Maternal depression during pregnancy and the postnatal period: risks and possible mechanisms for offspring depression at age 18 years.
Some small studies suggest that maternal postnatal depression is a risk factor for offspring adolescent depression. However, to our knowledge, no large cohort studies have addressed this issue. Furthermore, only 1 small study has examined the association between antenatal depression and later offspring depression. Understanding these associations is important to inform prevention. To investigate the hypothesis that there are independent associations between antenatal and postnatal depression with offspring depression and that the risk pathways are different, such that the risk is moderated by disadvantage (low maternal education) with postnatal depression but not with antenatal depression. Prospective investigation of associations between symptoms of antenatal and postnatal parental depression with offspring depression at age 18 years in a UK community-based birth cohort (Avon Longitudinal Study of Parents and Children) with data from more than 4500 parents and their adolescent offspring. Diagnosis of offspring aged 18 years with major depression using the International Classification of Diseases, 10th Revision. Antenatal depression was an independent risk factor. Offspring were 1.28 times (95% CI, 1.08-1.51; P = .003) more likely to have depression at age 18 years for each standard deviation increase in maternal depression score antenatally, independent of later maternal depression. Postnatal depression was also a risk factor for mothers with low education, with offspring 1.26 times (95% CI, 1.06-1.50; P = .01) more likely to have depression for each standard deviation increase in postnatal depression score. However, for more educated mothers, there was little association (odds ratio, 1.09; 95% CI, 0.88-1.36; P = .42). Analyses found that maternal education moderated the effects of postnatal but not antenatal depression. Paternal depression antenatally was not associated with offspring depression, while postnatally, paternal depression showed a similar pattern to maternal depression. The findings suggest that treating maternal depression antenatally could prevent offspring depression during adulthood and that prioritizing less advantaged mothers postnatally may be most effective.


Production and characterization of recombinant chicken insulin-like growth factor-I from Escherichia coli.
Recombinant chicken insulin-like growth factor-I (cIGF-I) has been produced in Escherichia coli after first modifying a plasmid that coded for a human IGF-I (hIGF-I) fusion protein, in order to introduce codons for the eight amino acid substitutions. The cIGF-I fusion protein, deposited in bacterial inclusion bodies, was dissolved under reducing conditions, desalted, subjected to anion-exchange chromatography to remove proteinases, refolded and partially purified by reverse-phase high-performance liquid chromatography. The fusion protein was cleaved with hydroxylamine after which cIGF-I was purified to homogeneity by three additional chromatographic steps. Recombinant cIGF-I was equipotent with hIGF-I in cell culture bioassays of protein synthesis and breakdown using rat L6 myoblasts and chick embryo fibroblasts. Binding of radiolabelled cIGF-I and hIGF-I was also equivalent in the two cell lines, as was their binding in ligand blots of chicken, sheep and human plasma. The cross-reactivity of cIGF-I in a polyclonal hIGF-I radioimmunoassay was 60% of that observed with hIGF-I. The availability of recombinant cIGF-I will facilitate investigations into the role of IGF-I in chicken growth and development.


Root and Foot Rot on Tomato Caused by Phytophthora infestans Detected in Belgium.
In January 2003, a severe root and foot rot was observed on 2-month-old wilted tomato (Lycopersicon esculentum Mill.) plants in a large-scale (2.5 ha) commercial greenhouse setting in Belgium. Tomato plants (10%) produced from healthy nursery-grown seedlings and planted to new, clean rockwool and drip irrigation with UV-disinfected water developed symptoms. Symptom development was restricted to lower plant parts with severe rotting of the entire root system and dark lesions girdling the stem base. No symptoms of disease were observed on the foliage or upper stems. Cross sections of the stem base revealed brown discoloration of internal tissue, including the vascular tissue and pith. Dark brown lesions also occurred on the roots. Sections of the stem base, the upper roots (sampled near to the stem base), and the lower roots (sampled on roots deeper in the rockwool) were plated separately on corn meal agar. The oomycete pathogen Phytophthora infestans (Mont.) de Bary was identified in each sample on the basis of morphological characteristics observed directly with light microscopy. Branched sporangiophores with slight swellings and characteristic lemon-shaped sporangia (35 × 20 μm and ratio length/width of 1.75 μm) at their tips were obvious after incubation in darkness at 24°C. Oospores and chlamydospores were not observed. After multiple soil treatment with oomycete-specific fungicides, the plants recovered. Since the occurrence of P. infestans on roots is unusual, the identity of the pathogen on the diseased plant tissues was confirmed with three techniques, DNA array identification, internal transcribed spacer (ITS) sequencing, and a polymerase chain reaction (PCR) amplification using P. infestans-specific primers. DNA was directly processed from separate samples of upper and lower root and stem base tissue. The DNA array used was originally developed to detect and identify the key fungal pathogens of tomato (2). Among detector probes for other tomato pathogens, this array contains oligonucleotide detector probes for P. infestans (PIN1: 5'-GGT TGT GGA CGC TGC TAT T and PIN2: 5'-AAT GGA GAA ATG CTC GAT TC). These probes are based on ITS sequences (ITS I and ITS II). Using conserved ribosomal primers OOMUP18Sc (5'-TGC GGA AGG ATC ATT ACC ACA C) and ITS4, oomycete DNA was amplified by PCR and simultaneously labeled with alkaline-labile digoxigenin (2). All generated amplicons strongly hybridized to the oligonucleotide detector probes for P. infestans and not to any other pathogen-specific detector probe present on the array. The pathogen could not be detected in roots and stem bases of symptomless plants. In addition, the ITS-region was sequenced and showed 100% homology with multiple GenBank accessions of P. infestans sequences. As a third confirmatory test, a PCR was performed on DNA extracts from infected root and stem base tissues using a primer set specific to P. infestans (O8-3/O8-4 [1]). A band of the expected size was produced for the infected stem base and root samples. Until now, this pathogen was known worldwide to cause late blight on potatoes and tomatoes. To our knowledge, this is the first report of root and foot rot of tomato caused by P. infestans. References: (1) H. S. Judelson and P. W. Tooley. Phytopathology 90:1112, 2000. (2) B. Lievens et al. FEMS Microbiol. Lett. 223:113, 2003.


An update on DNA barcoding: low species coverage and numerous unidentified sequences.
DNA barcoding was proposed in 2003, the Consortium for the Barcode of Life was established in 2004, and the movement has since attracted more than $80 million funding. Here we investigate how many species of multicellular animals have been barcoded. We compare the numbers in a public database (GenBank as of January 2012) with those in the Barcode of Life Database (BOLD) and find that GenBank contains COI (cytochrome c oxidase subunit 1) sequences for ca. 60 000 species while BOLD reports barcodes for ca. 150 000 species. The discrepancy is likely due to a large amount of unpublished data in BOLD. Overall, the species coverage remains sparse, growth rates are low, and the barcode accumulation curve for Metazoa is linear with only 4788 species having been added in 2011. In addition, the vast majority of species in the public database (73%) were barcoded by projects that are unlikely to be related to the DNA barcoding movement. Particularly surprising was the large number of DNA barcodes in GenBank that were not identified to species (Jan 2012: 74%), with insect barcodes often being identified only to order. Of these several hundred thousand have since been suppressed by NCBI because they did not satisfy the iBOL/GenBank early release agreement. Species coverage is considerably better for target taxa of DNA barcoding campaigns (e.g. birds, fishes, Lepidoptera), although it also falls short of published campaign targets. © The Willi Hennig Society 2012.


Treatment with botulinum toxin in children with chronic anal fissure.
Chronic anal fissures with painful defecation and bloodstained stools can be seen in children of all ages. Constipation may precede or appear in connection with the symptoms. Adult patients with anal fissures have been treated successfully with the injection of botulinum toxin into both the internal and external sphincter. The effect of botulinum toxin is reversible and lasts for 3-4 months. This pilot study attempted to examine whether botulinum toxin is also effective in paediatric cases of anal fissure, a treatment which not yet has been reported in the literature. Six boys and seven girls aged 1-10 years were treated with botulinum toxin (Botox ((R))) during 2002-2005 due to chronic anal fissure. Conventional treatment with laxatives and local anaesthetics had been unsuccessful in all cases. The treatment was given to five children under 2 years of age in a dosage of 1.25 Ux2. Eight children over 2 years of age were given 2.5 Ux2. The injections were given in the external sphincter on both sides of the fissure using EMG-stimulation for guidance and were performed under light anaesthetics (Diprivan ((R))). Follow-up was conducted at 1 and 3 months after treatment. Within one week, 11 of the children were free from pain and blood stained stools, according to their parent's observations. One 10-year old patient initially showed some improvement but soon experienced a recurrence. After another injection with a higher dosage 2 months later, the fissure healed. One 4-year old patient did not show any signs of improvement. The laxatives, which had been withdrawn after the injection treatment, were then reinstated. At the 3 month post-treatment examination the patient was finally symptom-free with no signs of a fissure. There were no negative side-effects detected in any of the cases. Seven recurrences were noted in 6 of the patients after 3-30 months, often in connection with an episode of constipation. Repeat injections were offered and accepted by four of these patients, once more producing good immediate results. Treatment with botulinum toxin in the external sphincter produces a quick and effective alleviation of pain with healing of chronic anal fissures in children. The treatment is not considered to carry any risks but requires light anaesthesia. Recurrences are common after the pharmacological effect has receded but can be cured with an additional injection.


Associations between school deprivation indices and oral health status.
Despite an overall improvement in oral health status in several countries over the past decades, chronic oral diseases (COD) remain a public health problem, occurring mostly among children in the lower social strata. The use of publicly available indicators at the school level may be an optimal strategy to identify children at high risk of COD in order to organize oral health promotion and intervention in schools. To investigate whether school deprivation indices were associated with schoolchildren oral health status. This ecological study used a sample of 316 elementary public schools in the province of Quebec, Canada. Data from two sources were linked using school identifiers: (i) Two school deprivation indices (in deciles) from the Ministry of Education, a poverty index based on the low income cut-offs established by Statistics Canada and a socioeconomic environment index defined by the proportions of maternal under-schooling and of unemployed parents and (ii) Oral health outcomes from the Quebec Schoolchildren Oral Health Survey 1998-99 aggregated at the school level. These included proportions of children with dental caries and reporting oral pain. The relation between school deprivation indices and oral health outcomes was assessed with linear regression for dental caries experience and logistic regression for oral pain. The mean DMF-S (mean number of decayed, missing and filled permanent teeth surfaces) by school was 0.7 (SD = 0.5); the average proportions of children with dental caries and reporting oral pain were 25.0% and 3.0%, respectively. The poverty index was not associated with oral health outcomes. For the socioeconomic environment index, dental caries experience was 6.9% higher when comparing schools in unfavourable socioeconomic environments to the most favourable ones [95% confidence interval (CI): 2.1, 11.7%]. Furthermore, the most deprived schools, as compared to least deprived ones, were almost three times as likely to have children reporting oral pain in the previous week. The school socioeconomic environment index was associated with oral health outcomes, and should be studied for its potential usefulness in planning school-based oral health promotion and screening strategies.


Towards an understanding of the avian virome.
The last two decades have seen the rise of viromics, the study of viral communities through the detection and characterization of virus genome sequences. Here we systematically review and summarize the scope and limitations of our current understanding of avian viromes, in both domesticated and wild-bird populations. We compare this viromic work to the broader literature on avian prokaryotic microbiomes, and highlight the growing importance of structured sampling and experimental design for testing explanatory hypotheses. We provide a number of recommendations for sample collection and preliminary data analysis to guide the development of avian viromics. Avian viromes have the potential to inform disease surveillance in poultry and improve our understanding of the risk of zoonotic viruses to human health.


Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues.
Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin's induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200-500%) insulin analogues that are truncated at residue 26 of the B-chain (B(26)). They show a structural convergence in the form of a new beta-turn at B(24)-B(26). We propose that the key element in insulin's transition, from an inactive to an active state, may be the formation of the beta-turn at B(24)-B(26) associated with a trans to cis isomerisation at the B(25)-B(26) peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B(25)-B(26) peptide bond or by the insertion of certain D-amino acids at B(26). The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes.


Children's exposure to intimate partner violence: an overview.
Children's exposure to intimate partner violence (IPV) is associated with significant emotional impairment and other harmful effects. It is increasingly recognized as a type of child maltreatment, with outcomes similar to other types of abuse and neglect. Children can experience harm from exposure to IPV, even when not directly involved in, or a witness to, the violence between caregivers. This review, based on a synthesis of best available evidence, addresses the epidemiology of children's exposure to IPV, including prevalence, risk and protective factors, and associated impairment, as well as strategies for identification, and interventions for prevention of exposure and impairment. Strategies for ensuring children's safety are also discussed. The article concludes with guidance specific to mental health clinicians.


Prospective evaluation of systematic use of peripherally inserted central catheters (PICC lines) for the home care after allogeneic hematopoietic stem cells transplantation.
Long-term catheters are often necessary for outpatient care after an allogeneic hematopoietic stem cell transplantation (HSCT), However, there is paucity of data on the use of peripherally inserted central catheter (PICC) in post-HSCT setting. We prospectively evaluated the systematic use of PICC in 37 consecutive patients returning home after HSCT. In 6 out of 37 patients, the PICC was exclusively used for weekly blood controls. In 31 patients, the PICC line was used at home for hydration (18), antibiotics (3), intravenous human Ig (7), transfusions (10), extracorporeal photopheresis (3), chemotherapy (2), artificial nutrition (1), and/or palliative care (1). PICC complications were reported in ten patients (27%), causing eight PICC removals. At the end of the study, 35 patients had their PICC removed. PICCs were used with a median duration of 67 days. Reasons for removal were that PICC was not considered to be useful any longer (16), suspicion of infection (inflammation without documentation) (5) or infection (2), patient's wish (4), death (4), accidental withdrawal (2), puncture site bleeding (1), and catheter change due to extracorporeal photopheresis (1). Three venous thromboses were reported (8%), requesting one PICC removal because of associated infection. In other cases, an antithrombotic treatment was initiated. Although the number of patients included in the study was small, our results suggest that PICC is a safe long-term venous access for home care after HSCT.


Muscarinic response in rat lacrimal glands.
A large variety of responses has been uncovered by recent investigations of conductance changes elicited by muscarinic agonists. In exocrine glands, the permeability to K+, Cl- and Na+ ions is increased, and internal Ca2+ serves as a second messenger. Patch-clamp analysis of the secreting cells has revealed three types of Ca2+-dependent channels, which are respectively selective for K+, for Cl-, and for monovalent cations. The channels differ in their sensitivity to the internal Ca2+ concentration, Cai. K+-selective channels are partially activated at rest, with Cai approx. 10 nmol l-1; Cl(-)-selective channels are activated between 100 nmol l-1 and 1 mumol l-1; activation of cationic channels requires micromolar Cai levels. Cell-attached recordings, performed either on isolated cells or on cell clusters, show an activation of all three channel types upon application of acetylcholine. In whole-cell recordings, mostly K+- and Cl(-)-selective channels are activated. The cell currents display slow oscillations linked to variations of Cai. Whole-cell currents rise after a delay of approx. 1 s, and decay with a time constant of approx. 0.7 s upon removal of acetylcholine. They do not depend on extracellular Ca2+. The recent demonstration that Ca2+-dependent currents can also be obtained when dialysing the cells with inositoltrisphosphate or with GTP gamma S, a non-hydrolysable analogue of guanosine triphosphate, opens promising leads to an analysis of intracellular events regulated by acetylcholine.


The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.
It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study. The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension. Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8). In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.


Memorising Milton's Paradise lost: a study of a septuagenarian exceptional memoriser.
At age 58, JB began memorising Milton's epic poem Paradise Lost. Nine years and thousands of study hours later, he completed this process in 2001 and recalled from memory all 12 books of this 10,565-line poem over a 3-day period. Now 74, JB continues to recite this work. We tested his memory accuracy by cueing his recall with two lines from the beginning or middle of each book and asking JB to recall the next 10 lines. JB is an exceptional memoriser of Milton, both in our laboratory tests in which he did not know the specific tests or procedures in advance, and in our analysis of a videotaped, prepared performance. Consistent with deliberate practice theory, JB achieved this remarkable ability by deeply analysing the poem's structure and meaning over lengthy repetitions. Our findings suggest that exceptional memorisers such as JB are made, not born, and that cognitive expertise can be demonstrated even in later adulthood.


Peer interactions of dysphoric adolescents.
The present study sought to extend our knowledge of dysphoric adolescents' dyadic peer interactions. Thirty female dyads (ages 13-17) were videotaped interacting during both a structured and an unstructured task. Fourteen of the dyads were each comprised of a dysphoric girl and a nondysphoric girl; the remaining dyads were comprised of two nondysphoric girls. Girls were considered dysphoric if they scored 10 or higher on the Beck Depression Inventory. Dysphoric subjects evaluated their performances more negatively than nondysphoric subjects and rated their partners more negatively overall. The partners of the dysphoric girls were viewed by raters as less positive and less happy. They saw the dysphoric teens as making more critical comments and evaluated them more negatively overall. There was also a tendency for these girls to reject their dysphoric partners and to become more passive during the unstructured task. The findings indicate that dysphoric adolescent girls evoke negative reactions from peers and negatively influence their peers' behavior. These negative reactions from others may lead to further difficulties in negotiating the developmental tasks of adolescence.


Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study.
TNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-kappaB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity. Multicenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4. uTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed-effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity. High uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN.


The Montreal procedure: The legacy of the great Wilder Penfield.
Wilder Penfield pioneered the early practice of brain surgery. In binding together the disciplines of neurosurgery, neurology, neuropathology, psychology, and related basic sciences, Penfield transformed our understanding of the field of neuroscience. He brought to the operating room the meticulous techniques of Sherrington, combined with methods of stimulation described by Foerster, which he complemented with expert knowledge of the neurocytology of nervous tissue. While developing surgical treatments for epilepsy, Penfield began to map the brain. He established the "Montreal procedure" for the surgical treatment of epilepsy. His scientific contributions on neurostimulation were transformative in their time and continue to resonate today. This article reviews the life of Wilder Penfield and summarizes key scientific contributions. Specifically, we detail the Montreal procedure. We additionally present a painting by Canadian artist Iris Hauser, which purports to display the hidden treasures of the human mind.


[Which is the role of the oral iron therapies for iron deficiency anemia in non-dialysis-dependent chronic kidney disease patients? Results from clinical experience].
Iron deficiency afflicts about 60% of dialysis patients and about 30% of non-dialysis-dependent CKD patients (ND-CKD). The role of iron deficiency in determining anemia in CKD patients is so relevant that guidelines from the Kidney Disease Improving Global Outcomes (KDIGO) initiative recommend treating it before starting with erythropoiesis-stimulating agents. KDIGO guidelines suggest oral iron therapy because it is commonly available and inexpensive, although it is often characterized by low bioavailability and low compliance due to adverse effects. A new-generation oral iron therapy is now available and seems to be promising. We therefore conducted a study to determine whether an association of iron sucrose, folic acid and vitamins C, B6, B12, can improve anemia in ND-CKD patients, stage 3-5. Our study shows that iron sucrose is a safe and effective oral iron therapy and that it is capable of correcting anemia in ND-CKD patients, although it does not seem to replete low iron stores.


Resuscitation of Vibrio vulnificus from the Viable but Nonculturable State.
Like many other gram-negative bacteria, the human pathogen Vibrio vulnificus is induced into a viable but nonculturable (VBNC) state by incubation at low temperatures. The ability of any bacterium to resuscitate from this dormant state would appear to be essential if the VBNC state is truly a survival strategy. The question as to whether the culturable cells which appear following removal of the inducing stress are a result of true resuscitation or of regrowth of a few residual culturable cells has long been debated. V. vulnificus was examined for its ability to resuscitate from this state following a temperature upshift. Several lines of investigation, including dilution studies, determination of the time necessary for appearance of a culturable population, and the effects of nutrient on recovery, all indicated that, at least for V. vulnificus, true resuscitation does occur. Our studies further suggest that nutrient is in some way inhibitory to the resuscitation of cells in the VBNC state and that studies which add nutrient in an attempt to detect resuscitation are able to detect only residual culturable cells which might be present and which were not inhibited by the added nutrient.


Curing characteristics of a composite. part 2: the effect of curing configuration on depth and distribution of cure.
The objective of this study was to examine the effect different configurations of curing would have on the depth and distribution of the cure within each configuration, for a specific resin-based composite (RBC). RBC was cured in a variety of configurations, consisting of 6mm molds of three different colors; large molds that simulated the condition of no mold at all; and 3-6mm diameter molds to check the effect of size. All specimens were cured for 20s with a quartz-halogen lamp and were allowed to cure for 24h in the dark. Transmission measurements were made for these same configurations. Knoop hardness measurements were made across the central plane of some configurations to determine the distribution of curing. Depths of cure and distribution of curing were significantly affected by changes in configuration. Under the configuration of no mold, the cure extended well beyond the periphery of the light guide due to scattering of the light. When a mold was used, a pronounced effect by the walls resulted in decreased hardness as the mold wall was approached, and the severity of this effect was dependent on the color of the mold. It is believed that this is due to absorption/reflection characteristics of light by the walls, with the white molds showing the least effect. Reducing the diameter of the molds resulted in significant decreases in depth of cure, which are attributed to light absorption by the walls that limits the penetration of light during the curing procedure. Configuration of curing has a significant effect on the depth of cure, but also significantly reduces the cure near the mold wall. This can have clinical ramifications for the cure along a stainless steel matrix band for Class II restorations, and for test procedures in general, where there is no standardization regarding configuration or where measurements are made on specimens.


Visualization of Brain Microstructure Through Spherical Harmonics Illumination of High Fidelity Spatio-Angular Fields.
Diffusion kurtosis imaging (DKI) is gaining rapid adoption in the medical imaging community due to its ability to measure the non-Gaussian property of water diffusion in biological tissues. Compared to traditional diffusion tensor imaging (DTI), DKI can provide additional details about the underlying microstructural characteristics of the neural tissues. It has shown promising results in studies on changes in gray matter and mild traumatic brain injury where DTI is often found to be inadequate. The DKI dataset, which has high-fidelity spatio-angular fields, is difficult to visualize. Glyph-based visualization techniques are commonly used for visualization of DTI datasets; however, due to the rapid changes in orientation, lighting, and occlusion, visually analyzing the much more higher fidelity DKI data is a challenge. In this paper, we provide a systematic way to manage, analyze, and visualize high-fidelity spatio-angular fields from DKI datasets, by using spherical harmonics lighting functions to facilitate insights into the brain microstructure.


The Frequency of Rapid Pupil Dilations as a Measure of Linguistic Processing Difficulty.
While it has long been known that the pupil reacts to cognitive load, pupil size has received little attention in cognitive research because of its long latency and the difficulty of separating effects of cognitive load from the light reflex or effects due to eye movements. A novel measure, the Index of Cognitive Activity (ICA), relates cognitive effort to the frequency of small rapid dilations of the pupil. We report here on a total of seven experiments which test whether the ICA reliably indexes linguistically induced cognitive load: three experiments in reading (a manipulation of grammatical gender match/mismatch, an experiment of semantic fit, and an experiment comparing locally ambiguous subject versus object relative clauses, all in German), three dual-task experiments with simultaneous driving and spoken language comprehension (using the same manipulations as in the single-task reading experiments), and a visual world experiment comparing the processing of causal versus concessive discourse markers. These experiments are the first to investigate the effect and time course of the ICA in language processing. All of our experiments support the idea that the ICA indexes linguistic processing difficulty. The effects of our linguistic manipulations on the ICA are consistent for reading and auditory presentation. Furthermore, our experiments show that the ICA allows for usage within a multi-task paradigm. Its robustness with respect to eye movements means that it is a valid measure of processing difficulty for usage within the visual world paradigm, which will allow researchers to assess both visual attention and processing difficulty at the same time, using an eye-tracker. We argue that the ICA is indicative of activity in the locus caeruleus area of the brain stem, which has recently also been linked to P600 effects observed in psycholinguistic EEG experiments.


Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial.
The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for 'point of care' management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma--the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis--the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. ClinicalTrials.gov: NCT01815710.


Priming metabolism with the type 5 phosphodiesterase: the role of cGMP-hydrolyzing enzymes.
The cyclic guanosine monophosphate (cGMP) signaling system is one of the most prominent regulators of many physiopathological processes in humans and rodents. It has been strongly established as an accomplished cellular signal involved in the regulation of energy homeostasis and cell metabolism, and pharmacological enhancement of cGMP has shown beneficial effects in metabolic disorders models. cGMP intracellular levels are finely regulated by phosphodiesterases (PDEs). The main enzyme responsible for the degradation of cGMP is PDE5. Preclinical and clinical studies have shown that PDE5 inhibitors (PDE5i) have beneficial effects on improving insulin resistance and glucose metabolism representing a promising therapeutic strategy for the treatment of metabolic disorders. This review aims to describe the molecular basis underlying the use of PDE5i to prompt cell metabolism and summarize current clinical trials assessing the effects of PDE5i on glucose metabolism.


Development and pre-clinical assessment of a 73 kD chimeric fusion protein as a defined sub-unit vaccine for leprosy.
Despite the advances toward the elimination of leprosy through widespread provision of multi-drug therapy to registered patients over the last 2 decades, new case detection rates have stabilized and leprosy remains endemic in a number of localized regions. A vaccine could overcome the inherent limitations of the drug treatment program by providing protection in individuals who are not already harboring the Mycobacterium leprae bacilli at the time of administration and effectively interrupt the transmission cycle over a wider timespan. In this report we present data validating the production of 73f, a chimeric fusion protein incorporating the M. leprae antigens ML2028, ML2346 and ML2044. The 73f protein was recognized by IgG in multibacillary (MB) leprosy patient sera and stimulated IFNγ production within whole blood assays of paucibacillary (PB) leprosy patient and healthy household contacts of MB patients (HHC). When formulated with a TLR4L-containing adjuvant (GLA-SE), 73f stimulated a strong and pluripotent Th1 response that inhibited M. leprae-induced inflammation in mice. We are using these data to develop new vaccine initiatives for the continued and long-term control of leprosy.


Assembled Plastid and Mitochondrial Genomes, as well as Nuclear Genes, Place the Parasite Family Cynomoriaceae in the Saxifragales.
Cynomoriaceae, one of the last unplaced families of flowering plants, comprise one or two species or subspecies of root parasites that occur from the Mediterranean to the Gobi Desert. Using Illumina sequencing, we assembled the mitochondrial and plastid genomes as well as some nuclear genes of a Cynomorium specimen from Italy. Selected genes were also obtained by Sanger sequencing from individuals collected in China and Iran, resulting in matrices of 33 mitochondrial, 6 nuclear, and 14 plastid genes and rDNAs enlarged to include a representative angiosperm taxon sampling based on data available in GenBank. We also compiled a new geographic map to discern possible discontinuities in the parasites' occurrence. Cynomorium has large genomes of 13.70-13.61 (Italy) to 13.95-13.76 pg (China). Its mitochondrial genome consists of up to 49 circular subgenomes and has an overall gene content similar to that of photosynthetic angiosperms, while its plastome retains only 27 of the normally 116 genes. Nuclear, plastid and mitochondrial phylogenies place Cynomoriaceae in Saxifragales, and we found evidence for several horizontal gene transfers from different hosts, as well as intracellular gene transfers.


Remote sensing of ocean chlorophyll: consequence of nonuniform pigment profile.
Remote sensing of ocean color, applied to the estimation of chlorophyll biomass, is discussed for the case where the vertical distribution of phytoplankton pigments is nonuniform. Using a spectral model of reflectance, the consequences of vertical structure are evaluated by sensitivity analysis on a generalized pigment profile. It is shown that the assumption of a vertically homogeneous chlorophyll distribution can lead to significant errors (relative error exceeding 100%) in the estimation from satellite data of photic depth and total pigment content in the photic zone. The errors are shown to be functions of the parameters of the pigment profile. It is further shown that, if the shape of the pigment profile is known from independent data, the entire pigment profile may be recovered from the satellite data by making slight changes in the existing algorithms for chlorophyll retrieval.


Potential 'ecological traps' of restored landscapes: koalas Phascolarctos cinereus re-occupy a rehabilitated mine site.
With progressively increasing anthropogenic habitat disturbances, restoration of impacted landscapes is becoming a critical element of biodiversity conservation. Evaluation of success in restoration ecology rarely includes faunal components, usually only encompassing abiotic and floral components of the ecosystems. Even when fauna is explicitly included, it is usually only species presence/absence criteria that are considered. If restoration is to have a positive outcome, however, populations in restored habitats should exhibit comparable survival and reproductive rates to populations found in undisturbed surroundings. If a species recolonises restored areas but later experiences decreased fitness, restored areas could become ecological sinks or traps. We investigated this possibility in a case study of koalas Phascolarctos cinereus occupying rehabilitated mining areas on North Stradbroke Island, Australia. Our holistic approach compared rehabilitated and undisturbed areas on the basis of their vegetation characteristics, of koalas' body condition, roosting trees, diet, as well as predator index. Koalas using rehabilitated areas appeared to be able to access an adequate supply of roosting and fodder trees, were in good condition and had high reproductive output. We did not find any significant differences in predator density between rehabilitated areas and undisturbed surroundings. The results presented in this study showed there was no evidence that the post-mining rehabilitated areas constitute ecological sinks or traps. However, to reach a definitive conclusion as to whether areas rehabilitated post-mining provide at least equivalent habitat to undisturbed locations, additional research could be undertaken to assess foliar nutrient/water/toxin differences and predation risk in rehabilitated areas compared with undisturbed areas. More generally, the evaluation of whether restoration successfully produces a functional ecological community should include criteria on the fitness of faunal populations reoccupying such sites, so as to ensure functioning ecosystems, rather than ecological sinks or traps, are the outcome.


Clinic Design and Continuity in Internal Medicine Resident Clinics: Findings of the Educational Innovations Project Ambulatory Collaborative.
Many internal medicine (IM) programs have reorganized their resident continuity clinics to improve trainees' ambulatory experience. Downstream effects on continuity of care and other clinical and educational metrics are unclear. This multi-institutional, cross-sectional study included 713 IM residents from 12 programs. Continuity was measured using the usual provider of care method (UPC) and the continuity for physician method (PHY). Three clinic models (traditional, block, and combination) were compared using analysis of covariance. Multivariable linear regression analysis was used to analyze the effect of practice metrics and clinic model on continuity. UPC, reflecting continuity from the patient perspective, was significantly different, and was highest in the block model, midrange in combination model, and lowest in the traditional model programs. PHY, reflecting continuity from the perspective of the resident provider, was significantly lower in the block model than in combination and traditional programs. Panel size, ambulatory workload, utilization, number of clinics attended in the study period, and clinic model together accounted for 62% of the variation found in UPC and 26% of the variation found in PHY. Clinic model appeared to have a significant effect on continuity measured from both the patient and resident perspectives. Continuity requires balance between provider availability and demand for services. Optimizing this balance to maximize resident education, and the health of the population served, will require consideration of relevant local factors and priorities in addition to the clinic model.


Serum Urate and Incident Cardiovascular Disease: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
There is controversy about whether serum urate (sUA) predicts future cardiovascular disease (CVD) independently of classical risk factors, and the age at which any prediction starts. We studied the sUA-CVD association among generally healthy adults. CARDIA recruited 5115 black and white individuals aged 18-30 years in 1985-1986 (year-0). Fatal and nonfatal CVD events by year 27 (n = 164) were ascertained during annual contacts and classified using medical records. The association with sUA (year-0, 10, 15 and 20) was modeled using Cox proportional hazards regression, pooling over gender-specific quartiles. Mean sUA concentration was higher in men than women, but increased over time in both genders. Those with elevated sUA had worse metabolic profiles that substantially deteriorated over time. Adjusting for demographic and lifestyle factors (the minimal model), baseline sUA concentration was positively associated with incident CVD (hazard ratio (HR) per mg/dL = 1.21; 95% confidence interval: 1.05, 1.39; P = 0.005). This positive association attenuated to nonsignificance in the full model accounting simultaneously for classical CVD risk factors (HR = 1.09; 0.94, 1.27; P = 0.24). Both the minimal and full models appeared to show stronger associations (than year-0 sUA) between year-10 sUA and incident CVD (HR = 1.27 and 1.12, respectively), but sUA was not statistically significant in the full model. Despite fewer events, year-15 sUA showed a significant sUA-CVD association pattern, with minimal model association magnitude comparable to year-10, and remained significant in the full model (HR = 1.19; 1.02, 1.40; P = 0.03). Hyperuricemia at year-15 strongly predicted CVD risk (HR = 2.11; 1.34, 3.33; P = 0.001), with some attenuation in the full model (HR = 1.68; P = 0.04). sUA may be an early biomarker for CVD in adults entering middle age. The prediction of CVD by sUA appeared to strengthen with aging. The potential complex relation of sUA with deterioration of a cluster of metabolic abnormalities warrants future exploration.


The Relationship between Self-Reported Exposure to Sugar-Sweetened Beverage Promotions and Intake: Cross-Sectional Analysis of the 2017 International Food Policy Study.
Sugar-sweetened beverage (SSB) consumption is independently associated with several non-communicable diseases, so policymakers are increasingly implementing measures, such as marketing regulation, to reduce intake. To help understand how such measures work, this study examined the association between SSB consumption and self-reported exposure to SSB promotions, both overall and by type of promotion, and whether these relationships vary between the UK, USA, Canada, Mexico, and Australia. Cross-sectional analysis of the online 2017 International Food Policy Study was performed (n = 15,515). Participants were grouped into 5265 (34%) non-, 5117 (33%) low-, and 5133 (33%) high-SSB consumers. Multinomial logistic regression models examined whether SSB consumption varied by exposure to total SSB promotion and by type: traditional, digital, recreational environment, and functional environment. Multiplicative interactions were included to investigate international variations. An additional unit of total self-reported SSB promotion exposure increased the likelihood of participants being low SSB consumers (relative risk ratio (RRR) = 1.08, 95% confidence interval (CI) = 1.06-1.10) and high SSB consumers (RRR = 1.13, 95% CI = 1.11-1.16). Only exposure to traditional and digital promotion increased the likelihood of participants being SSB consumers, though this may be explained by degree of exposure, which was not measured in this study. Some evidence illustrated international variation in these relationships.


Tailoring translational strength using Kozak sequence variants improves bispecific antibody assembly and reduces product-related impurities in CHO cells.
Optimal production of bispecific antibodies (bsAb) requires efficient and tailored co-expression and assembly of two distinct heavy and two distinct light chains. Here, we describe a novel technology to modulate the translational strength of antibody chains via Kozak sequence variants to produce bsAb in a single cell line. In this study, we designed and screened a large Kozak sequence library to identify 10 independent variants that can modulate protein expression levels from approximately 0.2 to 1.3-fold compared with the wild-type sequence in transient transfection. We used a combination of several of these variants, covering a wide range of translational strength, to develop stable single cell Chinese hamster ovary bispecific cell lines and compared the results with those obtained from the wild-type sequence. A significant increase in bispecific antibody assembly with a concomitant reduction in the level of product-related impurities was observed. Our findings suggest that for production of bsAb it can be advantageous to modify translational strength for selected protein chains to improve overall yield and product quality. By extension, tuning of translational strength can also be applied to improving the production of a wide variety of heterologous proteins.


Into and out of the tropics: global diversification patterns in a hyperdiverse clade of ectomycorrhizal fungi.
Ectomycorrhizal (ECM) fungi, symbiotic mutualists of many dominant tree and shrub species, exhibit a biogeographic pattern counter to the established latitudinal diversity gradient of most macroflora and fauna. However, an evolutionary basis for this pattern has not been explicitly tested in a diverse lineage. In this study, we reconstructed a mega-phylogeny of a cosmopolitan and hyperdiverse genus of ECM fungi, Russula, sampling from annotated collections and utilizing publically available sequences deposited in GenBank. Metadata from molecular operational taxonomic unit cluster sets were examined to infer the distribution and plant association of the genus. This allowed us to test for differences in patterns of diversification between tropical and extratropical taxa, as well as how their associations with different plant lineages may be a driver of diversification. Results show that Russula is most species-rich at temperate latitudes and ancestral state reconstruction shows that the genus initially diversified in temperate areas. Migration into and out of the tropics characterizes the early evolution of the genus, and these transitions have been frequent since this time. We propose the 'generalized diversification rate' hypothesis to explain the reversed latitudinal diversity gradient pattern in Russula as we detect a higher net diversification rate in extratropical lineages. Patterns of diversification with plant associates support host switching and host expansion as driving diversification, with a higher diversification rate in lineages associated with Pinaceae and frequent transitions to association with angiosperms.


Test-retest reliability of health utilities index scores: evidence from hip fracture.
There is relatively little evidence on the test-retest reliability of utility scores derived from multiattribute measures. The objective was to estimate test-retest reliability for Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) utility scores in patients recovering from hip fracture. We enrolled an inception cohort of hip fracture patients within 3 to 5 days of surgery. Baseline assessments included the Functional Independence Measure (FIM), Folstein Mini-Mental State Examinations, and the HUI2 and HUI3 questionnaire. Follow-up assessments at 1, 3, and 6 months also included a global change question. Test-retest reliability was assessed as agreement between 3- and 6-month scores using the intraclass correlation coefficient (ICC). Two approaches were used to classify patients as stable; a third approach based on the generalizability theory was also used. Patients were classified as stable if their FIM overall scores changed by 10 points or fewer and if they classified themselves as having experienced no or only a little change according to their global change question. Complete data at both the 3- and 6-month assessments based on self-report were available for 196 patients; 141 patients with complete data were classified as stable. The ICCs for HUI2 and HUI3 for stable patients were 0.71 and 0.72; the ICCs derived from the generalizability theory were 0.76 and 0.77. Test-retest reliability for HUI in this cohort was similar to reliability estimates for other preference-based multiattribute and generic health-profile measures--in the acceptable range for making valid group-level comparisons.


Beyond the Förster formulation for resonance energy transfer: the role of dark states.
Resonance Energy Transfer (RET) is investigated in pairs of charge-transfer (CT) chromophores. CT chromophores are an interesting class of π conjugated chromophores decorated with one or more electron-donor and acceptor groups in polar (D-π-A), quadrupolar (D-π-A-π-D or A-π-D-π-A) or octupolar (D(-π-A)(3) or A(-π-D)(3)) structures. Essential-state models accurately describe low-energy linear and nonlinear spectra of CT-chromophores and proved very useful to describe spectroscopic effects of electrostatic interchromophore interactions in multichromophoric assemblies. Here we apply the same approach to describe RET between CT-chromophores. The results are quantitatively validated by an extensive comparison with time-dependent density functional theory (TDDFT) calculations, confirming that essential-state models offer a simple and reliable approach for the calculation of electrostatic interchromophore interactions. This is an important result since it sets the basis for more refined treatments of RET: essential-state models are in fact easily extended to account for molecular vibrations in truly non-adiabatic approaches and to account for inhomogeneous broadening effects due to polar solvation. Optically forbidden (dark) states of quadrupolar and octupolar chromophores offer an interesting opportunity to verify the reliability of the dipolar approximation. In striking contrast with the dipolar approximation that strictly forbids RET towards or from dark states, our results demonstrate that dark states can take an active role in RET with interaction energies that, depending on the relative orientation of the chromophores, can be even larger than those relevant to allowed states. Essential-state models, whose predictions are quantitatively confirmed by TDDFT results, allow us to relate RET interaction energies towards allowed and dark states to the supramolecular symmetry of the RET-pair, offering reliable design strategies to optimize RET-interactions.


Mid-Infrared Scattering in γ-Al2O3 Catalytic Powders.
The energy efficiency of heterogeneous catalytic processes may be improved by using mid-infrared light to excite gas-phase reactants during the reaction, since vibrational excitation of molecules has been shown to increase their reactivity at the gas-catalyst interface. A primary challenge for such light-enabled catalysis is the need to ensure close coupling between light-excited molecules and the catalyst throughout the reactor. Thus, it is imperative to understand how to couple infrared light efficiently to molecules near and inside catalytic material. Heterogenous catalysts are often nanoscale metal particles supported on high surface area, porous oxide materials and exhibit feature sizes across multiple scattering regimes with respect to the mid-infrared wavelength. These complex powders make a direct measurement of the scattering properties challenging. Here, we demonstrate that a combination of directional hemispherical measurements along with the in-line transmission measurement allow for a direct measurement of the scattered light signal. We implement this technique to study the scattering behavior of the catalytic support material γ-Al2O3 (with and without metal loading) between 1040 and 1220 cm-1. We first study how both the mean grain size affects the scattering behavior by comparing three different mean grain sizes spanning three orders of magnitude (2, 40, and 900 µm). Furthermore, we study how the addition of metal catalyst nanoparticles, Ru, or Cu, to the support material impacts the light scattering behavior of the powder. We find that the 40 µm grain size scatters the most (up to 97% at 1220 cm-1) and that the addition of metal nanoparticles narrows the scattering angle but does not decrease the scattering efficiency. The strong scattering of the 40 µm grains makes them the most ideal support material of those studied for the given spectrum because of their ability to distribute light within the reactor. Finally, we estimate that less than 100 mW of laser power is needed to cause significant excitation for testing mid-infrared catalysis in a Harrick Praying Mantis diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) reactor, a magnitude easily available using commercial mid-infrared lasers. Our work also provides a mid-infrared foundation for a wide range of studies of light-enabled catalysis and can be extended to other wavelengths of light or to study the scattering behavior of other complex powders in other fields, including ceramics, biomaterials, and geology.


Emotional stress as a trigger for inflammatory skin disorders.
Dermatologic disorders comprise 15% to 20% of complaints seen in general practice. Skin disorders result in a negative impact to the patient not only physically but also psychologically, socially, and occupationally. The most common trigger for several inflammatory skin disorders, including psoriasis, is emotional stress. Understanding the significance of emotional triggers to common inflammatory dermatologic disorders is critical to the optimal management of these conditions. This article will provide an overview of the effects of emotional stress on skin disorders and psychotherapeutic options.


Supramolecular interactions between catalytic species allow rational control over reaction kinetics.
The adaptivity of biological reaction networks largely arises through non-covalent regulation of catalysts' activity. Such type of catalyst control is still nascent in synthetic chemical networks and thereby hampers their ability to display life-like behavior. Here, we report a bio-inspired system in which non-covalent interactions between two complementary phase-transfer catalysts are used to regulate reaction kinetics. While one catalyst gives bimolecular kinetics, the second displays autoinductive feedback, resulting in sigmoidal kinetics. When both catalysts are combined, the interactions between them allow rational control over the shape of the kinetic curves. Computational models are used to gain insight into the structure, interplay, and activity of each catalytic species, and the scope of the system is examined by optimizing the linearity of the kinetic curves. Combined, our findings highlight the effectiveness of regulating reaction kinetics using non-covalent catalyst interactions, but also emphasize the risk for unforeseen catalytic contributions in complex systems and the necessity to combine detailed experiments with kinetic modelling.


Nkx2.7 and Nkx2.5 function redundantly and are required for cardiac morphogenesis of zebrafish embryos.
Nkx2.7 is the tinman-related gene, as well as orthologs of Nkx2.5 and Nkx-2.3. Nkx2.7 and Nkx2.5 express in zebrafish heart fields of lateral plate mesoderm. The temporal and spatial expression patterns of Nkx2.7 are similar to those of Nkx2.5, but their functions during cardiogenesis remain unclear. Here, Nkx2.7 is demonstrated to compensate for Nkx2.5 loss of function and play a predominant role in the lateral development of the heart, including normal cardiac looping and chamber formation. Knocking down Nkx2.5 showed that heart development was normal from 24 to 72 hpf. However, when knocking down either Nkx2.7 or Nkx2.5 together with Nkx2.7, it appeared that the heart failed to undergo looping and showed defective chambers, although embryos developed normally before the early heart tube stage. Decreased ventricular myocardium proliferation and defective myocardial differentiation appeared to result from late-stage up-regulation of bmp4, versican, tbx5 and tbx20, which were all expressed normally in hearts at an early stage. We also found that tbx5 and tbx20 were modulated by Nkx2.7 through the heart maturation stage because an inducible overexpression of Nkx2.7 in the heart caused down-regulation of tbx5 and tbx20. Although heart defects were induced by overexpression of an injection of 150-pg Nkx2.5 or 5-pg Nkx2.7 mRNA, either Nkx2.5 or Nkx2.7 mRNA rescued the defects induced by Nkx2.7-morpholino(MO) and Nkx2.5-MO with Nkx2.7-MO. Therefore, we conclude that redundant activities of Nkx2.5 and Nkx2.7 are required for cardiac morphogenesis, but that Nkx2.7 plays a more critical function, specifically indicated by the gain-of-function and loss-of- function experiments where Nkx2.7 is observed to regulate the expressions of tbx5 and tbx20 through the maturation stage.


Distinct gene expression profiles characterize the histopathological stages of disease in Helicobacter-induced mucosa-associated lymphoid tissue lymphoma.
Long-term colonization of humans with Helicobacter pylori can cause the development of gastric B cell mucosa-associated lymphoid tissue lymphoma, yet little is known about the sequence of molecular steps that accompany disease progression. We used microarray analysis and laser microdissection to identify gene expression profiles characteristic and predictive of the various histopathological stages in a mouse model of the disease. The initial step in lymphoma development is marked by infiltration of reactive lymphocytes into the stomach and the launching of a mucosal immune response. Our analysis uncovered molecular markers of both of these processes, including genes coding for the immunoglobulins and the small proline-rich protein Sprr 2A. The subsequent step is characterized histologically by the antigen-driven proliferation and aggregation of B cells and the gradual appearance of lymphoepithelial lesions. In tissues of this stage, we observed increased expression of genes previously associated with malignancy, including the laminin receptor-1 and the multidrug-resistance channel MDR-1. Finally, we found that the transition to destructive lymphoepithelial lesions and malignant lymphoma is marked by an increase in transcription of a single gene encoding calgranulin AMrp-8.


Adaptation of a motivational interviewing intervention to improve antidepressant adherence among Latinos.
Poor antidepressant adherence is a significant issue in depression treatment that adversely affects treatment outcomes. Although being a common problem, it tends to be more common among Latinos. To address this problem, the current study adapted a Motivational Interviewing (MI) intervention to improve adherence among Latinos with depression. The adaptation process included six focus groups that elicited participants' perspectives (N = 30), applying the intervention with test cases (N = 7) to fine-tune the intervention, and eliciting feedback on the intervention (N = 5). The findings generated from these adaptation phases are described, along with a case example. Examples of adaptations to the MI included reframing antidepressant adherence as a way to luchar (struggle) against problems, focusing on motivation for improving depression and not just medication, refining methods for imparting antidepressant information, and inclusion of personalized visual feedback on dose-taking. The findings provide a description of the antidepressant issues experienced by a group of Latinos, as well as considerations for applying MI with this population. The intervention remained grounded in MI principles, but was contextualized for this Latino group.


Global Reprogramming of Host SUMOylation during Influenza Virus Infection.
Dynamic nuclear SUMO modifications play essential roles in orchestrating cellular responses to proteotoxic stress, DNA damage, and DNA virus infection. Here, we describe a non-canonical host SUMOylation response to the nuclear-replicating RNA pathogen, influenza virus, and identify viral RNA polymerase activity as a major contributor to SUMO proteome remodeling. Using quantitative proteomics to compare stress-induced SUMOylation responses, we reveal that influenza virus infection triggers unique re-targeting of SUMO to 63 host proteins involved in transcription, mRNA processing, RNA quality control, and DNA damage repair. This is paralleled by widespread host deSUMOylation. Depletion screening identified ten virus-induced SUMO targets as potential antiviral factors, including C18orf25 and the SMC5/6 and PAF1 complexes. Mechanistic studies further uncovered a role for SUMOylation of the PAF1 complex component, parafibromin (CDC73), in potentiating antiviral gene expression. Our global characterization of influenza virus-triggered SUMO redistribution provides a proteomic resource to understand host nuclear SUMOylation responses to infection.


Acute kidney injury in intensive care unit: incidence, risk factors and mortality rate.
Acute kidney injury (AKI) is a risk factor for increased mortality in critically ill patients. To assess the incidence, risk factors and outcome of patients who develop AKI in the intensive care units (ICUs), we retrospectively studied 235 patients admitted to the ICU of Shahid Mohamadi Hospital, Hormozgan, Iran, and compared those who developed AKI and those who did not. There were 31.1% of patients who developed AKI during ICU admission. There was a significant difference in the mean age, serum sodium (Na), potassium (K), urea, blood urea nitrogen (BUN) and creatinine (Cr) levels and also platelets, on admission, between patients with and without AKI. Acute physiology and chronic health evaluation (APACHE) II score on admission was significantly higher in AKI patients and Glasgow coma scale (GCS) was significantly lower. The mortality of AKI patients (72.6%) was significantly higher than non-AKI patients (25.91%). The number of underlying diseases and GCS and APACHE II score on admission were significantly different between the expired and survived patients. We conclude that age, first serum K level and APACHE II score on admission time were powerful independent predictors of developing AKI in ICU patients. The GCS on admission and the presence of two or more underlying diseases accurately predict the mortality in AKI positive ICU patients.


A 3D Printed Porous Titanium Alloy Rod with Diamond Crystal Lattice for Treatment of the Early-Stage Femoral Head Osteonecrosis in Sheep.
Instruments made of porous titanium alloy and fabricated with a 3D printed technique are increasingly used in experimental and clinical research. To date, however, few studies have assessed their use in early-stage osteonecrosis of the femoral head (ONFH). In this study, porous titanium alloy rods (Ti-Rod) with diamond crystal lattice, fabricated using an electron beam melting (EBM) technique, were implanted into sheep models (n=9) of early-stage ONFH for 6 months. Bone ingrowth and integration were investigated and compared with those of sheep (n=9) undergoing core decompression (CD) alone. Following Ti-Rod implantation, femoral heads showed fine osteointegration, with X-ray evaluation showing compact integration between peripheral bone and rods without radiolucent lines encircling the rods, as well as new bone growth along the metal trabeculae without the intervention of fibrous tissue. The regions of interest (ROIs) of femoral heads showed fine bone ingrowth after Ti-Rod implantation than CD alone. By micro-CT evaluation, the ratios of bone volume to total volume (BV/TV) of ROIs in Rod group was 930 % and 452 % higher than CD group after 3 (0.206 ± 0.0095 vs. 0.020 ± 0.0058, p < 0.05, n=3) and 6 (0.232 ± 0.0161 vs. 0.042 ± 0.0061, p < 0.05, n=3) months respectively. By histological evaluation, the BV/TV of ROIs in Rod group was 647 % and 422 % higher than CD group after 3 (0.157 ± 0.0061 vs. 0.021 ± 0.0061, p < 0.05, n=3) and 6 (0.235 ± 0.0145 vs. 0.045 ± 0.0059, p < 0.05, n=3) months respectively. The new bone grew along metal trabeculae into the center of the rod with a rapid bone ingrowth in Rod gorup. Whereas in CD group, new bone grew mainly at the periphery of the decompressive channel with a slow bone ingrowth. Mechanical analysis showed that maximum load on the femoral head-necks was 31 % greater 6 months after Ti-Rod implantation than after CD alone when the vertical press reached the apex (3751.75 ± 391.96 vs. 2858.25 ± 512.91 N, p < 0.05, n=3). The association of rod implantation with fine bone ingrowth, osteointegration, and favorable mechanical properties suggests that implantation of the porous titanium alloy rod with the diamond crystal lattice may be a beneficial intervention for patients with early-stage ONFH.


Selective regulation of intrinsic membrane proteins in HepG2.
Expression of three hepatocellular membrane proteins--the asialoglycoprotein receptor (hepatic binding protein) the insulin receptor and organic anion binding protein--have been studied in the HepG2 cell line. HepG2 grown in minimal essential medium supplemented with 10% fetal bovine serum maximally expressed hepatic binding protein and insulin receptor only at confluence while organic anion binding protein appeared independent of the state of cellular proliferation. When cells were grown in medium supplemented with dialyzed fetal bovine serum, adult bovine serum or in chemically defined medium, expression of hepatic binding protein and insulin receptor but not organic anion binding protein was reduced by 60 to 80%. Immunoblotting techniques revealed that cells grown in dialyzed fetal bovine serum contained virtually no mature, glycosylated 45 kD hepatic binding protein, but a small amount of 36 kD protein. Metabolic labeling of cells grown in dialyzed fetal bovine serum with [35S] methionine indicated reduced synthesis of the 45 kD hepatic binding protein and the absence of the 36 kD protein. Restoration of normal expression of hepatic binding protein and insulin receptor was achieved by addition to dialyzed fetal bovine serum of: fetal bovine serum; 2,000 dalton ultrafiltrate of fetal bovine serum, or 300 to 350 dalton fraction of the ultrafiltrate. The normal concentration of organic anion binding protein demonstrable in cells grown in dialyzed fetal bovine serum indicates that the low molecular weight factor(s) is not a generalized modulator of plasma membrane biogenesis. However, its effect on the steady-state level of the hepatic binding protein and insulin receptor, characteristic of mature hepatocytes, suggests a role for this fetal serum factor in hepatocellular differentiation.


Blood kinetics of Ebola virus in survivors and nonsurvivors.
Infection with Ebola virus (EBOV) results in a life-threatening disease, with reported mortality rates between 50%-70%. The factors that determine patient survival are poorly understood; however, clinical observations indicate that EBOV viremia may be associated with fatal outcome. We conducted a study of the kinetics of Zaire EBOV viremia in patients with EBOV disease (EVD) who were managed at an Ebola Treatment Centre in Sierra Leone during the recent West African outbreak. Data from 84 EVD patients (38 survivors, 46 nonsurvivors) were analyzed, and EBOV viremia was quantified between 2 and 13 days after symptom onset. Time since symptom onset and clinical outcome were used as independent variables to compare EBOV viral kinetics in survivors and nonsurvivors. In all patients, EBOV viremia kinetics was a quadratic function of time; however, EBOV viremia was 0.94 logarithm (log) copies per ml (cp/ml) (P = 0.011) higher in nonsurvivors than in survivors from day 2 after the onset of symptoms. Survivors reached peak viremia levels at an earlier time after symptom onset than nonsurvivors (day 5 versus day 7) and had lower mean peak viremia levels compared with nonsurvivors (7.46 log cp/ml; 95% CI, 7.17-7.76 vs. 8.60 log cp/ml; 95% CI, 8.27-8.93). Before reaching peak values, EBOV viremia similarly increased both in survivors and nonsurvivors; however, the decay of viremia after the peak was much stronger in survivors than in nonsurvivors. Our results demonstrate that plasma concentrations of EBOV are markedly different between survivors and nonsurvivors at very early time points after symptom onset and may be predicative of outcome. Further studies focused on the early phase of the disease will be required to identify the causal and prognostic factors that determine patient outcome. Italian Ministry of Health; Italian Ministry of Foreign Affairs; EMERGENCY's private donations; and Royal Engineers for DFID-UK.


Good isomerization of 2-cyclohexenol by two Ru(ii) complexes, synthesis and characterization of a reaction intermediate.
The catalytic activities of [RuClCp(PTA)2] (1) and [RuCp(PTA)2(H2O-κO)]OTf (2) were assessed for the redox isomerization of the cyclic allylic alcohol 2-cyclohexenol into cyclohexanone in water and biphasic media. Complex 2 showed unprecedented good TONs for the studied conversion both in water (TON = 647) and in the biphase of cyclohexene/H2O (TON = 3420) while 1 showed a lower but also good activity (water TON = 95, biphasic TON = 100). The catalytic reaction intermediate [RuCp(PTA)2(η2-C6H9OH)]CF3SO3 (3) was synthesized and characterized using NMR.


Degradation of the starch components amylopectin and amylose by barley α-amylase 1: role of surface binding site 2.
Barley α-amylase isozyme 1 (AMY1, EC 18.104.22.168) contains two surface binding sites, SBS1 and SBS2, involved in the degradation of starch granules. The distinct role of SBS1 and SBS2 remains to be fully understood. Mutational analysis of Tyr-380 situated at SBS2 previously revealed that Tyr-380 is required for binding of the amylose helix mimic, β-cyclodextrin. Also, mutant enzymes altered at position 380 displayed reduced binding to starch granules. Similarly, binding of wild type AMY1 to starch granules was suppressed in the presence of β-cyclodextrin. We investigated the role of SBS2 by comparing kinetic properties of the wild type AMY1 and the Y380A mutant enzyme in hydrolysis of amylopectin, amylose and β-limit dextrin, and the inhibition by β-cyclodextrin. Progress curves of the release of reducing ends revealed a bi-exponential hydrolysis of amylopectin and β-limit dextrin, whereas hydrolysis of amylose progressed mono-exponentially. β-Cyclodextrin, however, inhibited only one of the two reaction rates of amylopectin and β-limit dextrin hydrolysis, whereas hydrolysis of amylose was unaffected. The Y380A enzyme showed no detectable inhibition by β-cyclodextrin but displayed similar kinetics to the inhibited wild type AMY1. These results point to SBS2 as an important binding site in amylopectin depolymerization.


Forebrain origins and terminations of the medial forebrain bundle metabolically activated by rewarding stimulation or by reward-blocking doses of pimozide.
Using [14C]-2-deoxyglucose autoradiography, we determined which forebrain and diencephalic areas showed metabolic alterations in response to unilateral electrical stimulation of the posterior medial forebrain bundle at parameters chosen to produce a just-submaximal rewarding effect. At these parameters, only a few areas were activated. There was no detectable activation anterior or dorsal to the genu of the corpus callosum. Just anterior to the anterior commissure, there was strong activation of the vertical limb of the diagonal band of Broca, with a focus in the nucleus of the diagonal band. Just posterior to the anterior commissure, there was strong activation of compartment "c" of the medial forebrain bundle (MFB), with weaker activation of the bed nucleus of the stria terminalis and the medial preoptic area. At midhypothalamic levels, the dorsolateral, dorsomedial, and ventral MFB all showed activation. There was bilateral suppression of activity in the lateral habenula. Activation appeared to end in the anterior ventral tegmental area of Tsai. Reward-blocking doses of the neuroleptic pimozide activated the caudate and the lateral habenula but did not alter any of the unilateral effects of stimulation. Using longer pulse durations and/or shifting the site of stimulation to the substantia nigra activated many of the systems not activated in the first experiment, including all of the major dopaminergic projection systems, proving the capacity of the technique to reveal activation of these systems. The results permit one to define a discrete projection system that merits electrophysiological investigation as a likely substrate for the rewarding effect of MFB stimulation. They also suggest that dopaminergic projection systems may not form part of the reward pathway itself.


Fiber optics oximeter-densitometer for cardiovascular studies.
It is now possible to make continuous in vivo measurements of the oxygen saturation and total cardiac output of a patient on a real time basis by using the recently developed technique of fiber optics spectrophotometry. This paper describes instrumental features of a fiber optics oximeter-densitometer which has been used on experimental animals as well as on human beings for the measurement of oxygen saturation and dye concentration. The in vivo measurement made possible with this remote spectrophotometer has shown significant advantages over the in vitro method, which in the past has required withdrawal of blood samples and subsequent measurements with attendant time delays and inaccuracies. This instrument allows the correlation of oxygen saturation variations in various regions within the heart with intercardiac, ECG, and pressure measurements. The clinical data on this instrument have demonstrated its value in the diagnosis of heart defects.


Lessons from a double-transgenic neutrophil approach to induce antiproteinase 3 antibody-mediated vasculitis in mice.
ANCA to either PR3 or MPO are found in patients with necrotizing vasculitis and glomerulonephritis. ANCA binding to their target antigens on neutrophils and subsequent neutrophil activation are pivotal disease mechanisms that lead to vascular inflammation and necrosis. ANCA interaction with PR3 is more complex than with MPO as the neutrophil-specific CD177 receptor is involved in PR3 surface expression and PR3-ANCA-induced neutrophil activation. Modeling human disease is important to clinical research. Highly successful mouse models of MPO-ANCA vasculitis exist; however, recapitulating PR3-ANCA vasculitis has not been successful. We generated double-transgenic (DT) mice that expressed human PR3 and CD177 under a myeloid-specific huMRP8 promoter in an attempt to model PR3-ANCA vasculitis. DT mice strongly expressed the human transgenes in and on murine neutrophils and bound murine and human anti-PR3 antibodies. Nevertheless, passive transfer of these antibodies into LPS-primed DT mice or immunization of C57BL/6 mice with human PR3 followed by irradiation and transplantation of DT bone marrow failed to induce glomerulonephritis. Further analyses revealed that anti-PR3 antibodies did not activate DT neutrophils as shown by superoxide generation. Moreover, we found that mice did not properly process human pro-PR3 into mature PR3 and, consequently, the signaling complex between PR3, CD177, and CD11b, which promotes neutrophil activation by anti-PR3 antibodies, failed to form. We conclude that important species differences in PR3 and CD177 exist between men and mice that prevented successful generation of a murine anti-PR3 antibody model.


Effects of lifestyle modification on metabolic syndrome: a systematic review and meta-analysis.
To evaluate the effect of lifestyle modifications on metabolic syndrome (MetS) as assessed by its resolution and improved values for its components. This was a systematic review and meta-analysis. Searches were performed of MEDLINE and the Cochrane Database from January 1966 to October 2011 to identify randomized controlled trials (RCTs) related to the study objective. The included studies were RCTs restricted to the English language, with a follow-up period of 6 months or more, which reported overall resolution of MetS or values of MetS components (fasting blood glucose, waist circumference, high-density lipoprotein (HDL), triglycerides, and systolic and diastolic blood pressure (SBP, DBP)). Two investigators independently assessed study eligibility. The effect sizes were the relative proportion of patients with resolved MetS and mean differences in MetS component values from baseline to 1-year follow-up in a lifestyle-modification intervention (LMI) group versus a control (conventional lifestyle education or no treatment) group. Meta-analyses were conducted using a random-effects model. Eleven interventions in eight RCTs were used for the meta-analyses. The relative proportion of patients with resolved MetS in the intervention group was approximately 2.0 (95% CI 1.5 to 2.7) times greater in the intervention group compared with the control group (7 interventions, n = 2.839). LMI (5 interventions, n = 748) significantly reduced mean values for SBP by -6.4 mmHg (95% CI -9.7 to -3.2), DBP by -3.3 mmHg (95% CI -5.2 to -1.4), triglycerides by -12.0 mg/dl (95% CI -22.2 to -1.7), waist circumference by -2.7 cm (95% CI -4.6 to -0.9), and fasting blood glucose by -11.5 mg/dl (95% CI -22.4 to -0.6) (5 interventions), but reductions were not significant for HDL (1.3 mg/dl; 95% CI -0.6 to 3.1). The LMI was effective in resolving MetS and reducing the severity of related abnormalities (fasting blood glucose, waist circumference, SBP and DBP, and triglycerides) in subjects with MetS.


[Analysis of clinical characteristics and S gene mutation of hepatitis B virus (HBV) in patients with hepatitis B surface antigen RIA negative and HBV DNA positive].
We investigated hepatitis B virus (HBV) infection cases, who were HBsAg negative by radioimmunoassay (RIA) and HBV DNA positive for their clinical characteristics, the S gene mutation of hepatitis B virus (HBV), and usefulness of other HBsAg immunoassay. Among the patients requested for HBV DNA quantification, 16 patients positive in HBV DNA but negative in HBsAg RIA (BNIBT HBsAg Kit, China) were enrolled. The "a" determinant of HBV S gene was sequenced and clinical characteristics were reviewed. Additional HBsAg assay was performed using Architect HBsAg kit (Abbott laboratories, USA) employing chemiluminescent immunoassay method. Eleven of the 16 patients showed multiple mutations in the "a" determinant. These patients received liver transplantation several years ago and have been treated with hepatitis B immune globulin (HBIG) and antiviral drugs. G145R mutation was found in 8 patients and G145K, D144G, and D144A were also frequently found. Among 9 of the 11 patients tested for HBsAg by Architect HBsAg kit, 8 showed positive results. Among 4 of the remaining 5 patients, only 2 showed weak positive results (< or = 1 IU/mL) in Architect HBsAg kit. HBV DNA-positive/HBsAg RIA-negative results were mostly observed in the patients treated with HBIG after liver transplantation, in whom HBIG escape mutations were found. Majority of these cases were positive in Architect HBsAg assay, and it is recommended to use other HBsAg immunoassay methods that are more sensitive than RIA in the detection limit as well as in the detection of escape mutant in hospitals performing liver transplantation.


Effect of exercise-induced muscle damage on vascular function and skeletal muscle microvascular deoxygenation.
This paper investigated the effects of unaccustomed eccentric exercise-induced muscle damage (EIMD) on macro- and microvascular function. We tested the hypotheses that resting local and systemic endothelial-dependent flow-mediated dilation (FMD) and microvascular reactivity would decrease, V˙O2max would be altered, and that during ramp exercise, peripheral O2 extraction, evaluated via near-infrared-derived spectroscopy (NIRS) derived deoxygenated hemoglobin + myoglobin ([HHb]), would be distorted following EIMD In 13 participants, measurements were performed prior to (Pre) and 48 h after a bout of knee extensor eccentric exercise designed to elicit localized muscle damage (Post). Flow-mediated dilation and postocclusive reactive hyperemic responses measured in the superficial femoral artery served as a measurement of local vascular function relative to the damaged tissue, while the brachial artery served as an index of nonlocal, systemic, vascular function. During ramp-incremental exercise on a cycle ergometer, [HHb] and tissue saturation (TSI%) in the m. vastus lateralis were measured. Superficial femoral artery FMD significantly decreased following EIMD (pre 6.75 ± 3.89%; post 4.01 ± 2.90%; P < 0.05), while brachial artery FMD showed no change. The [HHb] and TSI% amplitudes were not different following EIMD ([HHb]: pre, 16.9 ± 4.7; post 17.7 ± 4.9; TSI%: pre, 71.0 ± 19.7; post 71.0 ± 19.7; all P > 0.05). At each progressive increase in workload (i.e., 0-100% peak), the [HHb] and TOI% responses were similar pre- and 48 h post-EIMD (P > 0.05). Additionally, V˙O2max was similar at pre- (3.0 ± 0.67 L min-1) to 48 h post (2.96 ± 0.60 L min-1)-EIMD (P > 0.05). Results suggest that moderate eccentric muscle damage leads to impaired local, but not systemic, macrovascular dysfunction.


Near-Infrared Activated Release of Doxorubicin from Plasmon Resonant Liposomes.
Precise control of drug release from nanoparticles can improve efficacy and reduce systemic toxicity associated with administration of certain medications. Here, we combined two phenomena, photothermal conversion in plasmon resonant gold coating and thermal sensitivity of liposome compositions, to achieve a drug delivery system that rapidly releases doxorubicin in response to external stimulus. Methods: Thermosensitive liposomes were loaded with doxorubicin and gold-coated to produce plasmon resonant drug delivery system. Plasmon resonance facilitates release of contents upon near-infrared laser illumination, thus providing spatial and temporal control of the process. This controlled delivery system was compared to thermosensitive liposomes without gold coating and to the FDA-approved Doxil that was gold-coated to create a plasmon resonant coating. Release of doxorubicin from the gold-coated thermosensitive liposomes was further confirmed by tests of cell viability. Results: Upon laser illumination at 760 nm and 88 mW/cm2 power density, permeability of plasmon resonant liposomes increased by three orders of magnitude, from 70×10-12 to 60,000x10-12 cm/s. In control experiments, mild hyperthermia (42°C) increased permeability of these thermosensitive liposomes to just 3,700×10-12 cm/s. Neither hyperthermia nor laser illumination elicit content release from Doxil or plasmon resonant Doxil obtained by gold coating. Laser-induced release of doxorubicin from plasmon resonant thermosensitive liposomes resulted in the loss of cell viability significantly greater than in any of the control groups. Conclusion: Combination of thermosensitive liposomes with plasmon resonant coating enables rapid, controlled release, not currently available in pharmaceutical formulations of anticancer drugs.


Improving National Intelligence for Public Health Preparedness: a methodological approach to finding local multi-sector indicators for health security.
The COVID-19 epidemic is the latest evidence of critical gaps in our collective ability to monitor country-level preparedness for health emergencies. The global frameworks that exist to strengthen core public health capacities lack coverage of several preparedness domains and do not provide mechanisms to interface with local intelligence. We designed and piloted a process, in collaboration with three National Public Health Institutes (NPHIs) in Ethiopia, Nigeria and Pakistan, to identify potential preparedness indicators that exist in a myriad of frameworks and tools in varying local institutions. Following a desk-based systematic search and expert consultations, indicators were extracted from existing national and subnational health security-relevant frameworks and prioritised in a multi-stakeholder two-round Delphi process. Eighty-six indicators in Ethiopia, 87 indicators in Nigeria and 51 indicators in Pakistan were assessed to be valid, relevant and feasible. From these, 14-16 indicators were prioritised in each of the three countries for consideration in monitoring and evaluation tools. Priority indicators consistently included private sector metrics, subnational capacities, availability and capacity for electronic surveillance, measures of timeliness for routine reporting, data quality scores and data related to internally displaced persons and returnees. NPHIs play an increasingly central role in health security and must have access to data needed to identify and respond rapidly to public health threats. Collecting and collating local sources of information may prove essential to addressing gaps; it is a necessary step towards improving preparedness and strengthening international health regulations compliance.


Longitudinal follow-up of adult survivors of Ewing sarcoma: A report from the Childhood Cancer Survivor Study.
Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.


Smoking relapse and early weaning among postpartum women: is there an association?
Smoking in the postpartum period may contribute to early weaning, although the nature and temporal aspect of the relationship are poorly understood. The objective of this study was to examine the association between early weaning and smoking relapse among women who stopped smoking during pregnancy. A secondary analysis of data from a randomized controlled trial was conducted. The participants were 228 women who had stopped smoking for pregnancy, who participated in a smoking relapse prevention trial, and who breastfed. Women who relapsed to daily smoking postpartum were compared with those who remained abstinent or smoked occasionally. The dependent variable was breastfeeding for less than 26 weeks (early weaning). Potential covariates included intended duration of breastfeeding, parity, partner's smoking, nicotine dependence, emotional health, return to paid employment, and various sociodemographic variables. Approximately two-thirds (65.1%) of the women who relapsed to daily smoking weaned before 26 weeks compared with 33.8 percent of the women who remained abstinent or smoked occasionally. Controlling for intended duration of breastfeeding, education, and return to paid employment, women who resumed daily smoking were almost four times more likely to wean early than those who abstained or smoked occasionally. Early weaning may result from psychological or physiological changes associated with tobacco use. Smoking relapse prevention in the postpartum period may be one of the most effective interventions in ensuring that women who stop smoking for pregnancy remain stopped and breastfeed their babies for the recommended duration.


Safe and efficacious use of procedural sedation and analgesia by nonanesthesiologists in a pediatric emergency department.
Children often require relief of pain and anxiety when undergoing diagnostic or therapeutic procedures in the emergency department (ED). Procedural sedation and analgesia (PSA) has become standard practice in the outpatient setting for such procedures. Few studies have looked at the overall success and incidence of complications of PSA as performed by nonanesthesiologists. To prospectively describe PSA as performed in a pediatric ED and to report the success of sedation and incidence of complications. Prospective descriptive study. Setting and Population Subjects aged 0 to 21 years presenting to the ED of an urban, tertiary care, children's hospital between May 1, 1997, and April 30, 1999, requiring PSA for a diagnostic or therapeutic procedure. A PSA form was designed and used by ED personnel to record pertinent clinical and demographic characteristics of patients, information related to the procedure, vital signs, and occurrence of complications. Success of sedation was defined a priori as successful completion of the procedure in a minimally responsive subject. Complications were defined as apnea, hypoxia (sustained pulse oximetry, <93%), seizure, arrhythmia, laryngospasm, stridor, hypotension, rash, vomiting, disinhibition, or aspiration. Follow-up telephone calls were made to families within 24 to 48 hours of discharge from the ED to document further complications. Rate of success of sedation and incidence of complications. Procedural sedation and analgesia was performed 1244 times in 1215 patients during the study. The median age of the patients was 5.9 years (mean age, 6.9 years; range, 2 months to 19.4 years). There were 791 boys (65.1%) and 424 girls (34.9%). A little more than half of the patients (643 or 52.9%) required PSA for fracture reduction and 396 (32.6%) for laceration repair. Intravenous (IV) fentanyl citrate and midazolam hydrochloride was provided in 734 sedation events (59.0%); IV ketamine hydrochloride, midazolam, and atropine sulfate in 293 (23.6%); and intramuscular ketamine, midazolam, and atropine in 82 (6.6%). Procedural sedation and analgesia was successfully provided in 1177 (98.6%) of 1194 sedation events. Complications occurred in 207 (17.8%) of 1161 events. The most common complication was hypoxia (79.1% of patients), followed by vomiting (6.2% of patients). No patient required intubation. One patient had an oral airway placed, 3 patients received flumazenil, 3 patients received naloxone hydrochloride, and 1 patient received naloxone and bag-valve-mask ventilation. Seventy (9.8%) of 717 patients, following discharge from the ED, reported minor complications related to PSA. The most common complication was vomiting (76.7% of patients), followed by persistent dizziness (6.8% of patients). Patients who received IV fentanyl and midazolam were significantly more likely to experience a complication during PSA (P<.001), while patients sedated using IV ketamine, midazolam, and atropine (P =.006) or IV midazolam alone (P =.005) were less likely. No difference in success of sedation or incidence of complications at follow-up was found between the types of PSA provided. Complications related to PSA occurred in 17.9% of patients, but most commonly consisted of hypoxia that was easily treated. Sedation was successful in 98.6% of patients. Procedural sedation and analgesia can be safely and effectively provided by nonanesthesiologists in a pediatric ED.