Validation of Innovative Techniques for Monitoring Nociception during General Anesthesia: A Clinical Study Using Tetanic and Intracutaneous Electrical Stimulation.
This study compares the analgesic indices Analgesia Nociception Index (heart rate variability), Surgical Pleth Index (photoplethysmography), and pupillary dilatation, to heart rate, mean arterial pressure, and bispectral index, with regard to diagnostic accuracy and prediction probability for nociceptive response. The primary endpoint was the correlation between Δ values and the remifentanil dose administered. We anesthetized 38 patients with propofol and increasing doses of remifentanil and applied standardized tetanic and intracutaneous electrical painful stimulations on each analgesic level. Baseline and Δ values of the Analgesia Nociception Index, the Surgical Pleth Index, pupillary dilatation, heart rate, mean arterial pressure, and bispectral index and their relation to remifentanil doses were analyzed by receiver operating characteristic curves, prediction probability (PK), and mixed-model analysis. Under propofol sedation, sensitivity and specificity of the Analgesia Nociception Index (PK = 0.98), the Surgical Pleth Index (PK = 0.87), and pupillary dilatation (PK = 0.98) for detecting both painful stimulations were high compared to heart rate (PK = 0.74), mean arterial pressure (PK = 0.75), and bispectral index (PK = 0.55). Baseline values had limited prediction probability toward the nociceptive response (Analgesia Nociception Index: PK = 0.7; Surgical Pleth Index: PK = 0.63; pupillary dilatation: PK = 0.67; and bispectral index: PK = 0.67). The remifentanil dose had an effect (P < 0.001) on all parameters except for bispectral index (P = 0.216). The Analgesia Nociception Index, the Surgical Pleth Index, and pupillary dilatation are superior in detecting painful stimulations compared to heart rate and mean arterial pressure but had limited predictive value. These effects are attenuated by increasing dosages of remifentanil. Our data confirm that bispectral index is not a marker of analgesia.


Constraints on anaerobic respiration in the hyperthermophilic Archaea Pyrobaculum islandicum and Pyrobaculum aerophilum.
Pyrobaculum islandicum uses iron, thiosulfate, and elemental sulfur for anaerobic respiration, while Pyrobaculum aerophilum uses iron and nitrate; however, the constraints on these processes and their physiological mechanisms for iron and sulfur reduction are not well understood. Growth rates on sulfur compounds are highest at pH 5 to 6 and highly reduced (<-420-mV) conditions, while growth rates on nitrate and iron are highest at pH 7 to 9 and more-oxidized (>-210-mV) conditions. Growth on iron expands the known pH range of growth for both organisms. P. islandicum differs from P. aerophilum in that it requires direct contact with insoluble iron oxide for growth, it did not produce any extracellular compounds when grown on insoluble iron, and it lacked 2,6-anthrahydroquinone disulfonate oxidase activity. Furthermore, iron reduction in P. islandicum appears to be completely independent of c-type cytochromes. Like that in P. aerophilum, NADH-dependent ferric reductase activity in P. islandicum increased significantly in iron-grown cultures relative to that in non-iron-grown cultures. Proteomic analyses showed that there were significant increases in the amounts of a putative membrane-bound thiosulfate reductase in P. islandicum cultures grown on thiosulfate relative to those in cultures grown on iron and elemental sulfur. This is the first evidence of this enzyme being used in either a hyperthermophile or an archaeon. Pyrobaculum arsenaticum and Pyrobaculum calidifontis also grew on Fe(III) citrate and insoluble iron oxide, but only P. arsenaticum could grow on insoluble iron without direct contact.


Sudden gains in face-to-face and internet-based cognitive therapy for social anxiety disorder.
Sudden gains are large and stable decreases in clinical symptoms between consecutive therapy sessions. This work examined the frequency and possible determinants of sudden gains in Cognitive Therapy for Social Anxiety Disorder, comparing face-to-face (CT) and internet-based (iCT) formats of treatment delivery. Data from 99 participants from a randomised controlled trial were analysed. The frequency of sudden gains was high: 64% and 51% of participants experienced a sudden gain in CT and iCT respectively. Having a sudden gain was associated with lower social anxiety symptoms at posttreatment and follow-up. There was evidence of reductions in negative social cognitions and self-focused attention immediately prior to the sudden gain, contrasting with no prior reductions in depression symptoms. Ratings of session videotapes in CT showed that clients' statements indicated greater generalised learning in sessions immediately prior to gains, compared to control sessions. This may suggest a role for generalised learning in facilitating these large symptom reductions. There were no significant differences in results between the CT and iCT treatment formats, suggesting that the therapy content appears to play a more important role in determining participants' large symptom improvements than the medium of treatment delivery.


A Behaviour Sequence Analysis of Nonverbal Communication and Deceit in Different Personality Clusters.
Despite difficulties in interpretation, nonverbal communication is especially important in forensic settings, such as police investigations. Three distinct clusters of personality disorders have been outlined as being associated with criminal behaviour. Understanding the similarities and differences between these personality clusters and nonverbal communication could help investigators look for key signs of psychological distress or deception. The current research proposes a novel approach to nonverbal communication: behaviour sequence analysis (BSA). An application of this approach is outlined to investigate whether criminals with different personality types are better at concealing emotions and nonverbal communication when being interrogated. The results indicate that while sequences are generally similar across clusters, individuals from different personality clusters exhibit unique patterns. This research provides an initial step towards a new area of nonverbal communication research and application, which could be used in future research to highlight increased possibility of deception or concealment of emotion.


Combined treatment of heterocyclic analogues and benznidazole upon Trypanosoma cruzi in vivo.
Chagas disease caused by Trypanosoma cruzi is an important cause of mortality and morbidity in Latin America but no vaccines or safe chemotherapeutic agents are available. Combined therapy is envisioned as an ideal approach since it may enhance efficacy by acting upon different cellular targets, may reduce toxicity and minimize the risk of drug resistance. Therefore, we investigated the activity of benznidazole (Bz) in combination with the diamidine prodrug DB289 and in combination with the arylimidamide DB766 upon T. cruzi infection in vivo. The oral treatment of T.cruzi-infected mice with DB289 and Benznidazole (Bz) alone reduced the number of circulating parasites compared with untreated mice by about 70% and 90%, respectively. However, the combination of these two compounds decreased the parasitemia by 99% and protected against animal mortality by 100%, but without providing a parasitological cure. When Bz (p.o) was combined with DB766 (via i.p. route), at least a 99.5% decrease in parasitemia levels was observed. DB766+Bz also provided 100% protection against mice mortality while Bz alone provided about 87% protection. This combined therapy also reduced the tissular lesions induced by T. cruzi infection: Bz alone reduced GPT and CK plasma levels by about 12% and 78% compared to untreated mice group, the combination of Bz with DB766 resulted in a reduction of GPT and CK plasma levels of 56% and 91%. Cure assessment through hemocultive and PCR approaches showed that Bz did not provide a parasitological cure, however, DB766 alone or associated with Bz cured ≥13% of surviving animals.


Tooth whitening effects on bracket bond strength in vivo.
To test the hypothesis that there is no difference between the bracket survival rate of brackets bonded to bleached and unbleached teeth. Thirty-eight patients who required comprehensive orthodontic treatment were included in the study. A split mouth technique was used with one arch exposed to in-office whitening gel containing 38% hydrogen peroxide for 30 minutes, while the unbleached arch served as the control. Patients were divided into two groups: Brackets bonded within 24 hours after bleaching and brackets bonded 2-3 weeks after bleaching. The bracket survival rate was computed using the log-rank test (Kaplan-Meier Analysis). A significantly higher rate of bracket failure was found with bleached teeth (16.6%) compared with unbleached teeth (1.8%) after 180 days. Brackets bonded within 24 hours of bleaching resulted in significantly higher clinical failure (14.5%) compared with those bonded after 3 weeks (2.1%). Adhesive Remnant Index scores of failed brackets revealed that the majority of failure in bleached teeth occurred in the enamel/resin interface. The hypothesis was rejected. Brackets bonded within 24 hours after bleaching have a significantly higher risk for bond failure. Orthodontic bonding should be delayed for 2-3 weeks if patients have a history of in-office bleaching with 38% hydrogen peroxide.


Transcranial magnetic stimulation during pregnancy.
The aim of the present study was to assess the safety and effectiveness of high-frequency repetitive transcranial magnetic stimulation (rTMS) in pregnant patients with depression. Thirty depressed pregnant patients received rTMS over the left prefrontal cortex for 6 days in a week, from Monday to Saturday for 3 weeks. The rTMS intensity was set at 100% of the motor threshold. A 25-Hz stimulation with a duration of 2 s was delivered 20 times with 30-s intervals. A session comprised 1,000 magnetic pulses. Depression was rated using the 17-item Hamilton depression rating scale (HAMD) before and after treatment. Response was defined as a 50% reduction of the HAMD score. Patients with HAMD scores less than 8 were considered to be in remission. The mean HAMD score for the study group decreased from 26.77 ± 5.58 to 13.03 ± 6.93 (p < 0.001) after 18 sessions of rTMS. After the treatment period, 41.4% of the study group demonstrated significant mood improvements as indexed by a reduction of more than 50% on the HAMD score. In addition, 20.7% attained remission (HAMD score < 8), 34.5% achieved a partial response, and 3.4% had worsening in HAMD scores at the end of treatment. Treatment was well tolerated, and no significant adverse effects were reported. rTMS was well tolerated and found to be statistically and clinically effective in pregnant patients with treatment-resistant depression. This study contributed to the existing evidence of the antidepressant effect of rTMS in the treatment of depression in pregnancy.


Curcumin and obesity.
Turmeric has been long recognized for its anti-inflammatory and health-promoting properties. Curcumin is one of the principal anti-inflammatory and healthful components of turmeric comprising 2-8% of most turmeric preparations. Experimental evidence supports the activity of curcumin in promoting weight loss and reducing the incidence of obesity-related diseases. With the discovery that obesity is characterized by chronic low-grade metabolic inflammation, phytochemicals like curcumin which have anti-inflammatory activity are being intensely investigated. Recent scientific research reveals that curcumin directly interacts with white adipose tissue to suppress chronic inflammation. In adipose tissue, curcumin inhibits macrophage infiltration and nuclear factor κB (NF-κB) activation induced by inflammatory agents. Curcumin reduces the expression of the potent proinflammatory adipokines tumor necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor type-1 (PAI-1), and it induces the expression of adiponectin, the principal anti-inflammatory agent secreted by adipocytes. Curcumin also has effects to inhibit adipocyte differentiation and to promote antioxidant activities. Through these diverse mechanisms curcumin reduces obesity and curtails the adverse health effects of obesity.


Membrane/Toxin Interaction Energetics via Serial Multiscale Molecular Dynamics Simulations.
Computing free energies of complex biomolecular systems via atomistic (AT) molecular dynamics (MD) simulations remains a challenge due to the need for adequate sampling and convergence. Recent coarse-grained (CG) methodology allows simulations of significantly larger systems (∼10(6) to 10(8) atoms) over longer (μs/ms) time scales. Such CG models appear to be capable of making semiquantitative predictions. However, their ability to reproduce accurate thermodynamic quantities remains uncertain. We have recently used CG MD simulations to compute the potential of mean force (PMF) or free energy profile of a small peptide toxin interacting with a lipid bilayer along a 1D reaction coordinate. The toxin studied was VSTx1 (Voltage Sensor Toxin 1) from spider venom which inhibits the archeabacterial voltage-gated potassium (Kv) channel KvAP by binding to the voltage-sensor (VS) domains. Here, we re-estimate this PMF profile using (i) AT MD simulations with explicit membrane and solvent and (ii) an implicit membrane and solvent (generalized Born; GBIM) model where only the peptide was explicit. We used the CG MD free energy simulations to guide the setup of the corresponding AT MD simulations. The aim was to avoid local minima in the AT simulations which would be difficult over shorter AT time scales. A cross-comparison of the PMF profiles revealed a conserved topology, although there were differences in the magnitude of the free energies. The CG and AT simulations predicted a membrane/water interface free energy well of -27 and -23 kcal/mol, respectively (with respect to water). The GBIM model, however, gave a reduced interfacial free energy well (-12 kcal/mol). In addition, the CG and GBIM models predicted a free energy barrier of +61 and +96 kcal/mol, respectively, for positioning the toxin at the center of the bilayer, which was considerably smaller in the AT simulations (+26 kcal/mol). Thus, we present a framework for serially combining CG and AT simulations to estimate the free energy of peptide/membrane interactions. Such approaches for combining simulations at different levels of granularity will become increasingly important in future studies of complex membrane/protein systems.


Air-filled postcranial bones in theropod dinosaurs: physiological implications and the 'reptile'-bird transition.
Pneumatic (air-filled) postcranial bones are unique to birds among extant tetrapods. Unambiguous skeletal correlates of postcranial pneumaticity first appeared in the Late Triassic (approximately 210 million years ago), when they evolved independently in several groups of bird-line archosaurs (ornithodirans). These include the theropod dinosaurs (of which birds are extant representatives), the pterosaurs, and sauropodomorph dinosaurs. Postulated functions of skeletal pneumatisation include weight reduction in large-bodied or flying taxa, and density reduction resulting in energetic savings during foraging and locomotion. However, the influence of these hypotheses on the early evolution of pneumaticity has not been studied in detail previously. We review recent work on the significance of pneumaticity for understanding the biology of extinct ornithodirans, and present detailed new data on the proportion of the skeleton that was pneumatised in 131 non-avian theropods and Archaeopteryx. This includes all taxa known from significant postcranial remains. Pneumaticity of the cervical and anterior dorsal vertebrae occurred early in theropod evolution. This 'common pattern' was conserved on the line leading to birds, and is likely present in Archaeopteryx. Increases in skeletal pneumaticity occurred independently in as many as 12 lineages, highlighting a remarkably high number of parallel acquisitions of a bird-like feature among non-avian theropods. Using a quantitative comparative framework, we show that evolutionary increases in skeletal pneumaticity are significantly concentrated in lineages with large body size, suggesting that mass reduction in response to gravitational constraints at large body sizes influenced the early evolution of pneumaticity. However, the body size threshold for extensive pneumatisation is lower in theropod lineages more closely related to birds (maniraptorans). Thus, relaxation of the relationship between body size and pneumatisation preceded the origin of birds and cannot be explained as an adaptation for flight. We hypothesise that skeletal density modulation in small, non-volant, maniraptorans resulted in energetic savings as part of a multi-system response to increased metabolic demands. Acquisition of extensive postcranial pneumaticity in small-bodied maniraptorans may indicate avian-like high-performance endothermy.


Exploiting genotyping by sequencing to characterize the genomic structure of the American cranberry through high-density linkage mapping.
The application of genotyping by sequencing (GBS) approaches, combined with data imputation methodologies, is narrowing the genetic knowledge gap between major and understudied, minor crops. GBS is an excellent tool to characterize the genomic structure of recently domesticated (~200 years) and understudied species, such as cranberry (Vaccinium macrocarpon Ait.), by generating large numbers of markers for genomic studies such as genetic mapping. We identified 10842 potentially mappable single nucleotide polymorphisms (SNPs) in a cranberry pseudo-testcross population wherein 5477 SNPs and 211 short sequence repeats (SSRs) were used to construct a high density linkage map in cranberry of which a total of 4849 markers were mapped. Recombination frequency, linkage disequilibrium (LD), and segregation distortion at the genomic level in the parental and integrated linkage maps were characterized for first time in cranberry. SSR markers, used as the backbone in the map, revealed high collinearity with previously published linkage maps. The 4849 point map consisted of twelve linkage groups spanning 1112 cM, which anchored 2381 nuclear scaffolds accounting for ~13 Mb of the estimated 470 Mb cranberry genome. Bin mapping identified 592 and 672 unique bins in the parentals and a total of 1676 unique marker positions in the integrated map. Synteny analyses comparing the order of anchored cranberry scaffolds to their homologous positions in kiwifruit, grape, and coffee genomes provided initial evidence of homology between cranberry and closely related species. GBS data was used to rapidly saturate the cranberry genome with markers in a pseudo-testcross population. Collinearity between the present saturated genetic map and previous cranberry SSR maps suggests that the SNP locations represent accurate marker order and chromosome structure of the cranberry genome. SNPs greatly improved current marker genome coverage, which allowed for genome-wide structure investigations such as segregation distortion, recombination, linkage disequilibrium, and synteny analyses. In the future, GBS can be used to accelerate cranberry molecular breeding through QTL mapping and genome-wide association studies (GWAS).


Children's Sleep Habits Questionnaire in Two Subpopulations from Cape Verde and Mozambique: Exploratory and Regression Analysis.
Children's sleep habits are profoundly affected by socio-economic, cultural, and environmental factors. We aim to describe the sleep habits of pediatric sub-populations from Cape Verde and Mozambique using the Children's Sleep Habits Questionnaire, and to ascertain the determinants of the questionnaire's score. We conducted cross-sectional surveys in surveillance appointments in Cape Verde and in a school in Maputo (Mozambique). The Cape Verde sample included 206 children (mean age: 6.5) and the Mozambique sample 454 children (mean age: 8). The Portuguese version of the Children's Sleep Habits Questionnaire was used to evaluate the children's sleep habits. The distributions of the questionnaire's scores across different levels of the demographic variables were compared using the Mann-Whitney and the Kruskal-Wallis tests. We used regression models to quantify the relationship between the demographic variables and the questionnaire's scores. Cape Verde sample: Questionnaire median score: 50 (range 36 - 81). Prevalence of sleep problems: 29.9% (cut-off = 56). Prevalence of parent-reported sleep problems: 22.8%. Co-sleeping: 63%. Bedtime television: 30%. Daytime nap: 63%. Questionnaire scores are associated with the mother's educational level, the children's age group, and with the frequency of daytime napping. Mozambique Sample: Median Questionnaire score: 48 (range 35 - 77). Prevalence of sleep problems: 28.4% (cut-off: 52). Percentage of parent-reported sleep problems: 6.9%. Co-sleeping: 29%. Bedtime television: 33%. Daytime nap: 23%. Questionnaire scores are associated with the mother's nationality, the father educational level, and with the frequency of bedtime television. Parents tend to overestimate the quality of their children's sleep. The prevalence of sleep disturbances and the cut-off values are higher than observed in previous studies, which may be due to the existence of different standards and cultural expectations across populations. Bedtime television, typically associated with more disturbed sleep, is frequent in both samples. Co-sleeping and daytime napping are frequent in the Cape Verde sample; wetting the bed is common and more prevalent than in previous studies. Bed-sharing increases the parents' awareness of their children's sleep quality, contributing to the high prevalence of parent-reported sleep problems. Parent-reported sleep problems underestimate the Children's Sleep Habits Questionnaire results. This is not necessarily indicative of more disturbed sleep and might reflect differences in sleep behavior, childcare practice, and cognitions and attitudes towards the concept of 'normal' sleep.


Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes.
This paper describes the methodology, results and limitations of the 2013 International Diabetes Federation (IDF) Atlas (6th edition) estimates of the worldwide numbers of prevalent cases of type 1 diabetes in children (<15 years). The majority of relevant information in the published literature is in the form of incidence rates derived from registers of newly diagnosed cases. Studies were graded on quality criteria and, if no information was available in the published literature, extrapolation was used to assign a country the rate from an adjacent country with similar characteristics. Prevalence rates were then derived from these incidence rates and applied to United Nations 2012 Revision population estimates for 2013 for each country to obtain estimates of the number of prevalent cases. Data availability was highest for the countries in Europe (76%) and lowest for the countries in sub-Saharan Africa (8%). The prevalence estimates indicate that there are almost 500,000 children aged under 15 years with type 1 diabetes worldwide, the largest numbers being in Europe (129,000) and North America (108,700). Countries with the highest estimated numbers of new cases annually were the United States (13,000), India (10,900) and Brazil (5000). Compared with the prevalence estimates made in previous editions of the IDF Diabetes Atlas, the numbers have increased in most of the IDF Regions, often reflecting the incidence rate increases that have been well-documented in many countries. Monogenic diabetes is increasingly being recognised among those with clinical features of type 1 or type 2 diabetes as genetic studies become available, but population-based data on incidence and prevalence show wide variation due to lack of standardisation in the studies. Similarly, studies on type 2 diabetes in childhood suggest increased incidence and prevalence in many countries, especially in Indigenous peoples and ethnic minorities, but detailed population-based studies remain limited.


Long-term follow-up of thoracoscopic talc pleurodesis for primary spontaneous pneumothorax.
The aim of the present study was to evaluate the long-term outcome of patients with primary spontaneous pneumothorax treated with talc pleurodesis. A follow-up study was undertaken in all patients with primary spontaneous pneumothorax who underwent talc pleurodesis for prolonged air leak or recurrence using thoracoscopy. In total, 112 patients underwent pleurodesis and follow-up data was obtained in 63 (56%) patients: 45 patients were available for clinical follow-up, 14 for telephone follow-up and four were dead. The causes of death were unrelated to the pleurodesis. There were no episodes of acute respiratory failure following pleurodesis. A total of 56 (95%) out of the cohort of 59 patients had a successful pleurodesis. Surgical pleurectomy was required in three (5%) patients for persistent air leak. Median duration of follow-up after talc pleurodesis was 118 months. Long-term success was observed in 53 (95%) out of 56 patients. Recurrent pneumothorax was observed in three (5%) out of 56 patients. Patients with successful talc pleurodesis had a median forced vital capacity (FVC) of 102% and median total lung capacity of 99% at follow-up. Comparing smokers and nonsmokers, the forced expiratory volume in one second (FEV(1)) was significantly lower in smokers and there was a tendency for the FEV(1)/FVC ratio to be lower in smokers. Talc pleurodesis in patients with primary spontaneous pneumothorax via thoracoscopy is an effective procedure associated with normal lung function in patients who do not smoke.


Hair Lead, Aluminum, and Other Toxic Metals in Normal-Weight and Obese Patients with Coronary Heart Disease.
The objective of the present study was to evaluate hair toxic metal levels in patients with obesity and/or coronary heart disease (CHD). Following a 2 × 2 factorial design, subjects without CHD were grouped into normal weight control (n = 123) and obese groups (n = 140). Patients suffering from CHD were divided into normal weight (n = 180) and obese CHD subjects (n = 240). Hair Al, As, Cd, Hg, Ni, and Pb levels were evaluated using inductively-coupled plasma mass-spectrometry. The data demonstrate that hair Al and Hg levels were higher in obese subjects as compared to normal weight controls. Normal weight CHD patients were characterized by significantly higher hair Al, As, Cd, and Pb levels when compared to healthy subjects. The highest hair Al, As, and Pb levels were observed in obese CHD patients, significantly exceeding the respective values in other groups. Factorial analysis revealed significant influence of factorial interaction (CHD*obesity) only for hair Pb content. Given the role of obesity as a risk factor for CHD, it is proposed that increased toxic metal accumulation in obesity may promote further development of cardiovascular diseases.


Atomistic simulation of tensile deformation behavior of ∑5 tilt grain boundaries in copper bicrystal.
Experiments on polycrystalline metallic samples have indicated that Grain boundary (GB) structure can affect many material properties related to fracture and plasticity. In this study, atomistic simulations are employed to investigate the structures and mechanical behavior of both symmetric and asymmetric ∑5[0 0 1] tilt GBs of copper bicrystal. First, the equilibrium GB structures are generated by molecular statics simulation at 0K. The results show that the ∑5 asymmetric GBs with different inclination angles (φ) are composed of only two structural units corresponding to the two ∑5 symmetric GBs. Molecular dynamics simulations are then conducted to investigate the mechanical response and the underlying deformation mechanisms of bicrystal models with different ∑5 GBs under tension. Tensile deformation is applied under both 'free' and 'constrained' boundary conditions. Simulation results revealed different mechanical properties of the symmetric and asymmetric GBs and indicated that stress state can play an important role in the deformation mechanisms of nanocrystalline materials.


European bats as carriers of viruses with zoonotic potential.
Bats are being increasingly recognized as reservoir hosts of highly pathogenic and zoonotic emerging viruses (Marburg virus, Nipah virus, Hendra virus, Rabies virus, and coronaviruses). While numerous studies have focused on the mentioned highly human-pathogenic bat viruses in tropical regions, little is known on similar human-pathogenic viruses that may be present in European bats. Although novel viruses are being detected, their zoonotic potential remains unclear unless further studies are conducted. At present, it is assumed that the risk posed by bats to the general public is rather low. In this review, selected viruses detected and isolated in Europe are discussed from our point of view in regard to their human-pathogenic potential. All European bat species and their roosts are legally protected and some European species are even endangered. Nevertheless, the increasing public fear of bats and their viruses is an obstacle to their protection. Educating the public regarding bat lyssaviruses might result in reduced threats to both the public and the bats.


Sustainable Surveillance of Neglected Tropical Diseases for the Post-Elimination Era.
The World Health Organization's (WHO's) 2030 road map for neglected tropical diseases (NTDs) emphasizes the importance of strengthened, institutionalized "post-elimination" surveillance. The required shift from disease-siloed, campaign-based programming to routine, integrated surveillance and response activities presents epidemiological, logistical, and financial challenges, yet practical guidance on implementation is lacking. Nationally representative survey programs, such as demographic and health surveys (DHS), may offer a platform for the integration of NTD surveillance within national health systems and health information systems. Here, we describe characteristics of DHS and other surveys conducted within the WHO Africa region in terms of frequency, target populations, and sample types and discuss applicability for post-validation and post-elimination surveillance. Maximizing utility depends not only on the availability of improved diagnostics but also on better understanding of the spatial and temporal dynamics of transmission at low prevalence. To this end, we outline priorities for obtaining additional data to better characterize optimal post-elimination surveillance platforms.


Evaluation of Gum of Moringa oleifera as a Binder and Release Retardant in Tablet Formulation.
The present study was undertaken to find out the potential of gum from Moringa oleifera to act as a binder and release retardant in tablet formulations. The effect of calcium sulphate dihydrate (water insoluble) and lactose (water soluble) diluent on the release of propranolol hydrochloride was studied. The DSC thermograms of drug, gum and mixture of gum/drug indicated no chemical interaction. Tablets (F1, F2, F3, and F4) were prepared containing calcium sulphate dihydrate as diluent, propranolol hydrochloride as model drug using 10%, 8%, 6% and 4% w/v of gum solution as binder. Magnesium stearate was used as lubricant. Physical and technological properties of granules and tablets like flow rate, Carr index, Hausner ratio, angle of repose, hardness, friability and disintegration time were determined and found to be satisfactory. Tablets were prepared by wet granulation method containing calcium sulphate dihydrate as excipient, propranolol hydrochloride as model drug using 10%, 20% and 30% of gum as release retardant, magnesium stearate was used as lubricant. Similarly tablets were prepared replacing lactose with calcium sulphate dihydrate. Despite of the widely varying physico-chemical characteristics of the excipients, the drug release profiles were found to be similar. The drug release increased with increasing proportions of the excipient and decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The values of release exponent 'n' are between 0.37 and 0.54. This implies that the release mechanism is Fickian. There is no evidence that the dissolution or erosion of the excipient has got any effect on the release of the drug. The t(50%) values for tablets containing calcium sulphate dihydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t(50%) values suggest that the nature of excipient used appeared to play a minor role in regulating the release, while the gum content was a major factor.


Russian gonococcal antimicrobial susceptibility programme (RU-GASP)--resistance in Neisseria gonorrhoeae during 2009-2012 and NG-MAST genotypes in 2011 and 2012.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major concern worldwide and gonococcal AMR surveillance globally is imperative for public health purposes. In Eastern Europe, gonococcal AMR surveillance is exceedingly rare. However, in 2004 the Russian gonococcal antimicrobial susceptibility programme (RU-GASP) was initiated. The aims of this study were to describe the prevalence and trends of gonococcal AMR from 2009 to 2012, and molecular epidemiological genotypes in 2011 and 2012 in Russia. Gonococcal isolates from 12-46 surveillance sites distributed across Russia, obtained in 2009 (n = 1200), 2010 (n = 407), 2011 (n = 423), and 2012 (n = 106), were examined for antimicrobial susceptibility using agar dilution method. Gonococcal isolates from 2011 and 2012 were investigated with N. gonorrhoeae multi-antigen sequence typing (NG-MAST). During 2009-2012, the proportions of gonococcal isolates resistant to ciprofloxacin, penicillin G, azithromycin and spectinomycin ranged from 25.5% to 44.4%, 9.6% to 13.2%, 2.3% to 17.0% and 0.9% to 11.6%, respectively. Overall, the resistance level to penicillin G was stable, the resistance level to ciprofloxacin was decreasing, however, the level of resistance to azithromycin increased. All isolates were susceptible to ceftriaxone using the US CLSI breakpoints. However, using the European breakpoints 58 (2.7%) of the isolates were resistant to ceftriaxone. Interestingly, this proportion was decreasing, i.e. from 4.8% in 2009 to 0% in 2012. In Russia, the diversified gonococcal population showed a high resistance to ciprofloxacin, penicillin G and azithromycin. In general, the MICs of ceftriaxone were relatively high, however, they were decreasing from 2009 to 2012. Ceftriaxone should be the first-line for empiric antimicrobial monotherapy of gonorrhoea in Russia. It is essential to further strengthen the surveillance of gonococcal AMR (ideally also gonorrhoea treatment failures) in Russia.


Diversity and dynamics of bacterial communities in early life stages of the Caribbean coral Porites astreoides.
In this study, we examine microbial communities of early developmental stages of the coral Porites astreoides by sequence analysis of cloned 16S rRNA genes, terminal restriction fragment length polymorphism (TRFLP), and fluorescence in situ hybridization (FISH) imaging. Bacteria are associated with the ectoderm layer in newly released planula larvae, in 4-day-old planulae, and on the newly forming mesenteries surrounding developing septa in juvenile polyps after settlement. Roseobacter clade-associated (RCA) bacteria and Marinobacter sp. are consistently detected in specimens of P. astreoides spanning three early developmental stages, two locations in the Caribbean and 3 years of collection. Multi-response permutation procedures analysis on the TRFLP results do not support significant variation in the bacterial communities associated with P. astreoides larvae across collection location, collection year or developmental stage. The results are the first evidence of vertical transmission (from parent to offspring) of bacteria in corals. The results also show that at least two groups of bacterial taxa, the RCA bacteria and Marinobacter, are consistently associated with juvenile P. astreoides against a complex background of microbial associations, indicating that some components of the microbial community are long-term associates of the corals and may impact host health and survival.


The Evolutionary Origin and Genetic Makeup of Domestic Horses.
The horse was domesticated only 5.5 KYA, thousands of years after dogs, cattle, pigs, sheep, and goats. The horse nonetheless represents the domestic animal that most impacted human history; providing us with rapid transportation, which has considerably changed the speed and magnitude of the circulation of goods and people, as well as their cultures and diseases. By revolutionizing warfare and agriculture, horses also deeply influenced the politico-economic trajectory of human societies. Reciprocally, human activities have circled back on the recent evolution of the horse, by creating hundreds of domestic breeds through selective programs, while leading all wild populations to near extinction. Despite being tightly associated with humans, several aspects in the evolution of the domestic horse remain controversial. Here, we review recent advances in comparative genomics and paleogenomics that helped advance our understanding of the genetic foundation of domestic horses.


Quality indicators in gastroscopy. Gastroscopy procedure.
Within the project "Quality indicators in digestive endoscopy", pioneered by the Spanish Society for Digestive Diseases (SEPD), the objective of this research is to suggest the structure, process, and results procedures and indicators necessary to implement and assess quality in the gastroscopy setting. First, a chart was designed with the steps to be followed during a gastroscopy procedure. Secondly, a team of experts in care quality and/or endoscopy performed a qualitative review of the literature searching for quality indicators for endoscopic procedures, including gastroscopies. Finally, using a paired analysis approach, a selection of the literature obtained was undertaken. For gastroscopy, a total of nine process indicators were identified (one preprocedure, eight intraprocedure). Evidence quality was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification scale.


Pomegranate (Punica granatum) seed linolenic acid isomers: concentration-dependent modulation of estrogen receptor activity.
Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 microM, ERbeta at 8.8 microM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 microM. PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 microM, antagonizing at 101/80 microM. AEA antagonized ERalpha/ERbeta at 150/140 microM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.


Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Penicillin-Susceptible and Penicillin-Resistant Pneumococcal Pneumonia.
Therapy to enhance host immune defenses may improve outcomes in serious infections, especially for antibiotic-resistant pathogens. Recombinant human plasma gelsolin (rhu-pGSN), a normally circulating protein, has beneficial effects in diverse preclinical models of inflammation and injury. We evaluated delayed therapy (24-48 hours after challenge) with rhu-pGSN in a mouse model of pneumococcal pneumonia. rhu-pGSN without antibiotics increased survival and reduced morbidity and weight loss after infection with either penicillin-susceptible or penicillin-resistant pneumococci (serotypes 3 and 14, respectively). rhu-pGSN improves outcomes in a highly lethal pneumococcal pneumonia model when given after a clinically relevant delay, even in the setting of antimicrobial resistance.


Cost-Effectiveness of Integrating Tobacco Cessation Into Post-Traumatic Stress Disorder Treatment.
We examined the cost-effectiveness of smoking cessation integrated with treatment for post-traumatic stress disorder (PTSD). Smoking veterans receiving care for PTSD (N = 943) were randomized to care integrated with smoking cessation versus referral to a smoking cessation clinic. Smoking cessation services, health care cost and utilization, quality of life, and biochemically-verified abstinence from cigarettes were assessed over 18-months of follow-up. Clinical outcomes were combined with literature on changes in smoking status and the effect of smoking on health care cost, mortality, and quality of life in a Markov model of cost-effectiveness over a lifetime horizon. We discounted cost and outcomes at 3% per year and report costs in 2010 US dollars. The mean of smoking cessation services cost was $1286 in those randomized to integrated care and $551 in those receiving standard care (P < .001). There were no significant differences in the cost of mental health services or other care. After 12 months, prolonged biochemically verified abstinence was observed in 8.9% of those randomized to integrated care and 4.5% of those randomized to standard care (P = .004). The model projected that Integrated Care added $836 in lifetime cost and generated 0.0259 quality adjusted life years (QALYs), an incremental cost-effectiveness ratio of $32 257 per QALY. It was 86.0% likely to be cost-effective compared to a threshold of $100 000/QALY. Smoking cessation integrated with treatment for PTSD was cost-effective, within a broad confidence region, but less cost-effective than most other smoking cessation programs reported in the literature.


Surveillance for foodborne-disease outbreaks--United States, 1988-1992.
Since 1973, CDC has maintained a collaborative surveillance program for collection and periodic reporting of data concerning the occurrence and causes of foodborne-disease outbreaks (FBDOs). This summary reviews data from January 1988 through December 1992. The surveillance system reviews data concerning FBDOs--defined as the occurrence of two or more cases of a similar illness resulting from the ingestion of a common food. Before 1992, only one case of intoxication by chemical, marine toxin, or Clostridium botulinum toxin as a result of the ingestion of food was required to constitute an FBDO. Since 1992, two or more cases have been required. State and local public health departments have primary responsibility for the identifying and investigating FBDOs. State and territorial health departments report these outbreaks to CDC on a standard form. During 1988-1992, a total of 2,423 outbreaks of foodborne disease were reported (451 in 1988, 505 in 1989, 532 in 1990, 528 in 1991, and 407 in 1992). These outbreaks caused a reported 77,373 persons to become ill. Among outbreaks for which the etiology was determined, bacterial pathogens caused the largest percentage of outbreaks (79%) and the largest percentage of cases (90%). Salmonella serotype Enteritidis accounted for the largest number of outbreaks, cases, and deaths; most of these outbreaks were attributed to eating undercooked, infected eggs. Chemical agents caused 14% of outbreaks and 2% of cases; parasites, 2% of outbreaks and 1% of cases; and viruses, 4% of outbreaks and 6% of cases. The number of FBDOs reported per year did not change substantially during the first 4 years but declined in 1992 as a result of the revised definition of an outbreak. During this reporting period, S. Enteritidis continued to be a major cause of morbidity and mortality. In addition, multistate outbreaks caused by contaminated produce and outbreaks caused by Escherichia coli O157:H7 became more prominent. State and local public health departments investigate FBDOs. At the regional and national level, surveillance data provide an indication of the etiologic agents, vehicles of transmission, and contributing factors associated with FBDOs and help direct public health actions.


Mycobacterium tuberculosis treatment modalities and recent insights.
Antimicrobial therapy of infections caused by M. tuberculosis is a challenge due to poor response to therapy and recurrent infections. Under in vitro conditions, antibiotics effectively kill M. tuberculosis within the first two weeks. However, an extended treatment time of 6-9 months is required to eradicate M. tuberculosis infection, mainly due to the intracellular survival of this pathogen and poor penetration of the antibiotics into the intracellular compartment of the host cells. Recent advances in the field of drug delivery have led to the use of different antibiotic incorporated nano- and micro- formulations such as liposomes, polymeric particles, mesoporous silica particles and particulate suspensions for targeted drug delivery applications into the intracellular compartment of the macrophages. The drug incorporated nano- and micro-particles are prone to be easily internalized, which leads to preferential delivery of the drugs into the tissues and organs of interest. Other advantages of these nano- and micro-particles over the free drugs are their comparatively higher stability and bioavailability. This review highlights the current strategies and challenges in treatment, the different antibiotics available, their modes of action, generation and mechanism of drug resistance and recent advances in the intracellular drug delivery using nanoparticles for the treatment of tuberculosis.


Nutrient transitions are a source of persisters in Escherichia coli biofilms.
Chronic and recurrent infections have been attributed to persisters in biofilms, and despite this importance, the mechanisms of persister formation in biofilms remain unclear. The plethora of biofilm characteristics that could give rise to persisters, including slower growth, quorum signaling, oxidative stress, and nutrient heterogeneity, have complicated efforts to delineate formation pathways that generate persisters during biofilm development. Here we sought to specifically determine whether nutrient transitions, which are a common metabolic stress encountered within surface-attached communities, stimulate persister formation in biofilms and if so, to then identify the pathway. To accomplish this, we established an experimental methodology where nutrient availability to biofilm cells could be controlled exogenously, and then used that method to discover that diauxic carbon source transitions stimulated persister formation in Escherichia coli biofilms. Previously, we found that carbon source transitions stimulate persister formation in planktonic E. coli cultures, through a pathway that involved ppGpp and nucleoid-associated proteins, and therefore, tested the functionality of that pathway in biofilms. Biofilm persister formation was also found to be dependent on ppGpp and nucleoid-associated proteins, but the importance of specific proteins and enzymes between biofilm and planktonic lifestyles was significantly different. Data presented here support the increasingly appreciated role of ppGpp as a central mediator of bacterial persistence and demonstrate that nutrient transitions can be a source of persisters in biofilms.


The integrated microbial genomes system: an expanding comparative analysis resource.
The integrated microbial genomes (IMG) system serves as a community resource for comparative analysis of publicly available genomes in a comprehensive integrated context. IMG contains both draft and complete microbial genomes integrated with other publicly available genomes from all three domains of life, together with a large number of plasmids and viruses. IMG provides tools and viewers for analyzing and reviewing the annotations of genes and genomes in a comparative context. Since its first release in 2005, IMG's data content and analytical capabilities have been constantly expanded through regular releases. Several companion IMG systems have been set up in order to serve domain specific needs, such as expert review of genome annotations. IMG is available at http://img.jgi.doe.gov.


Structural vascular disease in Africans: Performance of ethnic-specific waist circumference cut points using logistic regression and neural network analyses: The SABPA study.
A recently proposed model for waist circumference cut points (RPWC), driven by increased blood pressure, was demonstrated in an African population. We therefore aimed to validate the RPWC by comparing the RPWC and the Joint Statement Consensus (JSC) models via Logistic Regression (LR) and Neural Networks (NN) analyses. Urban African gender groups (N=171) were stratified according to the JSC and RPWC cut point models. Ultrasound carotid intima media thickness (CIMT), blood pressure (BP) and fasting bloods (glucose, high density lipoprotein (HDL) and triglycerides) were obtained in a well-controlled setting. The RPWC male model (LR ROC AUC: 0.71, NN ROC AUC: 0.71) was practically equal to the JSC model (LR ROC AUC: 0.71, NN ROC AUC: 0.69) to predict structural vascular -disease. Similarly, the female RPWC model (LR ROC AUC: 0.84, NN ROC AUC: 0.82) and JSC model (LR ROC AUC: 0.82, NN ROC AUC: 0.81) equally predicted CIMT as surrogate marker for structural vascular disease. Odds ratios supported validity where prediction of CIMT revealed -clinical -significance, well over 1, for both the JSC and RPWC models in African males and females (OR 3.75-13.98). In conclusion, the proposed RPWC model was substantially validated utilizing linear and non-linear analyses. We therefore propose ethnic-specific WC cut points (African males, ≥90 cm; -females, ≥98 cm) to predict a surrogate marker for structural vascular disease.


Oblique human symphyseal angle is associated with an evolutionary rate-shift early in the hominin clade.
The rate of change in primate mandibular symphyseal angles was modeled with particular aim of locating a rate-shift within the hominin clade. Prior work noted that the human symphyseal angle must have experienced a rapid rate of change in order to assume the modern human form, suggestive of the non-random work of natural selection. This study indicates that the rate of symphyseal evolution rose dramatically between Australopithecus anamensis and Australopithecus afarensis and continued throughout the diversification of the hominin clade. Noting the timing of this event, we speculate as to what ecological factors could have been at play in driving this rearrangement of the anterior mandible, contributing to the eventual appearance of the human chin.


Coronary microvascular dysfunction in patients with stable coronary artery disease: The CE-MARC 2 coronary physiology sub-study.
In patients with angina undergoing invasive management, no obstructive coronary artery disease (NOCAD) is a common finding, and angina may persist following percutaneous coronary intervention (PCI). Coronary microvascular dysfunction may be relevant. We aimed to assess the proportion of patients presenting with suspected CAD who had coronary microvascular dysfunction. Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC 2) was a prospective multicenter randomised controlled trial of functional imaging versus guideline-based management in patients with suspected CAD. Invasive coronary angiography was protocol-directed. Fractional flow reserve (FFR) and parameters of microvascular function (coronary flow reserve (CFR), index of microcirculatory resistance (IMR), resistance reserve ratio (RRR)) were measured in major epicardial coronary arteries with ≥40-≤90% diameter stenosis. An FFR value ≤0.80 indicated the presence of obstructive CAD. 267/1202 (22.2%) patients underwent angiography and 81 (30%) patients had FFR measured. 63 (78%) of these patients had microvascular function assessed in 85 arteries (mean age 58.5 ± 8.2 years; 47 (75%) male). 25/63 (40%) patients had NOCAD, and of these, 17 (68%) had an abnormality ≥1 parameter of microvascular function (abnormal IMR (≥25), abnormal CFR (<2.0), and abnormal RRR (<2.0) occurred in 10 (40%), 12 (48%), and 11 (44%), respectively). 38/63 (60%) patients had obstructive epicardial CAD. Of these patients, 15/38 (39%), 20/38 (53%), and 12/38 (32%) had an abnormal IMR, CFR and RRR, respectively. Coronary microvascular dysfunction is common in patients with angina. Invasive assessment of microvascular function may be informative and relevant for decision-making in patients with both NOCAD and obstructive epicardial CAD. ClinicalTrials.gov Identifier: NCT01664858.


A claim in search of evidence: reply to Manger's thermogenesis hypothesis of cetacean brain structure.
In a recent publication in Biological Reviews, Manger (2006) made the controversial claim that the large brains of cetaceans evolved to generate heat during oceanic cooling in the Oligocene epoch and not, as is the currently accepted view, as a basis for an increase in cognitive or information-processing capabilities in response to ecological or social pressures. Manger further argued that dolphins and other cetaceans are considerably less intelligent than generally thought. In this review we challenge Manger's arguments and provide abundant evidence that modern cetacean brains are large in order to support complex cognitive abilities driven by social and ecological forces.


Identifying cancer patients with greater need for information about sexual issues.
The aim of the research was to identify cancer patients who may have a greater need about sexuality-related information. The study explored the association between sexuality-related information need and socio-demographic factors, cancer type, types of cancer treatment, experienced adverse effects on sexuality, and changes experienced in relationships. This study used a survey design. Questionnaires were distributed and completed by 505 patients, with a diversity of cancer diagnoses, treated at a university hospital in Finland in 2009 and 2010. Information needs were rated using the international and well validated Information Needs Questionnaire (INQ). Sosiodemographic factors, cancer type, treatments, experienced adverse effects on sexuality and changed experienced in relationships were measured by using another questionnaire. Those patients with experiences of functional problems or other adverse effects on sexuality due to cancer or treatment found sexuality related information more important than those with no experiences of adverse effects on sexuality. Patients with experiences of weakened relationships due to cancer had greater information needs than those with experiences of strengthened relationships or no changes in relationships due to cancer. Cancer patients should be asked whether cancer or treatment has caused problems in their sexuality and possible relationships. Patients who experience problems in their sexuality or relationships should be provided an opportunity to discuss the issues. The whole oncology team have a role to play in patient sexuality guidance. The items on the INQ could be used as a reference tool for exploring patients' information needs.


Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise.
Brain endothelial cells form the blood-brain barrier (BBB) that regulates solute and macromolecule flux in and out of the brain, leukocyte migration, and maintains the homeostasis of the central nervous system. BBB dysfunction is associated with disruption of tight junctions (TJ) in the brain endothelium. We propose that alcohol abuse may impair BBB permeability through TJ modification. Primary cultured bovine brain microvascular endothelial cells (BBMEC) were treated with 50 mM ethanol (EtOH), and monolayer tightness was assessed by measurement of transendothelial electrical resistance (TEER). Changes in TEER were correlated with alterations in TJ protein distribution [occludin, zonula occludens-1 (ZO-1), claudin-5] using immunofluorescence (IF). Expression of myosin light chain (MLC) kinase (MLCK), ZO-1, claudin-5, and phosphorylated MLC, occludin and claudin-5 were determined by immunoprecipitation and Western blot. EtOH-induced changes in monocyte migration across in vitro BBB constructs were also examined. EtOH induced a decrease in TEER of BBMEC monolayers that was reversed by EtOH withdrawal. Treatment of BBMEC with EtOH or its metabolite, acetaldehyde, prior to monocyte application resulted in a 2-fold increase in monocyte migration across the BBB. IF demonstrated decrease in claudin-5 staining, occludin translocation from cell borders to cytoplasm and gap formation in EtOH-treated BBMEC monolayer. These changes paralleled significant increase in phosphorylation of MLC, occludin and claudin-5. EtOH-treated BBMEC showed reduction of total occludin and claudin-5 without changes in ZO-1 or MLC. TEER decrease, changes in occludin/claudin staining, increase in MLC, occludin and claudin-5 phosphorylation and enhanced monocyte migration across the BBB were all reversed by inhibition of MLCK. Inhibition of EtOH metabolism in BBMEC also reversed these events. These results suggest that EtOH activates MLCK leading to phosphorylation of MLC, occludin and claudin-5. Cytoskeletal alterations (MLC) and TJ changes (occludin and claudin-5 phosphorylation) result in BBB impairment (decrease in TEER). TJ compromise is associated with increased monocyte migration across the BBB.


A multiinstitutional review of central venous line complications: retained intravascular fragments.
There have been many reports of complications of central venous lines in children but limited discussion of the specific problem of retained intravascular fragments after attempted removal. We report on a series of 6 patients from 2 tertiary pediatric hospitals that had intravascular segments of long-term central venous lines that could not be removed and so were left in situ. We conducted a retrospective multiinstitutional review of long-term central venous lines (Broviacs, Port-A-Caths, and Hickmans) removed in the operating room with a focused chart review and prospective follow-up of those patients that had a failed attempt at removal. A total of 299 central venous lines were removed with 6 patients identified as having fragments of lines left behind (2%). The lines had been in place for an average of 37 +/- 12 months. The average follow-up period is now 5.4 +/- 3.9 years; none of the patients have developed any symptoms, evidence of thrombus, infection, or catheter migration. Given the 2% incidence rate, the issue of managing a stuck long-term central venous line will face most individuals who place these lines. We have demonstrated that simply ligating the catheter and leaving the fragment in place appears to be a safe option with minimal risk to the patient.


Modelling of the cathodic and anodic photocurrents from Rhodobacter sphaeroides reaction centres immobilized on titanium dioxide.
As one of a number of new technologies for the harnessing of solar energy, there is interest in the development of photoelectrochemical cells based on reaction centres (RCs) from photosynthetic organisms such as the bacterium Rhodobacter (Rba.) sphaeroides. The cell architecture explored in this report is similar to that of a dye-sensitized solar cell but with delivery of electrons to a mesoporous layer of TiO2 by natural pigment-protein complexes rather than an artificial dye. Rba. sphaeroides RCs were bound to the deposited TiO2 via an engineered extramembrane peptide tag. Using TMPD (N,N,N',N'-tetramethyl-p-phenylenediamine) as an electrolyte, these biohybrid photoactive electrodes produced an output that was the net product of cathodic and anodic photocurrents. To explain the observed photocurrents, a kinetic model is proposed that includes (1) an anodic current attributed to injection of electrons from the triplet state of the RC primary electron donor (PT) to the TiO2 conduction band, (2) a cathodic current attributed to reduction of the photooxidized RC primary electron donor (P+) by surface states of the TiO2 and (3) transient cathodic and anodic current spikes due to oxidation/reduction of TMPD/TMPD+ at the conductive glass (FTO) substrate. This model explains the origin of the photocurrent spikes that appear in this system after turning illumination on or off, the reason for the appearance of net positive or negative stable photocurrents depending on experimental conditions, and the overall efficiency of the constructed cell. The model may be a used as a guide for improvement of the photocurrent efficiency of the presented system as well as, after appropriate adjustments, other biohybrid photoelectrodes.


Imaging of multidrug resistance in cancer.
Primary intrinsic and/or acquired multidrug resistance (MDR) is the main obstacle to successful cancer treatment. Functional molecular imaging of MDR in cancer using single photon or positron emitters may be helpful to identify multidrug-resistant tumours and predict not only those patients who are resistant to treatment, with a clinically unfavourable prognosis, but also those who are susceptible to the development of drug toxicity or even certain tumours . Variations in the mdr1 gene product may directly affect the therapeutic effectiveness, and single nucleotide polymorphisms for the mdr1 gene may be associated with altered oral bioavailability of MDR1 substrates, drug resistance, and a susceptibility to some human diseases. The challenge of translating the concept of MDR modulation in vivo involves a complex cellular interplay between both malignant and normal cells. Integration and correlation of functional single photon emission tomography or positron emission tomography imaging findings with mdr1 genotype and clinical data may contribute to efficient management by selecting cancer patients with the appropriate molecular phenotype for maximal individual therapeutic benefit, as well as those who are non-responders. This review describes a role for functional imaging of classical mechanisms of MDR with an emphasis on readily available [(99m)Tc]MIBI scintigraphy. MIBI scintigraphy has been shown to be a non-invasive cost-effective in vivo assay of ATP-binding cassette transporters associated with MDR in cancer, including P-glycoprotein, multidrug-resistant protein 1 and breast cancer resistant protein. New imaging agents for molecular targets such as vascular endothelial growth factor and HER2 receptors, may potentially be combined with MDR imaging substrates to more accurately predict the therapeutic response to anticancer drugs, guiding individualised treatment while minimising the economic health costs of ineffective therapy in an era of personalised medicine.


Internationally educated nurses in Canada: predictors of workforce integration.
Global trends in migration accompanied with recent changes to the immigrant selection process may have influenced the demographic and human capital characteristics of internationally educated nurses (IENs) in Canada and in turn the assistance required to facilitate their workforce integration. This study aimed to describe the demographic and human capital profile of IENs in Canada, to explore recent changes to the profile, and to identify predictors of IENs' workforce integration. A cross-sectional, descriptive, correlational survey design was used. Eligible IENs were immigrants, registered and employed as regulated nurses in Canada. Data were collected in 2014 via online and paper questionnaires. Descriptive statistics were used to examine the data by year of immigration. Logistic regression modeling was employed to identify predictors of IENs' workforce integration measured as passing the licensure exam to acquire professional recertification and securing employment. The sample consisted of 2280 IENs, representative of all Canadian provincial jurisdictions. Since changes to the immigrant selection process in 2002, the IEN population in Canada has become more racially diverse with greater numbers emigrating from developing countries. Recent arrivals (after 2002) had high levels of human capital (knowledge, professional experience, language proficiency). Some, but not all, benefited from the formal and informal assistance available to facilitate their workforce integration. Professional experience and help studying significantly predicted if IENs passed the licensure exam on their first attempt. Bridging program participation and assistance from social networks in Canada were significant predictors if IENs had difficulty securing employment. Nurses will continue to migrate from a wide variety of countries throughout the world that have dissimilar nursing education and health systems. Thus, IENs are not a homogenous group, and a "one size fits all" model may not be effective for facilitating their professional recertification and employment in the destination country. Canada, as well as other countries, could consider using a case management approach to develop and tailor education and forms of assistance to meet the individual needs of IENs. Using technology to reach IENs who have not yet immigrated or have settled outside of urban centers are other potential strategies that may facilitate their timely entrance into the destination countries' nursing workforce.


Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke.
Analyses of some randomised trials show that calcium-channel blockers reduce the risk of stroke more than expected on the basis of mean blood pressure alone and that beta blockers are less effective than expected. We aimed to investigate whether the effects of these drugs on variability in blood pressure might explain these disparities in effect on stroke risk. The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) compared amlodipine-based regimens with atenolol-based regimens in 19 257 patients with hypertension and other vascular risk factors and the Medical Research Council (MRC) trial compared atenolol-based and diuretic-based regimens versus placebo in 4396 hypertensive patients aged 65-74 years. We expressed visit-to-visit variability of blood pressure during follow-up in the two trials as standard deviation (SD) and as transformations uncorrelated with mean blood pressure. For ASCOT-BPLA, we also studied within-visit variability and variability on 24 h ambulatory blood-pressure monitoring (ABPM). In ASCOT-BPLA, group systolic blood pressure (SBP) SD was lower in the amlodipine group than in the atenolol group at all follow-up visits (p<0.0001), mainly because of lower within-individual visit-to-visit variability. Within-visit and ABPM variability in SBP were also lower in the amlodipine group than in the atenolol group (all p<0.0001). Analysis of changes from baseline showed that variability decreased over time in the amlodipine group and increased in the atenolol group. The lower risk of stroke in the amlodipine group (hazard ratio 0.78, 95% CI 0.67-0.90) was partly attenuated by adjusting for mean SBP during follow-up (0.84, 0.72-0.98), but was abolished by also adjusting for within-individual SD of clinic SBP (0.99, 0.85-1.16). Findings were similar for coronary events. In the ABPM substudy, reduced variability in daytime SBP in the amlodipine group (p<0.0001) partly accounted for the reduced risk of vascular events, but reduced visit-to-visit variability in clinic SBP had a greater effect. In the MRC trial, group SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo group and the diuretic group during initial follow-up (all p<0.0001). Subsequent temporal trends in variability in blood pressure during follow-up in the atenolol group correlated with trends in stroke risk. The opposite effects of calcium-channel blockers and beta blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure. To prevent stroke most effectively, blood-pressure-lowering drugs should reduce mean blood pressure without increasing variability; ideally they should reduce both.


Site-specific response of bone to exercise in premenopausal women.
We studied the response of bone at specific skeletal sites to either lower body exercise alone or complemented with upper body exercise in premenopausal women. Thirty-five exercisers and 24 age-matched controls completed the 12-month study. Exercising women (N = 35) were randomly assigned to either lower body resistance plus jump exercise (LOWER) (N = 19) or to lower and upper body resistance plus jump exercise (UPPER + LOWER) (N = 16). Exercisers trained three times per week completing 100 jumps and 100 repetitions of lower body resistance with or without 100 repetitions of upper body resistance exercise at each session. Intensity for lower body exercise was increased using weighted vests for jump and resistance exercises, respectively. Intensity for upper body exercise was increased using greater levels of tautness in elastic bands. Bone mineral density (BMD) at the total hip, greater trochanter, femoral neck, lumbar spine and whole body were measured by dual energy X-ray absorptiometry (Hologic QDR-1000/W) at baseline, 6 and 12 months. Data were analyzed first including all enrolled participants who completed follow-up testing and secondly including only those women whose average attendance was > or =60% of prescribed sessions. Group differences in 12-month %change scores for BMD variables were analyzed by univariate ANCOVA adjusted for baseline differences in age. Post hoc tests were performed to determine which groups differed from one another. Initial analysis showed significant differences in greater trochanter BMD between each exercise group and controls, but not between exercise groups (2.7%+/-2.5% and 2.2%+/-2.8% vs. 0.7%+/-1.7%, for LOWER and UPPER + LOWER vs. controls, respectively; p < 0.02) and near significant group differences at the spine (p = 0.06). Excluding exercisers with low compliance, group differences at the greater trochanter remained, while spine BMD in UPPER + LOWER was significantly different from LOWER and controls, who were not significantly different from one another (1.4%+/-3.9% vs. -0.9%+/-1.7% and -0.6%+/-1.8%, for UPPER + LOWER vs. LOWER and controls, respectively; p < 0.05). No significant differences among groups were found for femoral neck, total hip or whole body BMD. Our data support the site-specific response of spine and hip bone density to upper and lower body exercise training, respectively. These data could contribute to a site-specific exercise prescription for bone health.


Prognosis of different glaucomas seen at a tertiary center: A 10-year overview.
This study aims to determine treatment patterns, long-term intraocular pressure (IOP) and perimetric control in different glaucomas seen at a tertiary eye center. Hospital-based, cross-sectional chart review of patients routinely following up at an outpatient glaucoma service. Patients with a follow-up of at least 10 years were evaluated. Their mean IOP, visual field (VF) status, and medications/surgery required at final assessment were noted. Descriptive statistics (mean, standard deviation, and range) were used for all parameters. A total of 230 patients met our inclusion and exclusion criteria, 79 having ocular hypertension with open angles or primary angle closure (PAC), 35 primary open angle glaucoma (POAG), 50 PAC glaucoma (PACG), 20 primary congenital glaucoma (PCG), 46 secondary glaucoma patients. Ocular hypertensives with open angles showed progression to POAG in 3.7%, those with PAC in 5.2%, at a mean IOP of 17.3 ± 3.37 mmHg and 17.13 ± 4.41 mmHg, respectively. A progression on Humphrey Field Analyzer was seen in 11% of POAG and PACG eyes at a mean IOP of 13.50 ± 5.07 and 13.09 ± 3.95 mmHg, respectively. Fifteen percent of primary congenital glaucomas (PCGs) showed a glaucomatous VF defect after 10 years. In secondary glaucoma eyes, the mean IOP at last follow-up visit was 12.38 ± 3.74 mmHg, with progression noted in 7.69% of eyes. This study provides evidence that routine delivery of care can provide well controlled IOP in glaucomas, both primary and secondary, and the VF stabilized in about 90% of patients over a period of 10 years, with the currently available glaucoma medications and trabeculectomy.


[Fluoride concentration in drinking water in small villages in the Cape province].
The purpose of the study was to update existing tables on the fluoride content of drinking water and thereby help curb its fluoride overdose from the use of fluoride containing tablets. The fluoride concentration in the drinking water of 57 villages in the Cape Province was determined by a combination fluoride ion selective electrode. This investigation showed that the number of available water sources decreased as follows: boreholes greater than dams greater than fountains = canals. Furthermore, boreholes contained more fluoride in the drinking water than fountains, dams or canals (p less than 0.10). Five out of 41 boreholes have less than or equal to 0.10 parts per million (ppm) fluoride in the drinking water, while 17 out of 26 dams, 4 out of 13 rivers and 3 out of 5 fountains and canals contained less than or equal to 0.10 ppm fluoride.


cobA function is required for both de novo cobalamin biosynthesis and assimilation of exogenous corrinoids in Salmonella typhimurium.
Salmonella typhimurium is able to synthesize cobalamin (B12) under anaerobic growth conditions. The previously described cobalamin biosynthetic mutations (phenotypic classes CobI, CobII, and CobIII) map in three operons located near the his locus (minute 41). A new class of mutant (CobIV) defective in B12 biosynthesis was isolated and characterized. These mutations map between the cysB and trp loci (minute 34) and define a new genetic locus, cobA. The anaerobic phenotype of cobA mutants suggests an early block in corrin ring formation; mutants failed to synthesize cobalamin de novo but did so when the corrin ring is provided as cobyric acid dicyanide or as cobinamide dicyanide. Under aerobic conditions, cobA mutants were unable to convert either cobyric acid dicyanide or cobinamide dicyanide to cobalamin but could use adenosylcobyric acid or adenosylcobinamide as a precursor; this suggests that the mutants are unable to adenosylate exogenous corrinoids. To explain the anaerobic CobI phenotype of a cobA mutant, we propose that the cobA gene product catalyzes adenosylation of an early intermediate in the de novo B12 pathway and also adenosylates exogenous corrinoids. Under anaerobic conditions, a substitute function, known to be encoded in the main Cob operons, is induced; this substitute function can adenosylate exogenous cobyric acid and cobinamide but not the early biosynthetic intermediate. The cobA gene of S. typhimurium appears to be functionally equivalent to the btuR gene of Escherichia coli.


The Extent and Specificity of Relative Age Effects on Mental Health and Functioning in Early Adolescence.
Although extensive evidence indicates that being younger within a school cohort is associated with poorer academic functioning, much less is known about such relative age effects (RAEs) for mental health--the focus of the current investigation. Data from 23,379 11- to 13-year-olds attending state-maintained secondary schools in England were analyzed to investigate RAEs on mental health measured using the Strengths and Difficulties Questionnaire. Participants were grouped into oldest, middle, and youngest thirds of their academic year based on their month of birth relative to their cohort. Hierarchical linear regression analysis evaluated RAEs and gender- or deprivation-related moderation of such effects. Relatively younger adolescents had significantly more emotional symptoms and peer problems compared with relatively older individuals in a year group, although effect sizes were small. These effects were not moderated by gender or deprivation. Impact of mental health difficulties on other aspects of functioning was also greater among relatively younger children. Larger RAEs are observed in the younger cohort (11-12 years) compared with those in the 12- to 13-year-olds, thereby indicating that RAEs might attenuate with age. Being relatively younger than classmates is associated with increased internalizing symptoms, poorer peer relationships, and higher impact of mental health difficulties on functioning at school and home. The findings support wider inclusion of relative age in understanding mental health difficulties and its inclusion as a potential risk factor in studies investigating the development of psychopathology, especially for internalizing symptoms. Possible mechanisms of the effects detected are discussed.


Using simplified models to communicate the importance of prevention, detection and preparedness before a disease outbreak.
Frontline farm workers and veterinary-policy-makers are arguably in the best positions to influence prevention, detection, and preparedness-for-control of farm animal diseases. It is important that such individuals make biologically sound decisions concerning the daily management and regulation of the health of animals. Such decisions should be based on a good understanding of key principles of disease spread and control. This paper summarises these principles, as described in previous publications, into simple models. These models may be used to communicate concepts to readers who may not have time to study more complex models. These models illustrate the relationship between the development of new disease cases (from existing cases, i.e., the reproductive ratio R) and (i) the duration of the period during which existing cases are available as infectious, (ii) contact rates, (iii) transmission rates and (iv) susceptibility. Understanding these concepts through models has great utility, facilitating better decisions for disease prevention, detection and preparedness-for-control, before an outbreak becomes unmanageable. These basic concepts apply to all animal species, including humans.


Saying "no" to professional recommendations: client values, beliefs, and evidence-based practice.
The purpose of this article is to explore the phenomenon of saying "no" to secondary prevention recommended by healthcare providers. Extracted findings from two qualitative studies in which participants have said "no" to provider recommendations for secondary prevention, specifically screening mammograms or treatment for latent tuberculosis infection, are discussed. Although these two studies focus on different aspects of secondary prevention, both studies emphasize how client values and beliefs impact health decisions. In evidence-based practice (EBP), both scientific evidence and client values and beliefs must be considered. Nurse practitioners (NPs) have the skill set and are in a position to assist clients to mediate between their values and beliefs and current scientific evidence. Several findings from the two qualitative studies are relevant for practice: qualitative studies provide information about values and beliefs for EBP, and findings from these particular qualitative studies demonstrated that women were protective about their health even though their values and beliefs did not align with current scientific evidence. Through client narratives, NPs can facilitate clients aligning personal values and beliefs with current scientific evidence in relationship to caring for self.


Detection of nonneutral substitution rates on mammalian phylogenies.
Methods for detecting nucleotide substitution rates that are faster or slower than expected under neutral drift are widely used to identify candidate functional elements in genomic sequences. However, most existing methods consider either reductions (conservation) or increases (acceleration) in rate but not both, or assume that selection acts uniformly across the branches of a phylogeny. Here we examine the more general problem of detecting departures from the neutral rate of substitution in either direction, possibly in a clade-specific manner. We consider four statistical, phylogenetic tests for addressing this problem: a likelihood ratio test, a score test, a test based on exact distributions of numbers of substitutions, and the genomic evolutionary rate profiling (GERP) test. All four tests have been implemented in a freely available program called phyloP. Based on extensive simulation experiments, these tests are remarkably similar in statistical power. With 36 mammalian species, they all appear to be capable of fairly good sensitivity with low false-positive rates in detecting strong selection at individual nucleotides, moderate selection in 3-bp elements, and weaker or clade-specific selection in longer elements. By applying phyloP to mammalian multiple alignments from the ENCODE project, we shed light on patterns of conservation/acceleration in known and predicted functional elements, approximate fractions of sites subject to constraint, and differences in clade-specific selection in the primate and glires clades. We also describe new "Conservation" tracks in the UCSC Genome Browser that display both phyloP and phastCons scores for genome-wide alignments of 44 vertebrate species.


The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics.
In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of experts specializing in nutrition, microbial physiology, gastroenterology, paediatrics, food science and microbiology to review the definition and scope of postbiotics. The term 'postbiotics' is increasingly found in the scientific literature and on commercial products, yet is inconsistently used and lacks a clear definition. The purpose of this panel was to consider the scientific, commercial and regulatory parameters encompassing this emerging term, propose a useful definition and thereby establish a foundation for future developments. The panel defined a postbiotic as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. The panel also discussed existing evidence of health-promoting effects of postbiotics, potential mechanisms of action, levels of evidence required to meet the stated definition, safety and implications for stakeholders. The panel determined that a definition of postbiotics is useful so that scientists, clinical triallists, industry, regulators and consumers have common ground for future activity in this area. A generally accepted definition will hopefully lead to regulatory clarity and promote innovation and the development of new postbiotic products.


Diagnostic outcomes following childhood non-specific abdominal pain: a record-linkage study.
Non-specific abdominal pain (NSAP) is the most common diagnosis on discharge following admission for abdominal pain in childhood. Our aim was to determine the risk of subsequent hospital diagnosis of organic and functional gastroenterological conditions following a diagnosis of NSAP, and to assess the persistence of this risk. An NSAP cohort of 268,623 children aged 0-16 years was constructed from linked English Hospital Episode Statistics from 1999 to 2011. The control cohort (1,684,923 children, 0-16 years old) comprised children hospitalised with unrelated conditions. Clinically relevant outcomes were selected and standardised rate ratios were calculated. From the NSAP cohort, 15,515 (5.8%) were later hospitalised with bowel pathology and 13,301 (5%) with a specific functional disorder. Notably, there was a 4.84 (95% CI 4.45 to 5.27) times greater risk of Crohn's disease following NSAP and a 4.23 (4.13 to 4.33) greater risk of acute appendicitis than in the control cohort. The risk of irritable bowel syndrome (IBS) was 7.22 (6.65 to 7.85) times greater following NSAP. The risks of inflammatory bowel disease (IBD), IBS and functional disorder (unspecified) were significantly increased in all age groups except <2-year-olds. The risk of underlying bowel pathology remained raised up to 10 years after first diagnosis with NSAP. Only a small proportion of those with NSAP go on to be hospitalised with underlying bowel pathology. However, their risk is increased even at 10 years after the first hospital admission with NSAP. Diagnostic strategies need to be assessed and refined and active surveillance employed for children with NSAP.


Flow-injection determination of retinol and tocopherol in pharmaceuticals with acidic potassium permanganate chemiluminescence.
A simple and rapid flow-injection method is reported for the determination of retinol, its derivatives and alpha-tocopherol by its enhancement effect on a potassium permanganate-formaldehyde chemiluminescence system in an acidic medium. Linear calibration graphs were obtained between 5.0 x 10(-8) to 5.0 x 10(-6) mol L(-1) for all-trans-retinol, 5.0 x 10.8 - 2.5 x 10(-6) mol L(-1) for all-trans-retinal, 5.0 x 10(-7) - 1.0 x 10.5 mol L(-1) for retinoic acid, 1.0 x 10(-7) - 5.0 x 10(-6) mol L(-1) for retinyl acetate and retinyl palmitate and 1.0 x 10(-8) - 5.0 x 10(-6) for alpha-tocopherol, with relative standard deviations (RSD; n = 4) in the range of 0.8 - 2.8%. The limits of detection (S/N = 3) were in the range of 5.0 x 10(-9) - 1.0 x 10(-7) mol L(-1) with a sample throughput of 100 h(-1). The influence of common ions, excipients in pharmaceutical preparations and related organic compounds were studied on the determination of retinol and alpha-tocopherol individually. The method was applied to determine retinol and alpha-tocopherol in pharmaceutical preparations, and the results obtained were in reasonable agreement with the amount labelled.


Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice.
The mechanisms of action of dietary fish oil (FO) on osteoporosis are not fully understood. This study showed FO decreased bone loss in ovariectomized mice because of inhibition of osteoclastogenesis. This finding supports a beneficial effect of FO on the attenuation of osteoporosis. Consumption of fish or n-3 fatty acids protects against cardiovascular and autoimmune disorders. Beneficial effects on bone mineral density have also been reported in rats and humans, but the precise mechanisms involved have not been described. Sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO) or 5% fish oil (FO). Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF-kappaB ligand (RANKL) expression and cytokine production in activated T-cells were analyzed by flow cytometry and ELISA, respectively. Osteoclasts were generated by culturing bone marrow (BM) cells with 1,25(OH)2D3. NF-kappaB activation in BM macrophages was measured by an electrophoretic mobility shift assay. Plasma lipid C16:1n6, C20:5n3, and C22:6n3 were significantly increased and C20:4n6 and C18:2n6 decreased in FO-fed mice. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO-fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4+ T-cells from CO-fed OVX mice, but there was no change in FO-fed mice. Selected n-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) added in vitro caused a significant decrease in TRACP activity and TRACP+ multinuclear cell formation from BM cells compared with selected n-6 fatty acids (linoleic acid [LA] and arachidonic acid [AA]). DHA and EPA also inhibited BM macrophage NF-kappaB activation induced by RANKL in vitro. TNF-alpha, interleukin (IL)-2, and interferon (IFN)-gamma concentrations from both sham and OVX FO-fed mice were decreased in the culture medium of splenocytes, and interleukin-6 was decreased in sham-operated FO-fed mice. In conclusion, inhibition of osteoclast generation and activation may be one of the mechanisms by which dietary n-3 fatty acids reduce bone loss in OVX mice.


High protein intake in human/maternal milk fortification for ≤1250 gr infants: intrahospital growth and neurodevelopmental outcome at two years.
Extrauterine growth restriction and failure to thrive remain a major problem in Extremely Low Birth Weight infants. Nutritional support in preterm babies has the objective to improve the achieve rate of growth similar to those of the fetus in utero at the equivalent gestational age. The aim of the study was to evaluate feeding tolerance, intrahospital growth, neurological outcome and anthropometric data until 24 months of corrected age (mca) from different protein intake assumed by preterm babies <1250 g during their stay in NICU. The study evaluates auxological/neurodevelopmental outcomes until 24 months of corrected age (mca) in preterm infants with different protein intake (control group-CG: 3,5g Kg‾¹ perday; intervention group-PSG: 4,8g Kg‾¹ per day). PSG group showed a significant higher length growth at 9 mca (p 0,04) and hearing/language score of Griffiths Mental Development Score (GMDS) at 12 (p 0,03) and 18 mca (p<0,05) comparing with CG. PSG-ELBW preterms showed an higher intrahospital head circumference (p 0,02) and length growth rate (p 0,04), greater Performance (p 0,04) and Hearing/Language (p 0,03) scores of GMDS at 3 and 12 mca. PSG-SGA preterms showed significantly higher scores in GMDS scores at 18 and 24 mca except for the locomotor domain. Supplemental enteral proteins lead to benefits of reduced postnatal growth restriction and better neurological outcome in preterm infants <1000 g and in those SGA <1250 g.


[Bone and soft tissue sarcomas treated at the Norwegian Radium Hospital 1980-99].
The Norwegian Radium Hospital's sarcoma group is a multidisciplinary group with a leading role in the diagnosis and treatment of bone and soft tissue sarcomas in Norway. From 1980 through 1999, 1,355 patients with soft tissue sarcoma and 458 patients with bone sarcoma were treated. In a retrospective analysis of trends over time, patients were allocated to consecutive five-year periods. Patient characteristics were relatively stable, but there was an increasing proportion of soft tissue sarcomas being referred without prior surgery. Treatment principles have remained unchanged, with surgery with or without radiotherapy dominating in soft tissue sarcoma and surgery with or without chemotherapy in bone sarcoma. The amputation rate for bone sarcoma has fallen from 78% to 17%, and survival has increased significantly for both soft tissue and bone sarcoma patients. The results indicate significant improvements in the quality of treatment of soft tissue and bone sarcoma. More resources for treatment and organizational development of a multidisciplinary group may contribute to improved quality of care.


von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin αIIbβ3.
von Willebrand disease type 2B (vWD-type 2B) is characterized by gain-of-function mutations in von Willebrand factor (vWF) that enhance its binding to the glycoprotein Ib-IX-V complex on platelets. Patients with vWD-type 2B have a bleeding tendency that is linked to loss of vWF multimers and/or thrombocytopenia. In this study, we uncovered evidence that platelet dysfunction is a third possible mechanism for bleeding tendency. We found that platelet aggregation, secretion, and spreading were diminished due to inhibition of integrin αIIbβ3 in platelets from mice expressing a vWD-type 2B-associated vWF (vWF/p.V1316M), platelets from a patient with the same mutation, and control platelets pretreated with recombinant vWF/p.V1316M. Impaired platelet function coincided with reduced thrombus growth. Further, αIIbβ3 activation and activation of the small GTPase Rap1 were impaired by vWF/p.V1316M following exposure to platelet agonists (thrombin, ADP, or convulxin). Conversely, thrombin- or ADP-induced Ca2+ store release, which is required for αIIbβ3 activation, was normal, indicating that vWF/p.V1316M acts downstream of Ca2+ release and upstream of Rap1. We found normal Syk phosphorylation and PLCγ2 activation following collagen receptor signaling, further implying that vWF/p.V1316M acts directly on or downstream of Ca2+ release. These data indicate that the vWD-type 2B mutation p.V1316M is associated with severe thrombocytopathy, which likely contributes to the bleeding tendency in vWD-type 2B.


Mummified seal carcasses in the McMurdo Sound Region, Antarctica.
Information was collected on 90 mummified carcasses of the "crabeater" seal in the ice-free areas of the McMurdo Sound region, Antarctica. The carcasses range from relatively well-preserved bodies to merely old, twisted, winddissected fragments of tissue. They are hard and dry and lie on the surface of the ground, mostly in valley bottoms. The arid, cold climate is ideal for retarding organic decay. One carcass was dated by radiocarbon analysis and found to be between 1600 and 2600 years old.


CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes.
The in vivo function of C-reactive protein (CRP) is unknown. Among the in vitro functions assigned to CRP is the ability to activate complement via the classical pathway. To date, there is no evidence supporting that CRP exerts this function in vivo. We here show a novel approach to assess CRP-mediated complement activation in vivo, which is based on the property that activated complement factors C3 and C4 fix to CRP during complement activation induced by this acute phase protein. We developed specific ELISAs for complexes between CRP and C4b, C4d, C3b, or C3d. We established that in vitro complement-CRP complexes were formed only during CRP-dependent activation, and not during activation by other activators, even in the presence of high CRP levels. Circulating levels of complement-CRP complexes were undetectable in normal donors, but significantly increased in nine patients following implantation of a renal allograft. Importantly, levels of complement-CRP complexes did not change in these patients upon a bolus infusion of mAb OKT3, which induces activation of the classical complement pathway, demonstrating in vivo that complement-CRP complexes are not formed during CRP-independent activation of complement, even when CRP is elevated. We conclude that measurement of complement-CRP complexes provides a suitable tool to study CRP-mediated activation of complement in vivo. Furthermore, increased levels of these complexes occur in clinical samples, indicating that CRP may induce activation of complement in vivo.


Clinical relevance of molecular genetics to paediatric sarcomas.
The application of cytogenetic and molecular genetic analyses to paediatric sarcomas has identified a number of characteristic changes associated with types and subtypes of sarcomas. This has led to increased understanding of the underlying molecular biology of some sarcomas and provided an important adjunct to standard morphological and immunohistochemical diagnoses. Characteristic genetic abnormalities, particularly specific chromosome translocations and associated fusion genes, have diagnostic and in some cases prognostic value. There is also the potential to detect micrometastastic disease. Fusion genes are most readily detected by fluorescence in situ hybridisation and reverse transcription-PCR technologies. The expression profiles of tumours with specific fusion genes are characteristically similar and the molecular signatures of sarcomas are also proving to be of diagnostic and prognostic value. Furthermore, fusion genes and other emerging molecular events associated with sarcomas represent potential targets for novel therapeutic approaches which are desperately required to improve the outcome of children with certain categories of sarcoma, including rhabdomyosarcomas and the Ewing's family of tumours. Increased understanding of the molecular biology of sarcomas is leading towards more effective treatments which may complement or be less toxic than conventional radiotherapy and cytotoxic chemotherapy. Here we review paediatric sarcomas that have associated molecular genetic changes which can increase diagnostic and prognostic accuracy and impact on clinical management.