ratio values for nicotine were well above those seen with saline. The effects of i.v. nicotine (3, 30 or 300 micrograms/kg) or mecamylamine (1.0 mg/kg) on heart rate, rectal temperature and pupillary diameter were measured in a third group of beagle dogs. Nicotine produced dose- and time-related changes in all three physiological parameters; the effects of mecamylamine were considerably greater than those seen with nicotine.


Turbomachinery computational fluid dynamics: asymptotes and paradigm shifts.
This paper reviews the development of computational fluid dynamics (CFD) specifically for turbomachinery simulations and with a particular focus on application to problems with complex geometry. The review is structured by considering this development as a series of paradigm shifts, followed by asymptotes. The original S1-S2 blade-blade-throughflow model is briefly described, followed by the development of two-dimensional then three-dimensional blade-blade analysis. This in turn evolved from inviscid to viscous analysis and then from steady to unsteady flow simulations. This development trajectory led over a surprisingly small number of years to an accepted approach-a 'CFD orthodoxy'. A very important current area of intense interest and activity in turbomachinery simulation is in accounting for real geometry effects, not just in the secondary air and turbine cooling systems but also associated with the primary path. The requirements here are threefold: capturing and representing these geometries in a computer model; making rapid design changes to these complex geometries; and managing the very large associated computational models on PC clusters. Accordingly, the challenges in the application of the current CFD orthodoxy to complex geometries are described in some detail. The main aim of this paper is to argue that the current CFD orthodoxy is on a new asymptote and is not in fact suited for application to complex geometries and that a paradigm shift must be sought. In particular, the new paradigm must be geometry centric and inherently parallel without serial bottlenecks. The main contribution of this paper is to describe such a potential paradigm shift, inspired by the animation industry, based on a fundamental shift in perspective from explicit to implicit geometry and then illustrate this with a number of applications to turbomachinery.


Perception and action in 'visual form agnosia'.
A single case study of a patient with 'visual form agnosia' is presented. A severe visual recognition deficit was accompanied by impairments in discriminating shape, reflectance, and orientation, although visual acuity and colour vision, along with tactile recognition and intelligence, were largely preserved. Neuropsychological and behavioural investigations have indicated that the patient is able to utilize visual pattern information surprisingly well for the control of hand movements during reaching, and can even read many whole words, despite being unable to make simple discriminative judgements of shape or orientation. She seems to have no awareness of shape primitives through Gestalt grouping by similarity, continuity or symmetry. It is proposed that many of these perceptual disorders might be the combined result of (1) a selective loss of the cortical elaboration of the magnocellular visual processing stream, and (2) a selective output disconnection from a central processor of visual boundaries and shape primitives in the occipital cortex.


Primate vaginal microbiomes exhibit species specificity without universal Lactobacillus dominance.
Bacterial communities colonizing the reproductive tracts of primates (including humans) impact the health, survival and fitness of the host, and thereby the evolution of the host species. Despite their importance, we currently have a poor understanding of primate microbiomes. The composition and structure of microbial communities vary considerably depending on the host and environmental factors. We conducted comparative analyses of the primate vaginal microbiome using pyrosequencing of the 16S rRNA genes of a phylogenetically broad range of primates to test for factors affecting the diversity of primate vaginal ecosystems. The nine primate species included: humans (Homo sapiens), yellow baboons (Papio cynocephalus), olive baboons (Papio anubis), lemurs (Propithecus diadema), howler monkeys (Alouatta pigra), red colobus (Piliocolobus rufomitratus), vervets (Chlorocebus aethiops), mangabeys (Cercocebus atys) and chimpanzees (Pan troglodytes). Our results indicated that all primates exhibited host-specific vaginal microbiota and that humans were distinct from other primates in both microbiome composition and diversity. In contrast to the gut microbiome, the vaginal microbiome showed limited congruence with host phylogeny, and neither captivity nor diet elicited substantial effects on the vaginal microbiomes of primates. Permutational multivariate analysis of variance and Wilcoxon tests revealed correlations among vaginal microbiota and host species-specific socioecological factors, particularly related to sexuality, including: female promiscuity, baculum length, gestation time, mating group size and neonatal birth weight. The proportion of unclassified taxa observed in nonhuman primate samples increased with phylogenetic distance from humans, indicative of the existence of previously unrecognized microbial taxa. These findings contribute to our understanding of host-microbe variation and coevolution, microbial biogeography, and disease risk, and have important implications for the use of animal models in studies of human sexual and reproductive diseases.


Radioisotope dating with a cyclotron.
By considering radioisotope dating as a problem in trace element detection, and by using the cyclotron as a high-energy mass spectrometer for this purpose, we have shown that one can greatly increase the maximum age that can be determined while simultaneously reducing the size of the sample required. The cyclotron can be used to detect atoms or simple molecules that are present at the 10(-16) level or greater. For (14)C dating one should be able to go back 40,000 to 100,000 years with 1- to 100-mg carbon samples; for (10)Be dating, 10 to 30 million years with 1-mm(3) to 10-cm(3) rock samples; for tritium dating, 160 years with a 1-liter water sample. The feasibility of the technique has been demonstrated experimentally by measuring the tritium/deuterium ratio in a sample 24 years old. For samples many half-lives old, the fractional error in the age is small even if rates of production or deposition of the isotopes. Although cyclotrons are expensive to build, their operating costs are relatively low. If several samples are dated per hour the cost per date may not be substantially higher than it is today for decay dating. There are already more than 50 cyclotrons in operation which have the potential to do radioisotope dating, and their application to important problems of dating and trace element analysis should prove very fruitful.


Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion.
Tumor progression to invasive carcinoma is associated with activation of SRC family kinase (SRC, YES, FYN) activity and loss of cellular cohesion. The hippo pathway-regulated cofactor YAP1 supports the tumorigenicity of RAS mutations but requires both inactivation of hippo signaling and YES-mediated phosphorylation of YAP1 for oncogenic activity. Exactly how SRC kinases are activated and hippo signaling is lost in sporadic human malignancies remains unknown. Here, we provide evidence that hippo-mediated inhibition of YAP1 is lost upon promoter methylation of the RAS effector and hippo kinase scaffold RASSF1A. We find that RASSF1A promoter methylation reduces YAP phospho-S127, which derepresses YAP1, and actively supports YAP1 activation by switching RASSF1 transcription to the independently transcribed RASSF1C isoform that promotes Tyr kinase activity. Using affinity proteomics, proximity ligation, and real-time molecular visualization, we find that RASSF1C targets SRC/YES to epithelial cell-cell junctions and promotes tyrosine phosphorylation of E-cadherin, β-catenin, and YAP1. RASSF1A restricts SRC activity, preventing motility, invasion, and tumorigenesis in vitro and in vivo, with epigenetic inactivation correlating with increased inhibitory pY527-SRC in breast tumors. These data imply that distinct RASSF1 isoforms have opposing functions, which provide a biomarker for YAP1 activation and explain correlations of RASSF1 methylation with advanced invasive disease in humans. The ablation of epithelial integrity together with subsequent YAP1 nuclear localization allows transcriptional activation of β-catenin/TBX-YAP/TEAD target genes, including Myc, and an invasive phenotype. These findings define gene transcript switching as a tumor suppressor mechanism under epigenetic control.


Optical security and encryption with totally incoherent light.
We present a method for securing and encrypting information optically by use of totally incoherent illumination. Encryption is performed with a multichannel optical processor working under natural (both temporal and spatially incoherent) light. In this way, the information that is to be secured can be codified by use of color signals and self-luminous displays. The encryption key is a phase-only mask, providing high security from counterfeiting. Output encrypted information is recorded as an intensity image that can be easily stored and transmitted optically or electrically. Decryption or authentication can also be performed optically or digitally. Experimental results are presented.


[Integrative neuroimaging for schizophrenia targeting early intervention and prevention (IN-STEP)].
The editorial of the new-year issue of Nature 2010 features "A decade for psychiatric disorders". The DALY estimation clearly shows that psychiatric disorders are the top source for burden of diseases to the individual life and society. Schizophrenia is a most devastating psychiatric disorder in which the onset is usually at youth and the cognitive dysfunction persists for life-long in some patients. Schizophrenia is associated with neurodevelopmental abnormalities. It has been unknown whether post-onset progressive pathology is also present in schizophrenia until the recent sophistication of in vivo neuroimaging techniques. Longitudinal neuroimaging studies on first-episode schizophrenia have shown a progressive deterioration of structure and function of neocortical regions in the early stage of the disorder. Insult to dendritic spines through glutamatergic dysfunction may underlie this process, which may in turn be a promising molecular target for intervention to improve the functional outcome of schizophrenia. More recently, the question of whether early intervention can be targeted at prodromal stage of schizophrenia has called special attention in psychiatry. In University of Tokyo, the integrative neuroimaging studies for schizophrenia targeting early intervention and prevention (IN-STEP) is ongoing. Through these efforts, we would like to contribute to the establishment of "youth mental health", where every youth in the community can know, prevent, and have easy access to needs- and value-based services, and pursue mental well-being and recovery.


Mapping the Long-Range Electron Transfer Route in Ligninolytic Peroxidases.
Combining a computational analysis with site-directed mutagenesis, we have studied the long-range electron transfer pathway in versatile and lignin peroxidases, two enzymes of biotechnological interest that play a key role for fungal degradation of the bulky lignin molecule in plant biomass. The in silico study established two possible electron transfer routes starting at the surface tryptophan residue previously identified as responsible for oxidation of the bulky lignin polymer. Moreover, in both enzymes, a second buried tryptophan residue appears as a top electron transfer carrier, indicating the prevalence of one pathway. Site-directed mutagenesis of versatile peroxidase (from Pleurotus eryngii) allowed us to corroborate the computational analysis and the role played by the buried tryptophan (Trp244) and a neighbor phenylalanine residue (Phe198), together with the surface tryptophan, in the electron transfer. These three aromatic residues are highly conserved in all the sequences analyzed (up to a total of 169). The importance of the surface (Trp171) and buried (Trp251) tryptophan residues in lignin peroxidase has been also confirmed by directed mutagenesis of the Phanerochaete chrysosporium enzyme. Overall, the combined procedure identifies analogous electron transfer pathways in the long-range oxidation mechanism for both ligninolytic peroxidases, constituting a good example of how computational analysis avoids making extensive trial-error mutagenic experiments.


Lean body weight scalar for the anesthetic induction dose of propofol in morbidly obese subjects.
The unique anesthetic risks associated with the morbidly obese (MO) population have been documented. Pharmacologic management of these patients may be altered because of the physiologic and anthropometric changes associated with obesity. Unfortunately, studies examining the effects of extreme obesity on the pharmacology of anesthetics have been sparse. Although propofol is the induction drug most frequently used in these patients, the appropriate induction dosing scalar for propofol remains controversial in MO subjects. Therefore, we compared different weight-based scalars for dosing propofol for anesthetic induction in MO subjects. Sixty MO subjects (body mass index ≥40 kg/m(2)) were randomized to receive a propofol infusion (100 mg · kg(-1) · h(-1)) for induction of anesthesia based on total body weight (TBW) or lean body weight (LBW). Thirty control subjects (body mass index ≤25 kg/m(2)) received a propofol infusion (100 mg · kg(-1) · h(-1)) based on TBW. Syringe drop was used as the marker for loss of consciousness (LOC), at which point the propofol infusion was stopped. The propofol dose required for syringe drop and time to LOC were recorded. Total propofol dose (mg/kg) required for syringe drop and time to LOC were similar between control subjects and MO subjects given propofol based on LBW. MO subjects receiving a propofol infusion based on TBW had a significantly larger propofol dose and significantly shorter time to LOC. There was a strong relationship between LBW and total propofol dose received in all 3 groups. LBW is a more appropriate weight-based scalar for propofol infusion for induction of general anesthesia in MO subjects.


Poor pregnancy outcome after octreotide treatment during pregnancy for familial hyperinsulinemic hypoglycemia: a case report.
Late familial hyperinsulinemic hypoglycemia is characterized by recurrent episodes of hypoglycemia and an inappropriate insulinemic response. Treatment with octreotide (somatostatin analogue) reduces the prevalence of clinical significant hypoglycemia and might be beneficial during pregnancy. To our knowledge this is the first report of a woman with late familial hyperinsulinemic hypoglycemia experiencing pregnancies with and without octreotide treatment. A 35-year-old Caucasian woman known to suffer from late familial hyperinsulinemic hypoglycemia due to a well-known mutation in the insulin receptor gene has been pregnant 6 times. The patient was treated with injections of Sandostatin LAR® (octreotide) during the first four pregnancies. Her first pregnancy in 1999 was unknown until approximately 25th gestational weeks with fatal intrauterine growth retardation. The following two pregnancies were terminated on parental request after a chorion villus biopsy revealed the mutation causing late familial hyperinsulinemic hypoglycemia. During the fourth pregnancy, in which the fetus also had the mutation, serial ultrasound examinations showed a small fetus with appropriate growth. At birth the girl was small for gestational age. She was admitted to the neonatal special care unit due to low blood glucose and intravenous glucose and early feeding was initiated. One day old, her condition deteriorated with signs of an abdominal catastrophe indicating necrotizing enterocolitis. After two laparotomies - both confirming necrotizing enterocolitis - the child died 8 days after birth.In the following two pregnancies Sandostatin LAR® was stopped before pregnancy and the patient was treated only with diet restriction and intensive glucose monitoring. Both pregnancies ended successfully. One child carried the mutation and was small for gestational age at birth while the other child did not carry the mutation and had normal birth weight. In a woman with late familial hyperinsulinemic hypoglycemia octreotide was given during the first four pregnancies resulting in 2 cases of early termination of pregnancy on parental request and 2 cases of inappropriate fetal growth and unviable outcome. The following two pregnancies treated with diet only had a successful outcome.


Fluid management of shock in severe malnutrition: what is the evidence for current guidelines and what lessons have been learned from clinical studies and trials in other pediatric populations?
Management of shock in children with severe malnutrition remains controversial. To date, the evidence supporting either benefit or harm of fluid resuscitation or rehydration is weak. This issue, however, is not unique to children with severe malnutrition; pediatric guidelines worldwide have a weak level of evidence and remain unsupported by appropriate clinical studies. In this review we give an overview of the current recommendations in other pediatric populations and appraise the strength of evidence supporting these. We summarize results from the only controlled trial ever undertaken, FEAST (Fluid Expansion As Supportive Therapy), which was conducted in resource-poor hospitals involving 3,141 African children with severe febrile illnesses and shock, including large subgroups with sepsis and malaria but excluding children with severe malnutrition. This high-quality trial provided robust evidence that fluid resuscitation increased the risk of death, leading to an excess mortality of 3 in every 100 children receiving fluid boluses, compared with controls receiving no boluses. These findings may have particular relevance to management of septic shock in children with severe malnutrition. However, they cannot be extrapolated to children with gastroenteritis, since this condition was not included in the trial. Current observational studies under way in East Africa may provide insights into myocardial and hemodynamic function in severe malnutrition, including responses to fluid challenge in those complicated by gastroenteritis. Such studies are an essential step for setting the research agenda regarding fluid management of shock in severe malnutrition.


Protective effect of fruits, vegetables and the Mediterranean diet on asthma and allergies among children in Crete.
Atopy is not uncommon among children living in rural Crete, but wheeze and rhinitis are rare. A study was undertaken to examine whether this discrepancy could be attributed to a high consumption of fresh fruit and vegetables or adherence to a traditional Mediterranean diet. A cross-sectional survey was performed in 690 children aged 7-18 years in rural Crete. Parents completed a questionnaire on their child's respiratory and allergic symptoms and a 58-item food frequency questionnaire. Adherence to a Mediterranean diet was measured using a scale with 12 dietary items. Children underwent skin prick tests with 10 common aeroallergens. 80% of children ate fresh fruit (and 68% vegetables) at least twice a day. The intake of grapes, oranges, apples, and fresh tomatoes-the main local products in Crete-had no association with atopy but was protective for wheezing and rhinitis. A high consumption of nuts was found to be inversely associated with wheezing (OR 0.46; 95% CI 0.20 to 0.98), whereas margarine increased the risk of both wheeze (OR 2.19; 95% CI 1.01 to 4.82) and allergic rhinitis (OR 2.10; 95% CI 1.31 to 3.37). A high level of adherence to the Mediterranean diet was protective for allergic rhinitis (OR 0.34; 95% CI 0.18 to 0.64) while a more modest protection was observed for wheezing and atopy. The results of this study suggest a beneficial effect of commonly consumed fruits, vegetables and nuts, and of a high adherence to a traditional Mediterranean diet during childhood on symptoms of asthma and rhinitis. Diet may explain the relative lack of allergic symptoms in this population.


Male sterility, protogyny, and pollen-pistil interference in Plantago maritima (Plantaginaceae), a wind-pollinated, self-incompatible perennial.
Evolution and maintenance of male sterility in seed plants can be explained by the maternal inheritance of mitochondria, which encode the trait, and by adaptive functions that enhance female fecundity in male-sterile compared to hermaphrodite individuals. Protogyny and male sterility can independently decrease the negative effect of pollen-pistil interference in self-incompatible species. In Plantago maritima, which possesses both traits, protogyny increases seed set in hermaphrodite individuals. This is shown both by a significantly positive association between seed set and retarded dehiscence of the anthers and by a more than 50% reduction in seed set following self-pollination. Male sterility does not seem to increase seed set further, as female and hermaphrodite plants do not differ significantly in mean seed set per capsule. Bagging experiments demonstrate strong self-incompatibility in the study populations. Hence, in P. maritima male sterility seems neither to prevent selfing nor to reduce the effect of pollen-pistil interference. Females had significantly larger stigmas than hermaphrodites, but seed set varied negatively with stigma length among females, indicating that the evolution of unisexuality in P. maritima is not due to prefertilization sex allocation. I therefore conclude that the genetical system of nucleocytoplasmic determination of gender is the main cause for maintenance of male sterility in P. maritima.


The role of nitric oxide in the local antiallodynic and antihyperalgesic effects and expression of delta-opioid and cannabinoid-2 receptors during neuropathic pain in mice.
Both delta-opioid receptor (DOPr) and cannabinoid-2 receptor (CB2R) agonists attenuate neuropathic pain, but the precise mechanism implicated in these effects is not completely elucidated. We investigated whether nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric-oxide synthases could modulate DOPr and/or CB2R antiallodynic and antihyperalgesic effects through the peripheral nitric oxide-cGMP-protein kinase G (PKG) pathway activation and affect their expression during neuropathic pain. In wild-type (WT) mice at 21 days after chronic constriction of sciatic nerve, we evaluated the effects of [d-Pen(2),d-Pen(5)]-enkephalin (DPDPE); (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH-015); and a NOS1 [N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N'-nitroguanidine tris(trifluoroacetate) salt; NANT], NOS2 [l-N(6)-(1-iminoethyl)-lysine; l-NIL], l-guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ], or PKG [(Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs] inhibitor administered alone or combined. Expression of DOPr and CB2R mRNA in the spinal cord and dorsal root ganglia of naive and nerve-injured WT, NOS1-knockout (KO), and NOS2-KO mice, also was assessed. The subplantar administration of NANT, l-NIL, ODQ, or Rp-8-pCPT-cGMPs dose-dependently inhibited neuropathic pain and enhanced the local effects of DPDPE or JWH-015. Moreover, although the basal levels of DOPr and CB2R mRNA were similar between WT and NOS-KO animals, nerve injury only decreased (DOPr) or increased (CB2R) their expression in the dorsal root ganglia of WT and NOS2-KO mice, and not in NOS1-KO mice. Results suggest that inactivation of the nitric oxide-cGMP-PKG peripheral pathway triggered by NOS1 and NOS2 enhanced the peripheral actions of DOPr and CB2R agonists and that nitric oxide synthesized by NOS1 is implicated in the peripheral regulation of DOPr and CB2R gene transcription during neuropathic pain.


Serotype 1 and 8 Pneumococci Evade Sensing by Inflammasomes in Human Lung Tissue.
Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S. pneumoniae, which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans.


Recovering 3D human body configurations using shape contexts.
The problem we consider in this paper is to take a single two-dimensional image containing a human figure, locate the joint positions, and use these to estimate the body configuration and pose in three-dimensional space. The basic approach is to store a number of exemplar 2D views of the human body in a variety of different configurations and viewpoints with respect to the camera. On each of these stored views, the locations of the body joints (left elbow, right knee, etc.) are manually marked and labeled for future use. The input image is then matched to each stored view, using the technique of shape context matching in conjunction with a kinematic chain-based deformation model. Assuming that there is a stored view sufficiently similar in configuration and pose, the correspondence process will succeed. The locations of the body joints are then transferred from the exemplar view to the test shape. Given the 2D joint locations, the 3D body configuration and pose are then estimated using an existing algorithm. We can apply this technique to video by treating each frame independently--tracking just becomes repeated recognition. We present results on a variety of data sets.


The Effect of Electrode Topography on the Magnetic Properties and MRI Application of Electrochemically-Deposited, Synthesized, Cobalt-Substituted Hydroxyapatite.
Magnetic nanoparticles are used to enhance the image contrast of magnetic resonance imaging (MRI). However, the development of magnetic nanoparticles with a low dose/high image contrast and non-toxicity is currently a major challenge. In this study, cobalt-substituted hydroxyapatite nanoparticles deposited on titanium (Ti-CoHA) and cobalt-substituted hydroxyapatite nanoparticles deposited on titanium dioxide nanotubes (TNT-CoHA) were synthesized by the electrochemical deposition method. The particle sizes of Ti-CoHA and TNT-CoHA were 418.6 nm and 127.5 nm, respectively, as observed using FE-SEM. It was shown that CoHA can be obtained with a smaller particle size using a titanium dioxide nanotube (TNT) electrode plate. However, the particle size of TNT-CoHA is smaller than that of Ti-CoHA. The crystal size of the internal cobalt oxide of CoHA was calculated by using an XRD pattern. The results indicate that the crystal size of cobalt oxide in TNT-CoHA is larger than that of the cobalt oxide in Ti-CoHA. The larger crystal size of the cobalt oxide in TNT-CoHA makes the saturation magnetization (Ms) of TNT-CoHA 12.6 times higher than that of Ti-CoHA. The contrast in MRIs is related to the magnetic properties of the particles. Therefore, TNT-CoHA has good image contrast at low concentrations in T₂ images. The relaxivity coefficient of the CoHA was higher for TNT-CoHA (340.3 mM-1s-1) than Ti-CoHA (211.7 mM-1s-1), and both were higher than the commercial iron nanoparticles (103.0 mM-1s-1). We showed that the TNT substrate caused an increase in the size of the cobalt oxide crystal of TNT-CoHA, thus effectively improving the magnetic field strength and MRI image recognition. It was also shown that the relaxivity coefficient rose with the Ms. Evaluation of biocompatibility of CoHA using human osteosarcoma cells (MG63) indicated no toxic effects. On the other hand, CoHA had an excellent antibacterial effect, as shown by E. coli evaluation, and the effect of TNT-CoHA powder was higher than that of Ti-CoHA powder. In summary, TNT-CoHA deposited electrochemically on the TNT substrates can be considered as a potential candidate for the application as an MRI contrast agent. This paper is a comparative study of how different electrode plates affect the magnetic and MRI image contrast of cobalt-substituted hydroxyapatite (CoHA) nanomaterials.


Initiating Exercise Interventions to Promote Wellness in Cancer Patients and Survivors.
Exercise is associated with significant reductions in the recurrence and mortality rates of several common cancers. Cancer survivors who exercise can potentially benefit from reduced levels of fatigue, and improved quality of life, physical function, and body composition (ie, healthier ratios of lean body mass to fat mass). The amount of activity required to achieve protective effects is moderate (eg, walking 30 minutes per day at 2.5 miles per hour). However, many healthcare providers report a lack of awareness of the appropriate exercise recommendations across the phases of cancer survivorship, considerations regarding the timing of exercise interventions, and the ability to refer patients to exercise programs specifically aimed at cancer survivors. The American College of Sports Medicine notes that exercise is generally safe for most cancer survivors, and inactivity should be avoided. Their guidelines for exercise call for 150 minutes of moderate or 75 minutes of vigorous aerobic activity per week, and 2 days per week of resistance training (eg, with exercise bands or light weights). Survivors with lymphedema, peripheral neuropathy, breast reconstruction, central lines, and ostomies should follow specific precautions. Providing health professionals with the training and tools needed to provide adequate recommendations to their patients is essential to improving patient outcomes. To facilitate adherence among communities with the greatest need and poor access to services, cultural and environmental adaptations are critical.


HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that Tax(HTLV-1) interferes with ß-selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type 1 (HTLV-1) infection has the potential to perturb thymic human αβ T-cell development. To verify that inference and to clarify the impact of HTLV-1 infection on human T-cell development, we investigated the in vivo effects of HTLV-1 infection in a "Human Immune System" (HIS) Rag2⁻/⁻γ(c)⁻/⁻ mouse model. These mice were infected with HTLV-1, at a time when the three main subpopulations of human thymocytes have been detected. In all but two inoculated mice, the HTLV-1 provirus was found integrated in thymocytes; the proviral load increased with the length of the infection period. In the HTLV-1-infected mice we observed alterations in human T-cell development, the extent of which correlated with the proviral load. Thus, in the thymus of HTLV-1-infected HIS Rag2⁻/⁻γc⁻/⁻ mice, mature single-positive (SP) CD4⁺ and CD8⁺ cells were most numerous, at the expense of immature and double-positive (DP) thymocytes. These SP cells also accumulated in the spleen. Human lymphocytes from thymus and spleen were activated, as shown by the expression of CD25: this activation was correlated with the presence of tax mRNA and with increased expression of NF-kB dependent genes such as bfl-1, an anti-apoptotic gene, in thymocytes. Finally, hepato-splenomegaly, lymphadenopathy and lymphoma/thymoma, in which Tax was detected, were observed in HTLV-1-infected mice, several months after HTLV-1 infection. These results demonstrate the potential of the HIS Rag2⁻/⁻γ(c)⁻/⁻ animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.


Reverse Takotsubo Cardiomyopathy in a Patient With Commotio Cordis.
Takotsubo cardiomyopathy (TCM), also known as stress cardiomyopathy or "broken heart syndrome", is characterized by acute transient regional left ventricular systolic dysfunction in the absence of obstructive coronary artery disease or acute plaque rupture. Atypical forms and rare anatomical variants can have different presentations; hence, recognition becomes more important. Prognosis is much more favorable if managed appropriately. An equally infrequent cause of cardiac arrest is commotio cordis (CC). This is defined as sudden cardiac death secondary to a blunt chest wall impact leading to ventricular arrhythmias. We report a case with findings of TCM and/or CC in a patient with a blunt chest trauma in the setting of motor vehicle accident.


Sexual function and erection capability among young men with spina bifida.
In a study of sexual function and erection capability, 15 young men with spina bifida were interviewed, underwent physical examination, and completed two consecutive night recordings of penile tumescence and rigidity with the Rigi-Scan (Dacomed Inc.). Eleven reported erections with stimulation. Rigi-Scan data showed that two subjects (both with lesions at the sacral level) had normal numbers and durations of erections, that seven others had abnormally brief and infrequent nocturnal erections, and that six had none. Ten subjects had at least 'some' glans sensation on physical examination. Self-reported erection capability was related to motor level and glans sensation. The number of nocturnal erections was related to sensory level. The study suggests that lower motor and sensory levels are associated with greater potential sexual function in males with spina bifida.


Negligible electromagnetic interaction between medical electronic equipment and 2.4 GHz band wireless LAN.
Wireless LANs using radio waves have recently gained popularity for installation in hospitals. Because electromagnetic waves transmitted from mobile telephones have been shown to cause interference with medical electronic equipment, prudence would seem necessary when introducing radio wave communication devices into hospitals. Therefore, we tested the effect of wireless LAN communication on medical electronic equipment and the effect of electronic equipment on wireless LAN communication. We observed nine pieces of electronic equipment in the operating mode while transmitting radio waves from a wireless LAN. Even when the access point was put very close to the medical electronic equipment surface and data was transmitted, no malfunction of the equipment was observed. The medical electronic equipment caused little change in the effectiveness of the communication device, although radio waves emitted from electric knives and a remote patient monitor reduced the reception rate to about 60%. The communication speed of the wireless LAN was temporarily reduced only when a microwave oven was located close to and facing the access point. Because output in Japan is limited to a maximum of 10 mW wireless LAN following the IEEE802.11b standard should be able to be installed safely in Japanese hospitals. However, wireless LAN access points should not be installed near microwave ovens.


The Effects of Pay-for-Performance Programs on Health, Health Care Use, and Processes of Care: A Systematic Review.
The benefits of pay-for-performance (P4P) programs are uncertain. To update and expand a prior review examining the effects of P4P programs targeted at the physician, group, managerial, or institutional level on process-of-care and patient outcomes in ambulatory and inpatient settings. PubMed from June 2007 to October 2016; MEDLINE, PsycINFO, CINAHL, Business Economics and Theory, Business Source Elite, Scopus, Faculty of 1000, and Gartner Research from June 2007 to February 2016. Trials and observational studies in ambulatory and inpatient settings reporting process-of-care, health, or utilization outcomes. Two investigators extracted data, assessed study quality, and graded the strength of the evidence. Among 69 studies, 58 were in ambulatory settings, 52 reported process-of-care outcomes, and 38 reported patient outcomes. Low-strength evidence suggested that P4P programs in ambulatory settings may improve process-of-care outcomes over the short term (2 to 3 years), whereas data on longer-term effects were limited. Many of the positive studies were conducted in the United Kingdom, where incentives were larger than in the United States. The largest improvements were seen in areas where baseline performance was poor. There was no consistent effect of P4P on intermediate health outcomes (low-strength evidence) and insufficient evidence to characterize any effect on patient health outcomes. In the hospital setting, there was low-strength evidence that P4P had little or no effect on patient health outcomes and a positive effect on reducing hospital readmissions. Few methodologically rigorous studies; heterogeneous population and program characteristics and incentive targets. Pay-for-performance programs may be associated with improved processes of care in ambulatory settings, but consistently positive associations with improved health outcomes have not been demonstrated in any setting. U.S. Department of Veterans Affairs.


The influence of vegetation height heterogeneity on forest and woodland bird species richness across the United States.
Avian diversity is under increasing pressures. It is thus critical to understand the ecological variables that contribute to large scale spatial distribution of avian species diversity. Traditionally, studies have relied primarily on two-dimensional habitat structure to model broad scale species richness. Vegetation vertical structure is increasingly used at local scales. However, the spatial arrangement of vegetation height has never been taken into consideration. Our goal was to examine the efficacies of three-dimensional forest structure, particularly the spatial heterogeneity of vegetation height in improving avian richness models across forested ecoregions in the U.S. We developed novel habitat metrics to characterize the spatial arrangement of vegetation height using the National Biomass and Carbon Dataset for the year 2000 (NBCD). The height-structured metrics were compared with other habitat metrics for statistical association with richness of three forest breeding bird guilds across Breeding Bird Survey (BBS) routes: a broadly grouped woodland guild, and two forest breeding guilds with preferences for forest edge and for interior forest. Parametric and non-parametric models were built to examine the improvement of predictability. Height-structured metrics had the strongest associations with species richness, yielding improved predictive ability for the woodland guild richness models (r(2) = ∼ 0.53 for the parametric models, 0.63 the non-parametric models) and the forest edge guild models (r(2) = ∼ 0.34 for the parametric models, 0.47 the non-parametric models). All but one of the linear models incorporating height-structured metrics showed significantly higher adjusted-r2 values than their counterparts without additional metrics. The interior forest guild richness showed a consistent low association with height-structured metrics. Our results suggest that height heterogeneity, beyond canopy height alone, supplements habitat characterization and richness models of forest bird species. The metrics and models derived in this study demonstrate practical examples of utilizing three-dimensional vegetation data for improved characterization of spatial patterns in species richness.


Hamilton's rule: A non-causal explanation?
The explanatory power of Hamilton's rule, the main explanatory principle of social evolution theory, is an ongoing subject of controversy. In this paper, we reinforce the case for the considerable value of the regression-based version of the rule in explaining the evolution of social traits. Although we agree that the rule can have an organizing role in social evolution research, we maintain that it does not explain in virtue of citing causes or providing an organizing framework. Instead, we argue it either provides an explanation by constraint or a non-causal counterfactual explanation.


Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial.
Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).


Standardization of techniques for using planar (2D) imaging for aerosol deposition assessment of orally inhaled products.
Two-dimensional (2D or planar) imaging with (99m)Tc radiolabels enables quantification of whole-lung and regional lung depositions for orally inhaled drug products. This article recommends standardized methodology for 2D imaging studies. Simultaneous anterior and posterior imaging with a dual-headed gamma camera is preferred, but imaging with a single-headed gamma camera is also acceptable. Correction of raw data for the effects of gamma ray attenuation is considered essential for accurate quantification, for instance, using transmission scanning with a flood-field source of (99m)Tc or (57)Co. Evidence should be provided of the accuracy of the quantification method, for instance, by determining "mass balance." Lung deposition may be expressed as a percentage of ex-valve or ex-device dose, but should also be given as mass of drug when possible. Assessment of regional lung deposition requires delineation of the lung borders, using X-ray computed tomography, radioactive gas scans ((133)Xe or (81m)Kr), or transmission scans. When quantifying regional lung deposition, the lung should be divided into outer (O) and inner (I) zones. A penetration index should be calculated, as the O/I ratio for aerosol, normalized to that for a radioactive gas or transmission scan. A variety of methods can be used to assess lung deposition and distribution. Methodology and results should be documented in detail, so that data from different centers may be compared. The use of appropriate methodology will provide greater confidence in the results of 2D imaging studies, and should allay concerns that such studies are qualitative or semiquantitative in nature.


Simvastatin Protects Osteoblasts from the Deleterious Effects of the Liquid Milieu of Multiple Myeloma.
Lytic bone lesions are the main clinical manifestation of multiple myeloma. The intense variety in this cell microenvironment, composed mainly of fibroblasts, osteoblasts, osteoclasts, immune cells and mesenchymal cells, is influenced by the massive presence of neoplastic plasma cells. Studies with statins have reported their action in stimulating the formation and reducing bone resorption. The aim of this study was to verify the in vitro response of human osteoblasts exposed to the supernatant (liquid milieu) of multiple myeloma. The data obtained indicate that simvastatin has positive effects on the growth of osteoblasts and protection against the anti-proliferative effects of multiple myeloma supernatant.


Raman spectroscopic mapping for the analysis of solar radiation induced skin damage.
The effects of simulated solar irradiation of an artificial skin model have been examined using Raman spectroscopy and the results are compared with cytotoxicological and histological profiling. Samples exposed for times varying between 30 minutes and 240 minutes were incubated post exposure for a period of 96 hours. The cytotoxicological response as measured by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay demonstrated a ~50% loss of viability of the artificial tissue after 120 minutes exposure. Histological staining of tissue sections showed considerable loss of cellular content in the epidermal layer at this endpoint. Raman spectroscopic mapping of tissue sections, coupled with K-means cluster analysis (KMCA) clearly identified the dermal and stratum corneum layers and differentiated further substructures of the epidermis. Post irradiation, a significant loss of DNA features in the basal layer was apparent in the results of the KMCA. Principal Components Analysis (PCA) of layers identified by the KMCA post exposure compared with controls indicated a significant increase in the lipidic signatures of the stratum corneum. In the dermal layer, little photodamage was observed, but a similar increase in lipidic signatures in the basal layer was accompanied by a decrease in DNA and protein contributions. The spectral profiles of the photodamage to the basal layer as identified by PCA are consistent over the exposure periods of 30-240 minutes, but an examination of the evolution of features associated with specific biochemical components indicated DNA damage and loss of lipidic signatures at the early exposure times, whereas changes in protein signatures appeared to evolve over longer periods. In comparison to the cytotoxicological responses, the study demonstrates that Raman spectroscopy can identify biochemical changes as a result of solar exposure at time points significantly earlier than changes in tissue viability are observed.


Serum eosinophil cationic protein in children with atopic dermatitis.
Eosinophil cationic protein (ECP) is a cytotoxic agent secreted by activated eosinophils during allergic and inflammatory processes. The aim of the study was to determine the ECP level, absolute and relative eosinophil count and IgE antibodies in children with atopic dermatitis (AD) compared with those of nonatopic children, and to assess the correlation of these laboratory parameters with the clinical severity of AD. This prospective study comprised 70 children. There were 49 children with AD aged 3-36 months, and the control group comprised 21 children with a negative personal and family history for atopic diseases. Detailed history, serum ECP levels (UniCAP FEIA), relative and absolute eosinophil counts and total serum IgE antibodies were determined in both groups. In the children with AD, skin involvement was measured by the SCORAD index. The calculated SCORAD index was between 16 and 83. IgE antibodies, relative and absolute eosinophil counts showed a significantly wider range of values and a statistically higher median (P < 0.001) in the patients with AD compared with the control group. These laboratory parameters did not correlate with the severity of AD. The serum ECP median level, in the children with AD, was 16.2 microg/L (range 3.01-65.30) compared with 5.92 microg/L (range 2.76-21.90) in the control group. Correlation of the total SCORAD index and the serum ECP levels was negative, weak (r = -0.065) and statistically not significant (P > 0.05). The same was found for the correlation of serum ECP and intensity of skin changes (r = -0.095) and serum ECP and subjective symptoms (r = -0.045). The correlation was positive, but weak and statistically not significant for the serum ECP and extent of the skin lesions (r = 0.079, P > 0.05). Elevated levels of ECP, relative and absolute eosinophil counts, as well as IgE antibodies were determined in the patients with AD. As these laboratory findings did not correlate with the severity of AD, they can be considered only as additional methods in the evaluation of patients with AD.


Comparison of the N-linked glycans from soluble and GPI-anchored CD59 expressed in CHO cells.
The N-linked glycosylation of recombinant human CD59, expressed in Chinese hamster ovary (CHO) cells with and without a membrane anchor, was compared to examine the effect of the anchor on glycan processing. N-Linked glycans were released with peptide-N-glycosidase F (PNGase F) within gel from SDS-PAGE-isolated soluble and glycosylphosphatidylinositol (GPI)-anchored human CD59 expressed in CHO cells. The anchored form contained core-fucosylated neutral and sialylated bi-, tri-, and tetraantennary glycans with up to four N-acetyllactosamine extensions. Exoglycosidase digestions and analysis by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry were used to define the relative amounts of the bi-, tri-, and tetraantennary glycans and to investigate the distribution of N-acetyllactosamine extensions between their antennae. Biantennary structures accounted for about 60% of the glycans, 30% of the triantennary structures, and about 10% of the tetraantennary structures. For tri- and tetraantennary glycans, those with extended antennae were found to be more abundant than those without extensions. The soluble form of CD59, expressed in CHO cells without the GPI anchor signal sequence, consisted almost entirely (97%) of biantennary glycans, of which 81% were unmodified, 17% contained one N-acetyllactosamine extension, and 2% contained two extensions. No compounds with longer extensions were found. A MALDI spectrum of the intact glycoprotein showed a distribution of glycans that matched those released with PNGase F. In addition, the protein was substituted with several small glycans, such as HexNAc, HexNAc-->Fuc, and HexNAc-->HexNAc, probably as the result of degradation of the mature N-linked glycans. The results show that the presence of the anchor increases the extent of glycan processing, possibly as the result of longer exposure to the glycosyltransferases or to a closer proximity of the protein to these enzymes.


Pathway signature and cellular differentiation in clear cell renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The purpose of this study is to define a biological pathway signature and a cellular differentiation program in ccRCC. We performed gene expression profiling of early-stage ccRCC and patient-matched normal renal tissue using Affymetrix HG-U133a and HG-U133b GeneChips combined with a comprehensive bioinformatic analyses, including pathway analysis. The results were validated by real time PCR and IHC on two independent sample sets. Cellular differentiation experiments were performed on ccRCC cell lines and their matched normal renal epithelial cells, in differentiation media, to determine their mesenchymal differentiation potential. We identified a unique pathway signature with three major biological alterations-loss of normal renal function, down-regulated metabolism, and immune activation-which revealed an adipogenic gene expression signature linked to the hallmark lipid-laden clear cell morphology of ccRCC. Culturing normal renal and ccRCC cells in differentiation media showed that only ccRCC cells were induced to undergo adipogenic and, surprisingly, osteogenic differentiation. A gene expression signature consistent with epithelial mesenchymal transition (EMT) was identified for ccRCC. We revealed significant down-regulation of four developmental transcription factors (GATA3, TFCP2L1, TFAP2B, DMRT2) that are important for normal renal development. ccRCC is characterized by a lack of epithelial differentiation, mesenchymal/adipogenic transdifferentiation, and pluripotent mesenchymal stem cell-like differentiation capacity in vitro. We suggest that down-regulation of developmental transcription factors may mediate the aberrant differentiation in ccRCC. We propose a model in which normal renal epithelial cells undergo dedifferentiation, EMT, and adipogenic transdifferentiation, resulting in ccRCC. Because ccRCC cells grown in adipogenic media regain the characteristic ccRCC phenotype, we have identified a new in vitro ccRCC cell model more resembling ccRCC tumor morphology.


Evidence-based interventional pain medicine according to clinical diagnoses. 18. Painful diabetic polyneuropathy.
In the industrialized world, polyneuropathy induced by diabetes mellitus (DM) is one of the most prevalent forms of neuropathy. Diabetic neuropathy can result from a direct toxic effect of glucose on nerve cells. Additionally, the damage of the nerve structures (central and peripheral) is accompanied by a microvascular dysfunction, which damages the vasa nervorum. More than 80% of the patients with DM-induced polyneuropathy have a distal and symmetric presentation. The initial symptoms are: signs of diminished sensation, burning feet, which may occur particularly during the night and worsen when touched, and tingling sensation in the feet. Attacks of shooting pain may also occur. Proper control of DM is mandatory. Based on the recently published National Institute for Health and Clinical Excellence guidelines, treatment of painful diabetic neuropathy should start with duloxetine or amitriptyline if duloxetine is contraindicated. If pain relief is inadequate, monotherapy with amitriptyline or pregabalin, or combination therapy with amitriptyline and pregabalin should be considered. If pain relief is still insufficient, tramadol instead of or in combination with a second-line agent should be considered. In patients who are unable to take oral medication, topical lidocaine can be considered for localized pain. There are currently four studies showing that spinal cord stimulation can potentially provide pain alleviation for the longer term in patients with painful diabetic polyneuropathy. Complications are mainly implant related, though infections also occur. The available evidence (2 C+) justifies spinal cord stimulation to be considered, preferably study related.


Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines.
These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).


Bar Coding MS(2) Spectra for Metabolite Identification.
Metabolite identifications are most frequently achieved in untargeted metabolomics by matching precursor mass and full, high-resolution MS(2) spectra to metabolite databases and standards. Here we considered an alternative approach for establishing metabolite identifications that does not rely on full, high-resolution MS(2) spectra. First, we select mass-to-charge regions containing the most informative metabolite fragments and designate them as bins. We then translate each metabolite fragmentation pattern into a binary code by assigning 1's to bins containing fragments and 0's to bins without fragments. With 20 bins, this binary-code system is capable of distinguishing 96% of the compounds in the METLIN MS(2) library. A major advantage of the approach is that it extends untargeted metabolomics to low-resolution triple quadrupole (QqQ) instruments, which are typically less expensive and more robust than other types of mass spectrometers. We demonstrate a method of acquiring MS(2) data in which the third quadrupole of a QqQ instrument cycles over 20 wide isolation windows (coinciding with the location and width of our bins) for each precursor mass selected by the first quadrupole. Operating the QqQ instrument in this mode yields diagnostic bar codes for each precursor mass that can be matched to the bar codes of metabolite standards. Furthermore, our data suggest that using low-resolution bar codes enables QqQ instruments to make MS(2)-based identifications in untargeted metabolomics with a specificity and sensitivity that is competitive to high-resolution time-of-flight technologies.


[A case of acute disseminated encephalomyelitis associated with Epstein-Barr virus reactivation during infliximab therapy].
A 31-year-old woman with Crohn's disease that had been refractory to drug therapies for 7 years had been treated with infliximab for a year. She was admitted to our hospital because of truncal ataxia and bulbar palsy, which presented following aseptic meningitis. Neurological examination revealed abducens paresis on the left, gaze-evoked nystagmus on upward and rightward gaze, right facial muscle weakness, bulbar palsy, weakness in the right upper extremity, limb ataxia predominantly on the left side, diminished sense in the lower extremities predominantly on the right, diffuse hyperreflexia in all extremities. Antibodies to Epstein-Barr virus (EBV) in serum demonstrated a previous infection pattern, and EBV-DNA was detected in peripheral blood and cerebrospinal fluid (CSF) by PCR. CSF analysis indicated pleocytosis, an elevation of IgG index and a marked increase in the level of myelin basic protein. FLAIR MRI images revealed multiple hyperintense lesions in the brainstem, subcortical white matter, and cervical spinal cord. Accordingly, we diagnosed her as having acute disseminated encephalomyelitis (ADEM), associated with reactivated EBV infection. Although gancyclovir, plasma exchange and intravenous high dose immunoglobulins were not effective, repetitive use of methylprednisolone pulse therapy alleviated her symptoms and the abnormal MRI lesions. It is suggested that the reactivated EBV infection caused by infliximab may have contributed to the development of ADEM in this case. Besides the demyelinating event directly induced by anti-TNF-alpha therapy, we should pay attention to the occurrence of reactivated EBV-triggered ADEM during anti-TNF-alpha therapy.


10 Years of GWAS Discovery: Biology, Function, and Translation.
Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.


Reliability and validity of the World Health Organization reading standards for paediatric chest radiographs used in the field in an impact study of Pneumococcal Conjugate Vaccine in Kilifi, Kenya.
Radiologically-confirmed pneumonia (RCP) is a specific end-point used in trials of Pneumococcal Conjugate Vaccine (PCV) to estimate vaccine efficacy. However, chest radiograph (CXR) interpretation varies within and between readers. We measured the repeatability and reliability of paediatric CXR interpretation using percent agreement and Cohen's Kappa and the validity of field readings against expert review in a study of the impact of PCV on pneumonia. CXRs were obtained from 2716 children admitted between 2006 and 2014 to Kilifi County Hospital, Kilifi, Kenya, with clinically-defined severe or very-severe pneumonia. Five clinicians and radiologists attended a three-day training course on CXR interpretation using a WHO standard. All CXRs were read once by two local primary readers. Discordant readings and 13% of concordant readings were arbitrated by a panel of three expert radiologists. To assess repeatability, a 5% median random sample was presented twice. Sensitivity and specificity of the primary readers' interpretations was estimated against the 'gold-standard' of the arbitrators' results. Of 2716 CXRs, 2 were uninterpretable and 159 were evaluated twice. The percent agreement and Kappa for RCP were 89% and 0.68 and ranged between 84-97% and 0.19-0.68, respectively, for all pathological findings. Intra-observer repeatability was similar to inter-observer reliability. Sensitivities of the primary readers to detect RCP were 69% and 73%; specificities were 96% and 95%. Intra- and inter-observer agreements on interpretations of radiologically-confirmed pneumonia are fair to good. Reasonable sensitivity and high specificity make radiologically-confirmed pneumonia, determined in the field, a suitable measure of relative vaccine effectiveness.


Grape-seed procyanidins act as antiinflammatory agents in endotoxin-stimulated RAW 264.7 macrophages by inhibiting NFkB signaling pathway.
Procyanindin extract (PE) is a mixture of polyphenols, mainly procyanidins, obtained from grape seed with putative antiinflammatory activity. We evaluated the PE effect on RAW 264.7 macrophages stimulated with lipopolysaccharide plus interferon-gamma that show a rapid enhanced production of prostaglandin E2 (PGE2) and nitric oxide (NO). Our results demonstrated that PE significantly inhibited the overproduction of NO, dose and time dependently. PE caused a marked inhibition of PGE2 synthesis when administered during activation. Moreover, PE pretreatment diminished iNOS mRNA and protein amount dose dependently (10-65 microg/mL). PE (65 microg/mL) pretreatment inhibited NFkappaB (p65) translocation to nucleus by nearly 40%. Trimeric and longer oligomeric-rich procyanidin fractions from PE (5-30 microg/mL) inhibited iNOS expression but not the monomeric forms catechin and epicatechin. Thus, we show that the degree of polymerization is important in determining procyanidin effects. PE was considerably a more effective inhibitor of NO biosynthesis (IC50 = 50 microg/mL) in comparison to other antiinflammatories, such as aspirin (3 mM), indomethacin (20 microM), and dexamethasone (9 nM). In conclusion, PE modulates inflammatory response in activated macrophages by the inhibition of NO and PGE2 production, suppression of iNOS expression, and NFkB translocation. These results demonstrate an immunomodulatory role of grape seed procyanidins and thus a potential health-benefit in inflammatory conditions that exert an overproduction of NO and PGE2.


Trends in Incidence of Hospitalized Acute Myocardial Infarction in the Cardiovascular Research Network (CVRN).
Monitoring trends in cardiovascular events can provide key insights into the effectiveness of prevention efforts. Leveraging data from electronic health records provides a unique opportunity to examine contemporary, community-based trends in acute myocardial infarction hospitalizations. We examined trends in hospitalized acute myocardial infarction incidence among adults aged ≥25 years in 13 US health plans in the Cardiovascular Research Network. The first hospitalization per member for acute myocardial infarction overall and for ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction was identified by International Classification of Diseases, Ninth Revision, Clinical Modification primary discharge codes in each calendar year from 2000 through 2008. Age- and sex-adjusted incidence was calculated per 100,000 person-years using direct adjustment with 2000 US census data. Between 2000 and 2008, we identified 125,435 acute myocardial infarction hospitalizations. Age- and sex-adjusted incidence rates (per 100,000 person-years) of acute myocardial infarction decreased an average 3.8%/y from 230.5 in 2000 to 168.6 in 2008. Incidence of ST-segment elevation myocardial infarction decreased 8.7%/y from 104.3 in 2000 to 51.7 in 2008, whereas incidence of non-ST-segment elevation myocardial infarction increased from 126.1 to 129.4 between 2000 and 2004 and then decreased thereafter to 116.8 in 2008. Age- and sex-specific incidence rates generally reflected similar patterns, with relatively larger decreases in ST-segment elevation myocardial infarction rates in women compared with men. As compared with 2000, the age-adjusted incidence of ST-segment elevation myocardial infarction in 2008 was 48% lower among men and 61% lower among women. Among a large, diverse, multicenter community-based insured population, there were significant decreases in incidence of hospitalized acute myocardial infarction and the more serious ST-segment elevation myocardial infarctions between 2000 and 2008. Decreases in ST-segment elevation myocardial infarctions were most pronounced among women. While ecologic in nature, these secular decreases likely reflect, at least in part, results of improvement in primary prevention efforts.


Quantifying size and diversity of the human T cell alloresponse.
Alloreactive T lymphocytes are the primary mediators of immune responses in transplantation, both in the graft-versus-host and host-versus-graft directions. While essentially all clones comprising the human T cell repertoire have been selected on self-peptide presented by self-human leukocyte antigens (self-HLAs), much remains to be understood about the nature of clones capable of responding to allo-HLA molecules. Quantitative tools to study these cells are critical to understand fundamental features of this important response; however, the large size and diversity of the alloreactive T cell repertoire in humans presents a great technical challenge. We have developed a high-throughput T cell receptor (TCR) sequencing approach to characterize the human alloresponse. We present a statistical method to model T cell clonal frequency distribution and quantify repertoire diversity. Using these approaches, we measured the diversity and frequency of distinct alloreactive CD4+ and CD8+ T cell populations in HLA-mismatched responder-stimulator pairs. Our findings indicate that the alloimmune repertoire is highly specific for a given pair of individuals, that most alloreactive clones circulate at low frequencies, and that a high proportion of TCRs is likely able to recognize alloantigens.


Site-Selective and Rewritable Labeling of DNA through Enzymatic, Reversible, and Click Chemistries.
Current methods for bioconjugation rely on the introduction of stable linkers that lack the required versatility to perform sequential functionalizations. However, sequential manipulations are an increasing requirement in chemical biology because they can underpin multiple analyses of the same sample to provide a wider understanding of cell behavior. Here, we present a new method to site-selectively write, remove, and rewrite chemical functionality to a biomolecule, DNA in this case. Our method combines the precision and robustness of methyltransferase-directed labeling with the reversibility of acyl hydrazones and the efficiency of click chemistry. Underpinning the method is a new S-adenosyl-l-methionine derivative to site-selectively label DNA with a bifunctional chemical handle containing an acyl hydrazone-linker and a terminal azide. Functional tags are conjugated via the azide and can be removed (i.e., untagged) when needed at the acyl hydrazone via exchange with hydroxyl amine. The formed hydrazide-labeled DNA is a versatile intermediate that can be either rewritten to reset the original chemical handle or covalently reacted with a permanent tag. This ability to write, tag, untag, and permanently tag DNA is exploited to sequentially introduce two fluorescent dyes on DNA. Finally, we demonstrate the potential of the method by developing a protocol to sort labeled DNA using magnetic beads, with subsequent amplification of the sorted DNA sample for further analysis. The presented method opens new avenues for site-selective bioconjugation and should underpin integrative approaches in chemical biology where sequential functionalizations of the same sample are required.


Adjunctive therapies during veno-venous extracorporeal membrane oxygenation.
Veno-venous extracorporeal membrane oxygenation (VV ECMO) restores gas exchanges in severely hypoxemic patients. The need for adjunctive therapies usually originates either from refractory hypoxemia during ECMO (defined as the persistence of low blood oxygen levels despite extracorporeal support) or from the attempt to give a specific therapy for acute respiratory distress syndrome (ARDS). In this review, therapeutic strategies to treat refractory and persistent hypoxemia during ECMO are evaluated. In the second part, therapies that can be added on top of VV ECMO to address inflammation and altered vascular permeability in ARDS are examined. The therapies currently available often allow for an effective treatment of hypoxemia during ECMO. ARDS is still lacking a specific therapy, with low-grade evidence sustaining the majority of currently used drugs.


Legacy and social media respectively influence risk perceptions and protective behaviors during emerging health threats: A multi-wave analysis of communications on Zika virus cases.
Both legacy media, such as television and newspapers, and online social media are potentially important but incompletely understood sources of information in the face of emerging public health risks. This research aimed to understand media effects on risk perceptions and behaviors concerning the Zika virus in the United States. We analyzed a multi-wave nationally representative survey (N = 29,062) and the volume of communications in social and legacy media (i.e., legacy media data from news sources and databases, N = 2,660 and social media data from Twitter, N = 1,605,752) in the United States between April and October 2016, dates coinciding with the early cases of local transmission of Zika in the United States (i.e., 25 weeks). The present study conducted econometric analyses (i.e., Granger causality tests) to assess the associations of legacy and social media coverage with risk perceptions and protective behaviors in the total sample and specific groups separated by pregnancy status/intent, geographic region, income, education level, age, and ethnicity. The results from the overall sample suggested that changes in the volume of information in legacy and social media (i.e., Twitter) were followed by different changes in community risk perceptions and protective behaviors. Specifically, social media coverage correlated with the level of risk perceptions, whereas the legacy media coverage correlated with the level of protective behaviors. Analyses across different subpopulations, including those of different pregnancy status/intent, geographic Zika risk, income, education level, age, and ethnicity, replicated the social media associations with risk perceptions in most cases. However, legacy media and protective behaviors were linked only in some vulnerable subpopulations (e.g., the less-educated populations). Understanding how media coverage relates to Zika risk perceptions and protective behaviors will help to facilitate effective risk communications by healthcare professionals and providers, particularly when a health risk emerges.


Bottom-up biases in feature-selective attention.
Previous studies of feature-selective attention have focused on situations in which attention is directed to one of two spatially superimposed stimuli of equal salience. While such overlapping stimuli should maximize stimulus interactions, it is still unknown how bottom-up biases favoring one or the other stimulus influence the efficiency of feature-selective attention. We examined the integration of bottom-up contrast and top-down feature-selection biases on stimulus processing. Two fully overlapping random dot kinematograms (RDKs) of light and dark dots were presented on a gray background of intermediate luminance. On each trial, human participants attended one RDK to detect brief coherent motion targets, while ignoring any events in the unattended RDK. Concurrently, through changes in background luminance, stimulus contrast could be set to five different levels: the stimuli could either be equal, or one of the two stimuli could have twice or four times the contrast of the other stimulus. This manipulation introduced a bottom-up bias toward the stimulus with the higher contrast while keeping the difference between the stimuli constant. Stimulus processing was measured by means of steady-state visual evoked potentials (SSVEPs). SSVEP amplitudes generally increased with higher contrast of the driving stimulus. At earlier levels of processing, attention increased the slope of this linear relation, i.e., attention multiplicatively enhanced SSVEP amplitudes. However, at later levels of processing, attention had an additive effect. These effects of attention can be attributed to the differential integration of gain enhancement and inhibitory stimulus competition at different levels of the visual processing hierarchy.


Implementing the Free Water Protocol does not Result in Aspiration Pneumonia in Carefully Selected Patients with Dysphagia: A Systematic Review.
The Frazier Free Water Protocol was developed with the aim of providing patients with dysphagia an option to consume thin (i.e. unthickened) water in-between mealtimes. A systematic review was conducted of research published in peer-reviewed journals. An electronic search of the EMBASE, CINAHL and MEDLINE databases was completed up to July 2016. A total of 8 studies were identified for inclusion: 5 randomised controlled trials, 2 cohort studies with matched cases and 1 single group pre-post intervention prospective study. A total of 215 rehabilitation inpatients and 30 acute patients with oropharyngeal dysphagia who required thickened fluids or were to remain 'nil by mouth', as determined by bedside swallow assessment and/or videofluoroscopy/fiberoptic endoscopic evaluation of swallowing, were included. Meta-analyses of the data from the rehabilitation studies revealed (1) low-quality evidence that implementing the protocol did not result in increased odds of having lung complications and (2) low-quality evidence that fluid intake may increase. Patients' perceptions of swallow-related quality of life appeared to improve. This review has found that when the protocol is closely adhered to and patients are carefully selected using strict exclusion criteria, including an evaluation of their cognition and mobility, adult rehabilitation inpatients with dysphagia to thin fluids can be offered the choice of implementing the Free Water Protocol. Further research is required to determine if the Free Water Protocol can be implemented in settings other than inpatient rehabilitation.


Clarifying appeals to dignity in medical ethics from an historical perspective.
Over the past few decades the concept of (human) dignity has deeply pervaded medical ethics. Appeals to dignity, however, are often unclear. As a result some prefer to eliminate the concept from medical ethics, whereas others try to render it useful in this context. We think that appeals to dignity in medical ethics can be clarified by considering the concept from an historical perspective. Firstly, on the basis of historical texts we propose a framework for defining the concept in medical debates. The framework shows that dignity can occur in a relational, an unconditional, a subjective and a Kantian form. Interestingly, all forms relate to one concept since they have four features in common: dignity refers, in a restricted sense, to the 'special status of human beings'; it is based on essential human characteristics; the subject of dignity should live up to it; and it is a vulnerable concept, it can be lost or violated. We argue that being explicit about the meaning of dignity will prevent dignity from becoming a conversation-stopper in moral debate. Secondly, an historical perspective on dignity shows that it is not yet time to dispose of dignity in medical ethics. At least Kantian and relational dignity can be made useful in medical ethics.


A 160 μW 8-Channel Active Electrode System for EEG Monitoring.
This paper presents an active electrode system for gel-free biopotential EEG signal acquisition. The system consists of front-end chopper amplifiers and a back-end common-mode feedback (CMFB) circuit. The front-end AC-coupled chopper amplifier employs input impedance boosting and digitally-assisted offset trimming. The former increases the input impedance of the active electrode to 2 GΩ at 1 Hz and the latter limits the chopping induced output ripple and residual offset to 2 mV and 20 mV, respectively. Thanks to chopper stabilization, the active electrode achieves 0.8 μVrms (0.5-100 Hz) input referred noise. The use of a back-end CMFB circuit further improves the CMRR of the active electrode readout to 82 dB at 50 Hz. Both front-end and back-end circuits are implemented in a 0.18 μm CMOS process and the total current consumption of an 8-channel readout system is 88 μA from 1.8 V supply. EEG measurements using the proposed active electrode system demonstrate its benefits compared to passive electrode systems, namely reduced sensitivity to cable motion artifacts and mains interference.


AU-rich RNA binding proteins in hematopoiesis and leukemogenesis.
Posttranscriptional mechanisms are now widely acknowledged to play a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation, and tumorigenesis. Although much attention has focused on microRNAs as regulators of mRNA stability/translation, recent data have highlighted the role of several diverse classes of AU-rich RNA-binding protein in the regulation of mRNA decay/stabilization. AU-rich elements are found in the 3'-untranslated region of many mRNAs that encode regulators of cell growth and survival, such as cytokines and onco/tumor-suppressor proteins. These are targeted by a burgeoning number of different RNA-binding proteins. Three distinct types of AU-rich RNA binding protein (ARE poly-U-binding degradation factor-1/AUF1, Hu antigen/HuR/HuA/ELAVL1, and the tristetraprolin/ZFP36 family of proteins) are essential for normal hematopoiesis. Together with 2 further AU-rich RNA-binding proteins, nucleolin and KHSRP/KSRP, the functions of these proteins are intimately associated with pathways that are dysregulated in various hematopoietic malignancies. Significantly, all of these AU-rich RNA-binding proteins function via an interconnected network that is integrated with microRNA functions. Studies of these diverse types of RNA binding protein are providing novel insight into gene-regulatory mechanisms in hematopoiesis in addition to offering new opportunities for developing mechanism-based targeted therapeutics in leukemia and lymphoma.


Urban parasitology: visceral leishmaniasis in Brazil.
Since the early 1980s, visceral leishmaniasis (VL) which is, in general, a rural zoonotic disease, has spread to the urban centers of the north, and now the south and west of Brazil. The principal drivers differ between cities, though human migration, large urban canid populations (animal reservoir), and a decidedly peripatetic and adaptable sand fly vector are the primary forces. The exact number of urban cases remains unclear as a result of challenges with surveillance. However, the number of urban cases registered continues to increase annually. Most control initiatives (e.g. culling infected dogs and household spraying to kill the sand fly) could be effective, but have proven hard to maintain at large scales due to logistical, financial and other reasons. In this article, the urbanization of VL in Brazil is reviewed, touching on these and other topics related to controlling VL within and outside Brazil.


Detecting and targeting neurodegenerative disorders using electrospun nanofibrous matrices: current status and applications.
Neurodegeneration is defined as the progressive atrophy and loss of function of neurons; it is present in neurodegenerative disorders such as Multiple Sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases. The detection of such disorders is performed by various imaging modalities while their therapeutic management is quite challenging. Besides, the pathogenesis of neurodegenerative disorders is still under ongoing research due to complex and multi-factorial mechanisms. Currently, targeting the specific proteins responsible for neurodegeneration is of great interest to many researchers. Furthermore, nanotechnology-based approaches for targeting the affected neurons became an emerging field of interest. Nanostructures of various forms have been developed aiming to act as therapeutics for neurodegeneration, in which electrospun nanofibers seem to play an important role as biomedical products for both detection and management of the diseases. Electrospinning is an intriguing method able to produce nanofibers with a wide range of sizes and morphological characteristics. Such nanofibrous matrices can be delivered through different administration routes to target various diseases. In this review, the most recent advancements in electrospun nanofibrous systems that target or detect multiple neurodegenerative diseases have been enlightened and an introduction to the general aspects of neurodegenerative diseases and the electrospinning process has been made. Finally, future perspectives of neurodegeneration targeting were also discussed.