Racial discrimination and breast cancer incidence in US Black women: the Black Women's Health Study.
Perceived discrimination may contribute to somatic disease. The association between perceived discrimination and breast cancer incidence was assessed in the Black Women's Health Study. In 1997, participants completed questions on perceived discrimination in two domains: "everyday" discrimination (e.g., being treated as dishonest) and major experiences of unfair treatment due to race (job, housing, and police). Cox proportional hazards models were used to estimate incidence rate ratios, controlling for breast cancer risk factors. From 1997 to 2003, 593 incident cases of breast cancer were ascertained. In the total sample, there were weak positive associations between cancer incidence and everyday and major discrimination. These associations were stronger among the younger women. Among women aged less than 50 years, those who reported frequent everyday discrimination were at higher risk than were women who reported infrequent experiences. In addition, the incidence rate ratio was 1.32 (95% confidence interval: 1.03, 1.70) for those who reported discrimination on the job and 1.48 (95% confidence interval: 1.01, 2.16) for those who reported discrimination in all three situations - housing, job, and police - relative to those who reported none. These findings suggest that perceived experiences of racism are associated with increased incidence of breast cancer among US Black women, particularly younger women.


Silver overlayer-modified surface-enhanced Raman scattering-active gold substrates for potential applications in trace detection of biochemical species.
Because Ag and Au nanoparticles (NPs) possess well-defined localized surface plasmon resonance (LSPR) they are popularly employed in the studies of surface-enhanced Raman scattering (SERS). As shown in the literature and in our previous studies, the advantage of SERS-active Ag NPs is their higher SERS enhancement over Au NPs. On the other hand, the disadvantage of SERS-active Ag NPs compared to Au NPs is their serious decay of SERS enhancement in ambient laboratory air. In this work, we develop a new strategy for preparing highly SERS-active Ag NPs deposited on a roughened Au substrate. This strategy is derived from the modification of electrochemical underpotential deposition (UPD) of metals. The coverage of Ag NPs on the roughened Au substrate can be as high as 0.95. Experimental results indicate that the SERS of Rhodamine 6G (R6G) observed on this developed substrate exhibits a higher intensity by ca. 50-fold of magnitude, as compared with that of R6G observed on the substrate without the deposition of Ag NPs. The limit of detection (LOD) for R6G measured on this substrate is markedly reduced to 2×10(-15)M. Moreover, aging of SERS effect observed on this developed substrate is significantly depressed, as compared with that observed on a generally prepared SERS-active Ag substrate. These aging tests were performed in an atmosphere of 50% relative humidity (RH) and 20% (v/v) O2 at 30°C for 60 day. Also, the developed SERS-active substrate enables it practically applicable in the trace detection of monosodium urate (MSU)-containing solution in gouty arthritis without a further purification process.


Responsiveness of carotenoids to a high vegetable diet intervention designed to prevent breast cancer recurrence.
Epidemiological studies suggest that a high vegetable diet may reduce risk for breast cancer and may also improve prognosis after the diagnosis of breast cancer. Circulating carotenoids may serve as a biomarker of vegetable and fruit intake, although several factors affect their bioavailability from food sources and may influence concentrations. One purpose of this study was to identify factors predictive of serum carotenoid, retinol, and alpha-tocopherol concentrations in 79 postsurgically resected breast cancer patients at enrollment and at 12 months in a feasibility study of a high vegetable, low fat diet intervention to reduce risk for cancer recurrence. Another purpose was to identify variables associated with change in these serum concentrations 12 months after randomization into control and intervention groups. The diet intervention (versus control) group had significantly greater increases in carotenoid intakes (P < 0.03) and significantly greater increases in serum concentrations of lutein, alpha- and beta-carotene, lycopene, and retinol (P < 0.04). Stepwise multiple regression revealed the level of dietary intake to be predictive of most serum carotenoid concentrations at baseline and 12 months, with additional associations between selected micronutrient concentrations and serum cholesterol, body mass index, age, percentage of energy intake from fat, and alcohol intake also observed at these time points. Intervention group change in serum carotenoid concentrations was inversely associated with baseline level, age, and change in serum cholesterol concentration and positively associated with change in carotenoid and alcohol intake. Circulating carotenoid concentrations are responsive to a high vegetable diet intervention, which also included reduced dietary fat and increased fiber intakes, to reduce risk for breast cancer recurrence.


Single-File Escape of Colloidal Particles from Microfluidic Channels.
Single-file diffusion is a ubiquitous physical process exploited by living and synthetic systems to exchange molecules with their environment. It is paramount to quantify the escape time needed for single files of particles to exit from constraining synthetic channels and biological pores. This quantity depends on complex cooperative effects, whose predominance can only be established through a strict comparison between theory and experiments. By using colloidal particles, optical manipulation, microfluidics, digital microscopy, and theoretical analysis we uncover the self-similar character of the escape process and provide closed-formula evaluations of the escape time. We find that the escape time scales inversely with the diffusion coefficient of the last particle to leave the channel. Importantly, we find that at the investigated microscale, bias forces as tiny as 10^{-15} N determine the magnitude of the escape time by drastically reducing interparticle collisions. Our findings provide crucial guidelines to optimize the design of micro- and nanodevices for a variety of applications including drug delivery, particle filtering, and transport in geometrical constrictions.


Variable expression of pathogenesis-related protein allergen in mountain cedar (Juniperus ashei) pollen.
Allergic diseases have been increasing in industrialized countries. The environment is thought to have both direct and indirect modulatory effects on disease pathogenesis, including alterating on the allergenicity of pollens. Certain plant proteins known as pathogenesis-related proteins appear to be up-regulated by certain environmental conditions, including pollutants, and some have emerged as important allergens. Thus, the prospect of environmentally regulated expression of plant-derived allergens becomes yet another potential environmental influence on allergic disease. We have identified a novel pathogenesis-related protein allergen, Jun a 3, from mountain cedar (Juniperus ashei) pollen. The serum IgE from patients with hypersensitivity to either mountain cedar or Japanese cedar were shown to bind to native and recombinant Jun a 3 in Western blot analysis and ELISA. Jun a 3 is homologous to members of the thaumatin-like pathogenesis-related (PR-5) plant protein family. The amounts of Jun a 3 extracted from mountain cedar pollen varied up to 5-fold in lots of pollen collected from the same region in different years and between different regions during the same year. Thus, Jun a 3 may contribute not only to the overall allergenicity of mountain cedar pollen, but variable levels of Jun a 3 may alter the allergenic potency of pollens produced under different environmental conditions.


Decision limits and the reporting of cardiac troponin: Meeting the needs of both the cardiologist and the ED physician.
Cardiac troponin is the preferred biomarker for defining the acute coronary syndrome and acute myocardial infarction. Currently, the only decision limit formally endorsed with regard to the cardiac troponins is the 99th percentile. This is a "rule-in" criterion, intended to ensure that only persons with the acute coronary syndrome are reviewed. The 99th percentile is an arbitrary cut point and there are many problems associated with its application, including defining a truly healthy population, the difficulty of standardisation of cardiac troponin assays, especially but not only cardiac troponin I, and the effects of age and sex on this parameter. The Emergency Department (ED) screens many more persons for possible acute coronary syndromes than actually have the condition and their needs are best met by a "rule-out" test that enables them to clear their busy departments of the many persons who do not actually have the condition. The needs of the ED are not optimally met using the 99th percentile. The index of individuality for the cardiac troponins is small and significant changes consistent with an acute coronary syndrome can occur without the 99th percentile being exceeded. It appears that the ED may be better served by use of delta troponin changes rather than the 99th percentile, but there are problems with this approach, particularly in persons who present late when troponin release has plateaued. In addition, there are many non-acute coronary syndrome causes for cardiac troponin release. The needs of the cardiologist and the ED physician are so different that it may be inappropriate for both groups to use the same diagnostic criteria for cardiac troponin, and it is of great importance that cardiac troponin measurement be used as only one part of the assessment of the person presenting with possible acute coronary syndrome.


A Three-wave Study of Antecedents of Work-Family Enrichment: The Roles of Social Resources and Affect.
On the basis of conservation of resources theory (Hobfoll, ) and the resource-gain-development perspective (Wayne, Grzywacz, Carlson, & Kacmar, ), this paper examines the differential impact of specific social resources (supervisory support and family support) on specific types of affect (job satisfaction and family satisfaction, respectively), which, in turn, influence work-to-family enrichment and family-to-work enrichment, respectively. A sample of 276 Chinese workers completed questionnaires in a three-wave survey. The model was tested with structural equation modelling. Job satisfaction at time 2 partially mediated the relationship between time 1 supervisory support and time 3 work-to-family enrichment (capital), and the effect of supervisory support on work-to-family enrichment (affect) was fully mediated by job satisfaction. Family satisfaction at time 2 fully mediated the relationship between time 1 family support and time 3 family-to-work enrichment (affect, efficiency). Implications for theory, practice and future research are discussed.


The potential for mapping nematode distributions for site-specific management.
The success of site-specific nematode management depends on a grower or advisor being able to afford to make a map of an infestation that is accurate enough for management decisions. The spatial dependence of nematode infestations and correlation of soil attributes with nematode density were assessed to investigate the scale of sampling required to obtain correlated observations of density and the use of soils data to reduce the cost of sampling. Nematodes and soil were sampled on a 76.2 x 76.2-m grid in two irrigated corn (Zea mays) fields for 2 years. Nematodes of each of three species were found in 36% to 77% of the cores from a field. Spatial dependence was detected for 10 of 16 distributions, and 22% to 67% of the variation in density within a field could be attributed to spatial correlation. Density was correlated to distances of 115 to 649 m in the directions of 0, 45, 90, and 135 degrees from the crop row, and distances varied with direction. Correlations between nematode density and soil attributes were inconsistent between species and fields. These results indicate a potential for mapping nematode infestations for site-specific management, but provide no evidence for reducing the cost of sampling by substituting soils data for nematode counts when making a map.


Extreme Conditioning Programs: Potential Benefits and Potential Risks.
CrossFit, Insanity, Gym Jones, and P90X are examples of extreme conditioning programs (ECPs). ECPs typically involve high-volume and high-intensity physical activities with short rest periods between movements and use of multiple joint exercises. Data on changes in fitness with ECPs are limited to CrossFit investigations that demonstrated improvements in muscle strength, muscular endurance, aerobic fitness, and body composition. However, no study has directly compared CrossFit or other ECPs to other more traditional forms of aerobic and resistance training within the same investigation. These direct comparisons are needed to more adequately evaluate the effectiveness of ECPs. Until these studies emerge, the comparisons with available literature suggest that improvements in CrossFit, in terms of muscular endurance (push-ups, sit-ups), strength, and aerobic capacity, appear to be similar to those seen in more traditional training programs. Investigations of injuries in ECPs are limited to two observational studies that suggest that the overall injury rate is similar to that seen in other exercise programs. Several cases of rhabdomyolysis and cervical carotid artery dissections have been reported during CrossFit training. The symptoms, diagnosis, and treatment of these are reviewed here. Until more data on ECPs emerge, physical training should be aligned with US Army doctrine. If ECPs are included in exercise programs, trainers should (1) have appropriate training certifications, (2) inspect exercise equipment regularly to assure safety, (3) introduce ECPs to new participants, (4) ensure medical clearance of Soldiers with special health problems before participation in ECPs, (4) tailor ECPs to the individual Soldier, (5) adjust rest periods to optimize recovery and reduce fatigue, (6) monitor Soldiers for signs of overtraining, rhabdomyolysis, and other problems, and (7) coordinate exercise programs with other unit training activities to eliminate redundant activities and minimize the risk of overuse injuries.


Data-driven models of dominantly-inherited Alzheimer's disease progression.
See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article.Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.


Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans.
Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.


Lighting and quantitative parameters of visual tasks.
The paper discloses the results of a series of tests carried out to evaluate the complexity of visual tasks for the purpose of specifying the fundamental principles for the standardization of lighting conditions. In addition to the parameters of the difficulty of visual tasks which are in current use in the practice of standardization, i.e., target dimensions, target contrast with the background, a certain number of additional characteristics are proposed and examined. The results of tests to evaluate the influence of these characteristics on the complexity of the visual task are reported. The relationship between the difficulties of visual tasks performed at different working levels of the visual analyzer is considered. It is shown that the degree of influence of external parameters on the complexity of a visual task depends to a great extent on the working conditions. The experimental data obtained result in certain conclusions and propositions regarding further investigations of the influence of qualitative and quantitative lighting characteristics on the visual capacity.


Sequential outbreaks due to a new strain of Neisseria meningitidis serogroup C in northern Nigeria, 2013-14.
Background Neisseria meningitidis serogroup C (NmC) outbreaks occur infrequently in the African meningitis belt; the most recent report of an outbreak of this serogroup was in Burkina Faso, 1979. Médecins sans Frontières (MSF) has been responding to outbreaks of meningitis in northwest Nigeria since 2007 with no reported cases of serogroup C from 2007-2012. MenAfrivac®, a serogroup A conjugate vaccine, was first used for mass vaccination in northwest Nigeria in late 2012. Reactive vaccination using polysaccharide ACYW135 vaccine was done by MSF in parts of the region in 2008 and 2009; no other vaccination campaigns are known to have occurred in the area during this period. We describe the general characteristics of an outbreak due to a novel strain of NmC in Sokoto State, Nigeria, in 2013, and a smaller outbreak in 2014 in the adjacent state, Kebbi. Methods Information on cases and deaths was collected using a standard line-list during each week of each meningitis outbreak in 2013 and 2014 in northwest Nigeria. Initial serogroup confirmation was by rapid Pastorex agglutination tests. Cerebrospinal fluid (CSF) samples from suspected meningitis patients were sent to the WHO Reference Laboratory in Oslo, where bacterial isolates, serogrouping, antimicrobial sensitivity testing, genotype characterisation and real-time PCR analysis were performed. Results In the most highly affected outbreak areas, all of the 856 and 333 clinically suspected meningitis cases were treated in 2013 and 2014, respectively. Overall attack (AR) and case fatality (CFR) rates were 673/100,000 population and 6.8% in 2013, and 165/100,000 and 10.5% in 2014. Both outbreaks affected small geographical areas of less than 150km2 and populations of less than 210,000, and occurred in neighbouring regions in two adjacent states in the successive years. Initial rapid testing identified NmC as the causative agent. Of the 21 and 17 CSF samples analysed in Oslo, NmC alone was confirmed in 11 and 10 samples in 2013 and 2014, respectively. Samples confirmed as NmC through bacterial culture had sequence type (ST)-10217. Conclusions These are the first recorded outbreaks of NmC in the region since 1979, and the sequence (ST)-10217 has not been identified anywhere else in the world. The outbreaks had similar characteristics to previously recorded NmC outbreaks. Outbreaks of NmC in 2 consecutive years in northern Nigeria indicate a possible emergence of this serogroup. Increased surveillance for multiple serogroups in the region is needed, along with consideration of vaccination with conjugate vaccines rather than for NmA alone.


Optimizing pentose utilization in yeast: the need for novel tools and approaches.
Hexose and pentose cofermentation is regarded as one of the chief obstacles impeding economical conversion of lignocellulosic biomass to biofuels. Over time, successful application of traditional metabolic engineering strategy has produced yeast strains capable of utilizing the pentose sugars (especially xylose and arabinose) as sole carbon sources, yet major difficulties still remain for engineering simultaneous, exogenous sugar metabolism. Beyond catabolic pathways, the focus must shift towards non-traditional aspects of cellular engineering such as host molecular transport capability, catabolite sensing and stress response mechanisms. This review highlights the need for an approach termed 'panmetabolic engineering', a new paradigm for integrating new carbon sources into host metabolic pathways. This approach will concurrently optimize the interdependent processes of transport and metabolism using novel combinatorial techniques and global cellular engineering. As a result, panmetabolic engineering is a whole pathway approach emphasizing better pathways, reduced glucose-induced repression and increased product tolerance. In this paper, recent publications are reviewed in light of this approach and their potential to expand metabolic engineering tools. Collectively, traditional approaches and panmetabolic engineering enable the reprogramming of extant biological complexity and incorporation of exogenous carbon catabolism.


Parental Knowledge about Urban Preschool Children's Oral Health Risk.
Dental caries is one of the most prevalent and significant health problems in the United States. According to the American Academy of Pediatric Dentistry, more than one-fourth of children between the ages of two and five years experience early childhood caries before entering kindergarten. The purpose of this study was to explore parent's knowledge of preschool children's oral health risk factors. A descriptive design was used with a convenience sample of 87 parents of children who attended day care centers and preschools. Seventeen knowledge questions were used to assess parents' knowledge of their child's oral health. Results showed that parents lacked knowledge in some aspects of oral health care. The majority of parents knew that baby teeth are important, and both baby and permanent teeth should be brushed. Fewer, however, perceived that cavities in baby teeth lead to cavities in permanent teeth. Similarly, parents knew the role of food in the dental caries, but fewer perceived that cavities may be caused by using a bottle or infant drinking cup to drink fluid other than water and frequent snacking. Findings illuminate the knowledge gaps in this sample of parents of preschoolers. Pediatric nurses can play a key role in promoting children's oral health and preventing dental caries by proving anticipatory guidance and education to children and their parents at well child visits, during hospitalization, and in school and community settings.


Cell-cycle regulation of cohesin stability along fission yeast chromosomes.
Sister chromatid cohesion is mediated by cohesin, but the process of cohesion establishment during S-phase is still enigmatic. In mammalian cells, cohesin binding to chromatin is dynamic in G1, but becomes stabilized during S-phase. Whether the regulation of cohesin stability is integral to the process of cohesion establishment is unknown. Here, we provide evidence that fission yeast cohesin also displays dynamic behavior. Cohesin association with G1 chromosomes requires continued activity of the cohesin loader Mis4/Ssl3, suggesting that repeated loading cycles maintain cohesin binding. Cohesin instability in G1 depends on wpl1, the fission yeast ortholog of mammalian Wapl, suggestive of a conserved mechanism that controls cohesin stability on chromosomes. wpl1 is nonessential, indicating that a change in wpl1-dependent cohesin dynamics is dispensable for cohesion establishment. Instead, we find that cohesin stability increases at the time of S-phase in a reaction that can be uncoupled from DNA replication. Hence, cohesin stabilization might be a pre-requisite for cohesion establishment rather than its consequence.


Prehospital management of evolving critical illness by the primary care provider.
The factors that limit primary care providers (PCPs) from intervening for adults with evolving, acute, severe illness are less understood than the increasing frequency of management by acute care providers. Rates of prehospital patient management by a PCP and of communication with acute care teams were measured in a multicenter, cross-sectional, descriptive study conducted in all four of the adult medical ICUs of the three hospitals in central Massachusetts that provide tertiary care. Rates were measured for 390 critical care encounters, using a validated instrument to abstract the medical record and conduct telephone interviews. PCPs implemented prehospital management for eight episodes of acute illness among 300 encounters. Infrequent prehospital management by PCPs was attributed to their lack of awareness of the patient's evolving acute illness. Only 21% of PCPs were aware of the acute illness before their patient was admitted to an ICU, and 33% were not aware that their patient was in an ICU. Rates of PCP involvement were not appreciably different among provider groups or by patient age, sex, insurance status, hospital, ICU, or ICU staffing model. We identified lack of PCP awareness of patients' acute illness and high rates of PCP referral to acute care providers as the most frequent barriers to prehospital management of evolving acute illness. These findings suggest that implementing processes that encourage early patient-PCP communication and increase rates of prehospital management of infections and acute exacerbations of chronic diseases could reduce use of acute care services.


Alterations of oxidative stress biomarkers due to in utero and neonatal exposures of airborne manganese.
Neonatal rats were exposed to airborne manganese sulfate (MnSO4) (0, 0.05, 0.5, or 1.0 mg Mn/m3) during gestation (d 0-19) and postnatal days (PNDs) 1-18. On PND 19, rats were killed, and we assessed biochemical end points indicative of oxidative stress in five brain regions: cerebellum, hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine synthetase (GS) and tyrosine hydroxylase (TH) protein levels, metallothionein (MT), TH and GS mRNA levels, and reduced and oxidized glutathione (GSH and GSSG, respectively) levels were determined for all five regions. Mn exposure (all three doses) significantly (p = 0.0021) decreased GS protein levels in the cerebellum, and GS mRNA levels were significantly (p = 0.0008) decreased in the striatum. Both the median and high dose of Mn significantly (p = 0.0114) decreased MT mRNA in the striatum. Mn exposure had no effect on TH protein levels, but it significantly lowered TH mRNA levels in the olfactory bulb (p = 0.0402) and in the striatum (p = 0.0493). Mn exposure significantly lowered GSH levels at the median dose in the olfactory bulb (p = 0.0032) and at the median and high dose in the striatum (p = 0.0346). Significantly elevated (p = 0.0247) GSSG, which can be indicative of oxidative stress, was observed in the cerebellum of pups exposed to the high dose of Mn. These data reveal that alterations of oxidative stress biomarkers resulting from in utero and neonatal exposures of airborne Mn exist. Coupled with our previous study in which similarly exposed rats were allowed to recover from Mn exposure for 3 wk, it appears that many of these changes are reversible. It is important to note that the doses of Mn utilized represent levels that are a hundred- to a thousand-fold higher than the inhalation reference concentration set by the United States Environmental Protection Agency.


Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency.
Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by skeletal abnormalities such as hypoplasia of the mandible and clavicles and acro-osteolysis. Other features include cutaneous atrophy and lipodystrophy. Two genetic loci are known for MAD: lamin A/C (LMNA), encoding structural nuclear lamina proteins, and zinc metalloproteinase (ZMPSTE24), a membrane-bound endoprotease involved in post-translational proteolytic cleavage of carboxy terminal residues of prelamin A to form mature lamin A. Mutational analysis of ZMPSTE24 in an additional patient with MAD and determination of functional activity of mutant ZMPSTE24 in a yeast growth arrest pheromone diffusion (halo) assay. We previously reported a Belgian woman with MAD who had ZMPSTE24 mutations and died of complications of chronic renal failure at the age of 27.5 years. We now report a 37-year-old Australian man with MAD who also had compound heterozygous mutations in the ZMPSTE24 gene, a null mutation, Phe361fsX379, and a missense mutation, Asn265Ser, which is partially active in the yeast complementation assay. He also developed end-stage renal disease and, despite receiving a cadaveric renal transplantation, died prematurely at the age of 37 years. Renal biopsies of both patients revealed focal segmental glomerulosclerosis, and the female patient had the collapsing variant. These observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency.


[Association between cutaneous leishmaniasis incidence and the human development index and its components in four endemic states of Venezuela].
Assess potential relationships between the Human Development Index (HDI) and its components and the incidence of cutaneous leishmaniasis (CL) in four endemic States of Venezuela (Mérida, Trujillo, Lara and Sucre) in the period 1994-2003. Socioeconomical data (classified according the World Bank) was obtained from the National Institute of Statistics, and the epidemiological data from the Ministry of Health, both from Venezuela. For this ecological study the annual variation of the variables was assessed and also regression models were done. The HDI varied in the period from 0.6746 in 1994 to 0.8144 in 2003 (p=0.90). During this time an increase in the cumulative incidence of Leishmaniasis was observed, particularly from 1998 (7.3 cases/100,000 pop) to 1999 (11.3 cases/100,000 pop). Analyzing the linear regression models, it was observed that the relationship between epidemiological and social variables was different at States levels. For Mérida and Trujillo it was observed a significant decrease in the CL regard to the increase of literacy (p<0.05), of the gross combined enrollment (p<0.05), life expectancy (p<0.05), money income (p<0.05) and the HDI (p<0.05). This information reflects the significant influence of socioeconomical indicators on the CL incidence at Trujillo and Merida, being an inverse relationship between both types of variables; with an increase or improvement in the socioeconomical indicators, the disease incidence rate decreased.


A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor.
Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.


Effects of body weight-supported treadmill training on heart rate variability and blood pressure variability in individuals with spinal cord injury.
Individuals with spinal cord injury are prone to cardiovascular dysfunction and an increased risk of cardiovascular disease. Body weight-supported treadmill training (BWSTT) may enhance ambulation in individuals with incomplete spinal cord injury; however, its effects on cardiovascular regulation have not been investigated. The purpose of this study was to examine the effects of 6-mo of BWSTT on the autonomic regulation of heart rate (HR) and blood pressure (BP) in individuals with incomplete tetraplegia. Eight individuals [age 27.6 yr (SD 5.2)] with spinal cord injury [C4-C5; American Spinal Injury Association B-C; 9.6 yr (SD 7.5) postinjury] participated. Ten-minute HR and finger arterial pressure (Finapres) recordings were collected during 1) supine rest and 2) an orthostatic stress (60 degrees head-up tilt) before and after 6 mo of BWSTT. Frequency domain measures of HR variability [low-frequency (LF) power, high-frequency (HF) power, and LF-to-HF ratio] and BP variability (systolic and diastolic LF power) were used as clinically valuable indexes of neurocardiac and neurovascular control, respectively. There was a significant reduction in HR [61.9 (SD 6.9) vs. 55.7 beats/min (SD 7.7); P=0.05] and LF-to-HF ratio [1.23 (SD 0.47) vs. 0.99 (SD 0.40); P < 0.05] after BWSTT. There was a significant reduction in LF systolic BP [183.1 (SD 46.8) vs. 158.4 mmHg2 (SD 45.2); P < 0.01] but no change in BP. There were no significant effects of training on HR variability or BP variability during 60 degrees head-up tilt. In conclusion, individuals with incomplete tetraplegia retain the ability to make positive changes in cardiovascular autonomic regulation with BWSTT without worsening orthostatic intolerance.


Coactivator MYST1 regulates nuclear factor-κB and androgen receptor functions during proliferation of prostate cancer cells.
In prostate cancer (PCa), the functional synergy between androgen receptor (AR) and nuclear factor-κ B (NF-κB) escalates the resistance to therapeutic regimens and promotes aggressive tumor growth. Although the underlying mechanisms are less clear, gene regulatory abilities of coactivators can bridge the transcription functions of AR and NF-κB. The present study shows that MYST1 (MOZ, YBF2 and SAS2, and TIP60 protein 1) costimulates AR and NF-κB functions in PCa cells. We demonstrate that activation of NF-κB promotes deacetylation of MYST1 by sirtuin 1. Further, the mutually exclusive interactions of MYST1 with sirtuin 1 vs AR regulate the acetylation of lysine 16 on histone H4. Notably, in AR-lacking PC3 cells and in AR-depleted LNCaP cells, diminution of MYST1 activates the cleavage of poly(ADP-ribose) polymerase and caspase 3 that leads to apoptosis. In contrast, in AR-transformed PC3 cells (PC3-AR), depletion of MYST1 induces cyclin-dependent kinase (CDK) N1A/p21, which results in G2M arrest. Concomitantly, the levels of phospho-retinoblastoma, E2F1, CDK4, and CDK6 are reduced. Finally, the expression of tumor protein D52 (TPD52) was unequivocally affected in PC3, PC3-AR, and LNCaP cells. Taken together, the results of this study reveal that the functional interactions of MYST1 with AR and NF-κB are critical for PCa progression.


Ultrastructural analysis of primary endings in deaf white cats: morphologic alterations in endbulbs of Held.
Changes in structure and function of the auditory system can be produced by experimentally manipulating the sensory environment, and especially dramatic effects result from deprivation procedures. An alternative deprivation strategy utilizes naturally occurring lesions. The congenitally deaf white cat represents an animal model of sensory deprivation because it mimics a form of human deafness called the Scheibe deformity and permits studies of how central neurons react to early-onset cochlear degeneration. We studied the synaptic characteristics of the endbulb of Held, a prominent auditory nerve terminal in the cochlear nucleus. Endbulbs arise from the ascending branch of the auditory nerve fiber and contact the cell body of spherical bushy cells. After 6 months, endbulbs of deaf white cats exhibit alterations in structure that are clearly distinguishable from those of normal hearing cats, including a diminution in terminal branching, a reduction in synaptic vesicle density, structural abnormalities in mitochondria, thickening of the pre- and postsynaptic densities, and enlargement of synapse size. The hypertrophied membrane densities are suggestive of a compensatory response to diminished transmitter release. These data reveal that early-onset, long-term deafness produces unambiguous alterations in synaptic structure and may be relevant to rehabilitation strategies that promote aural/oral communication.


Antimicrobial efficacy of a high-power diode laser, photo-activated disinfection, conventional and sonic activated irrigation during root canal treatment.
To evaluate the antimicrobial effect of a diode laser irradiation, photo-activated disinfection (PAD), conventional and sonic activated irrigation with 2.5% sodium hypochlorite (NaOCl) on Enterococcus faecalis. Root canals of 120 human extracted teeth with single straight canals were prepared with ProTaper files, sterilized, contaminated with an E. faecalis suspension and incubated for 7 days. They were then randomly distributed into six groups: G1, diode laser irradiation (2 W, 3 × 20 s); G2, PAD (100 mW, 60 s); G3, PAD with 3D Endoprobe (100 mW, 60 s); G4, 30-gauge syringe irrigation with NaOCl (60 s); G5, sonic agitation of NaOCl with the EndoActivator system (60 s); G6, 30-gauge syringe irrigation with NaCl (60 s). The pattern of colonization was visualized by scanning electron microscopy. The root canals were sampled by flushing with saline solution at baseline and after the treatments. The number of bacteria in each canal was determined by plate count. The presence and the absence of E. faecalis in root canals were also demonstrated by polymerase chain reaction (PCR). There was a significant reduction in the bacterial population after all treatments (P < 0.001). The PAD, using both laser systems, and the sonic activated NaOCl irrigation were significantly more effective than diode irradiation and single NaOCl irrigation in reducing CFUs (P < 0.05). High-power diode laser and single NaOCl irrigation had an equal antibacterial effect (P > 0.05). The PAD and EndoActivator system were more successful in reducing the root canal infection than the diode laser and NaOCl syringe irrigation alone.


Can pulsed xenon ultraviolet light systems disinfect aerobic bacteria in the absence of manual disinfection?
Whereas pulsed xenon-based ultraviolet light no-touch disinfection systems are being increasingly used for room disinfection after patient discharge with manual cleaning, their effectiveness in the absence of manual disinfection has not been previously evaluated. Our study indicates that pulsed xenon-based ultraviolet light systems effectively reduce aerobic bacteria in the absence of manual disinfection. These data are important for hospitals planning to adopt this technology as adjunct to routine manual disinfection.


Alternative oxidase 1 (Aox1) gene expression in roots of Medicago truncatula is a genotype-specific component of salt stress tolerance.
Alternative oxidase (AOX) is the central component of the non-phosphorylating alternative respiratory pathway in plants and may be important for mitochondrial function during environmental stresses. Recently it has been proposed that Aox can be used as a functional marker for breeding stress tolerant plant varieties. This requires characterization of Aox alleles in plants with different degree of tolerance in a certain stress, affecting plant phenotype in a recognizable way. In this study we examined Aox1 gene expression levels in Medicago truncatula genotypes differing in salt stress tolerance, in order to uncover any correlation between Aox expression and tolerance to salt stress. Results demonstrated a specific induction of Aox1 gene expression in roots of the tolerant genotype that presented the lowest modulation in phenotypic and biochemical stress indices such as morphologic changes, protein level, lipid peroxidation and ROS generation. Similarly, in a previous study we reported that induction of antioxidant gene expression in the tolerant genotype contributed to the support of the antioxidant cellular machinery and stress tolerance. Correlation between expression patterns of the two groups of genes was revealed mainly in 48 h treated roots. Taken together, results from both experiments suggest that M. truncatula tolerance to salt stress may in part due to an efficient control of oxidative balance thanks to (i) induction of antioxidant systems and (ii) involvement of the AOX pathway. This reinforces the conclusion that differences in antioxidant mechanisms can be essential for salt stress tolerance in M. truncatula and possibly the corresponding genes, especially Aox, could be utilized as functional marker.


Integrative genomics identifies 7p11.2 as a novel locus for fever and clinical stress response in humans.
Fever predicts clinical outcomes in sepsis, trauma and during cardiovascular stress, yet the genetic determinants are poorly understood. We used an integrative genomics approach to identify novel genomic determinants of the febrile response to experimental endotoxemia. We highlight multiple integrated lines of evidence establishing the clinical relevance of this novel fever locus. Through genome-wide association study (GWAS) of evoked endotoxemia (lipopolysaccharide (LPS) 1 ng/kg IV) in healthy subjects of European ancestry we discovered a locus on chr7p11.2 significantly associated with the peak febrile response to LPS (top single nucleotide polymorphism (SNP) rs7805622, P = 2.4 × 10(-12)), as well as with temperature fluctuation over time. We replicated this association in a smaller independent LPS study (rs7805622, P = 0.03). In clinical translation, this locus was also associated with temperature and mortality in critically ill patients with trauma or severe sepsis. The top GWAS SNPs are not located within protein-coding genes, but have significant cis-expression quantitative trait loci (eQTL) associations with expression of a cluster of genes ∼400 kb upstream, several of which (SUMF2, CCT6A, GBAS) are regulated by LPS in vivo in blood cells. LPS- and cold-treatment of adipose stromal cells in vitro suggest genotype-specific modulation of eQTL candidate genes (PSPH). Several eQTL genes were up-regulated in brown and white adipose following cold exposure in mice, highlighting a potential role in thermogenesis. Thus, through genomic interrogation of experimental endotoxemia, we identified and replicated a novel fever locus on chr7p11.2 that modulates clinical responses in trauma and sepsis, and highlight integrated in vivo and in vitro evidence for possible novel cis candidate genes conserved across human and mouse.


Venous thromboembolism: reducing the risk in a Role 3 setting.
Venous thromboembolism (VTE) represents a significant preventable cause of hospital mortality. VTE assessment and prophylaxis rates are key patient safety and quality of care indicators. The aim of this study was to audit low molecular weight heparin (LMWH) and graduated elasticated compression stockings (GECS) prescriptions compared with the current Clinical Guidelines for Operations. Complete audit loop in the Role 3 Hospital, Camp Bastion, Afghanistan. A multifaceted intervention programme incorporating physician and nurse education and pre-printed medication charts was introduced to improve VTE assessment and prophylaxis rates. Only 111/301 (36.9%) of patients in the pre-intervention cohort had a VTE risk assessment performed; this improved to 142/155 (91.6%, p<0.0001) post-intervention. A total of 57/88 (64.8%) patients prescribed LMWH pre-intervention had a documented assessment of bleeding risk performed; this rose to 65/66 (98.5%, p=0.0003) post-intervention. In pre-intervention, only 63/213 (29.6%) patients had a documented reassessment of VTE and bleeding risk at 24 h; reassessment rates rose to 68.8% (66/96 patients, p<0.0001) post-intervention. Of those patients at risk of VTE without ongoing bleeding risk, 62/96 (64.6%) had LMWH prescribed pre-intervention; this rose to 57/62 (91.9%) post-intervention (p<0.0001). Inappropriate LMWH prescription rates fell from 26/190 (13.7%) to 4/85 (4.7%, p=0.035) post-intervention. In those patients in whom GECS were not contraindicated, prescription rates rose from 23/95 (24.2%) to 42/62 (67.7%, p<0.0001) post-intervention. Inclusion of pre-printed LMWH/GECS prescriptions and risk assessment stickers in the mediction chart significantly improved rates of VTE risk assessment and prophylaxis. These easily reproducible and low-cost interventions could improve patient safety on deployment.


Clinical outcomes after lumbar discectomy for sciatica: the effects of fragment type and anular competence.
The surgical treatment of sciatica with discectomy is ineffective in a sizable percentage of patients, and reherniation occurs after 5% to 15% of such procedures. The purpose of the present study was to determine if competence of the disc anulus and the type of herniation could be used to predict postoperative clinical outcomes following lumbar discectomy. A prospective observational study of 187 consecutive patients undergoing single-level primary lumbar discectomy was conducted. A single surgeon performed all of the procedures, and an independent examiner evaluated 180 of the patients clinically at a minimum of two and a median of six years after surgery. The extent of anular deficiency and the presence of disc fragments were determined. On the basis of these intraoperative findings, disc herniations were classified into four categories: (1) Fragment-Fissure herniations (eighty-nine patients), (2) Fragment-Defect herniations (thirty-three patients), (3) Fragment-Contained herniations (forty-two patients), and (4) No Fragment-Contained herniations (sixteen patients). The effects of disc herniation morphology and preoperative variables on subsequent clinical outcome were determined with the Student t test for continuous variables and chi-square analysis for categorical variables. Patients in the Fragment-Fissure group, who had disc fragments and a small anular defect, had the best overall outcomes and the lowest rates of reherniation (1%) and reoperation (1%). Patients in the Fragment-Contained group had a 10% rate of reherniation and a 5% rate of reoperation. Patients in the Fragment-Defect group, who had extruded fragments and massive posterior anular loss, had a 27% rate of reherniation and a 21% rate of reoperation. Patients in the No Fragment-Contained group did poorly: 38% had recurrent or persistent sciatica, and the standard outcomes scores were less improved compared with those in the other groups (p < 0.001). Intraoperative findings, as described in the present study, were more clearly associated with outcomes than were demographic, socioeconomic, or clinical variables. The degree of anular competence after discectomy and the type of herniation appear to have value for the prediction of the recurrence of sciatica, reoperation, and clinical outcome following lumbar discectomy. Prognostic study, Level I-1 (prospective study). See p. 2 for complete description of levels of evidence.


Comparison of Ciaglia and Griggs Percutaneous Tracheostomy Techniques - A Biomechanical Animal Study.
The two most common commercial percutaneous dilation tracheotomy (PDT) sets apply different techniques. Our aim was to investigate the biomechanical properties of these two techniques on an animal model, that simulate a human trachea. Biomechanical properties of the different steps of the Ciaglia Blue Rhino® and Griggs Portex® techniques were measured on 20 pig cadavers. We found that the use of the two different devices created equal sized openings in the trachea (p >0.05). The force needed to insert the Griggs forceps was 1.8 kg average compared to 2.51 kg using the Ciaglia dilator (p <0.00001). The calculated total energy expenditure in the Ciaglia Blue Rhino® kit was 1.46 times greater than the Griggs Portex® kit (p <0.0001). This was mainly due to the amount of energy required during the final dilator stage, which was 4 times more using the Ciaglia Blue Rhino® dilator than the Portex® Griggs-dilator forceps. We conducted a series of biomechanical properties experiments on an animal model of PDT using two popular commercial kits - Griggs Portex® guidewire dilating forceps by Smiths Medical and Ciaglia Blue-Rhino® by Cook Medical. The Ciaglia technique required almost 50% more energy to perform a PDT (p <0.0001), mainly because of the force exerted during the final dilator insertion stage compared to the Griggs forceps. Further research is needed to examine if these properties are related to some of the PDT complications. Ronen O, Rosin I, Taitelman UZ, Altman E. Comparison of Ciaglia and Griggs Percutaneous Tracheostomy Techniques - A Biomechanical Animal Study. Indian J Crit Care Med 2019;23(6):247-250.


Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells.
Propagation and differentiation of stem cell populations are tightly regulated to provide sufficient cell numbers for tissue formation while maintaining the stem cell pool. Embryonic parts of the mammalian placenta are generated from differentiating trophoblast stem cells (TSCs) invading the maternal decidua. Here we demonstrate that lysine-specific demethylase 1 (Lsd1) regulates differentiation onset of TSCs. Deletion of Lsd1 in mice results in the reduction of TSC number, diminished formation of trophectoderm tissues and early embryonic lethality. Lsd1-deficient TSCs display features of differentiation initiation, including alterations of cell morphology, and increased migration and invasion. We show that increased TSC motility is mediated by the premature expression of the transcription factor Ovol2 that is directly repressed by Lsd1 in undifferentiated cells. In summary, our data demonstrate that the epigenetic modifier Lsd1 functions as a gatekeeper for the differentiation onset of TSCs, whereby differentiation-associated cell migration is controlled by the transcription factor Ovol2.


Involvement of IFN-gamma in Bacillus Calmette-Guérin-induced but not in tumor-induced sensitization to TNF-induced lethality.
In healthy mice, murine (m) TNF is fairly lethal, whereas human (h) TNF (a selective murine TNF-R55 agonist) is rather harmless. However, we and others observed that mice suffering from a bacterial infection, such as Bacillus Calmette-Guérin (BCG), or bearing i.m. some types of tumor, develop a hypersensitivity to the IL-6-inducing and lethal properties of hTNF. This is a cardinal problem as it severely limits the potential use of hTNF-R55-specific agonists for systemic treatment of human cancer. Using mice carrying a targeted disruption in the gene encoding the IFN-gamma receptor (IFN-gamma Ro/o), we here report that endogenous IFN-gamma plays a crucial role in the development of TNF hypersensitivity during BCG infection. Indeed, both the lethality and the IL-6 induced by hTNF were drastically reduced in IFN-gamma Ro/o mice as compared with control mice. These results demonstrate that the enhancement of TNF effects is at least an equally important mechanism by which IFN-gamma contributes to BCG-induced hypersensitivity as the previously described augmentation of TNF production. Experiments in athymic nude mice, either depleted of NK cells or not, revealed that the latter cell population is an important source of the sensitizing IFN-gamma during BCG infection. In contrast, IFN-gamma Ro/o mice were as susceptible as control mice to the sensitizing effects of tumors. mTNF, which interacts with both mTNF-R55 and mTNF-R75 and causes lethality on its own, is as toxic in IFN-gamma Ro/o mice as in wt control mice; this means that TNF-induced IFN-gamma does not play a role in mTNF-induced lethality.


Influence of N-linked glycosylation of porcine reproductive and respiratory syndrome virus GP5 on virus infectivity, antigenicity, and ability to induce neutralizing antibodies.
Porcine reproductive and respiratory syndrome virus (PRRSV) glycoprotein 5 (GP5) is the most abundant envelope glycoprotein and a major inducer of neutralizing antibodies in vivo. Three putative N-linked glycosylation sites (N34, N44, and N51) are located on the GP5 ectodomain, where a major neutralization epitope also exists. To determine which of these putative sites are used for glycosylation and the role of the glycan moieties in the neutralizing antibody response, we generated a panel of GP5 mutants containing amino acid substitutions at these sites. Biochemical studies with expressed wild-type (wt) and mutant proteins revealed that the mature GP5 contains high-mannose-type sugar moieties at all three sites. These mutations were subsequently incorporated into a full-length cDNA clone. Our data demonstrate that mutations involving residue N44 did not result in infectious progeny production, indicating that N44 is the most critical amino acid residue for infectivity. Viruses carrying mutations at N34, N51, and N34/51 grew to lower titers than the wt PRRSV. In serum neutralization assays, the mutant viruses exhibited enhanced sensitivity to neutralization by wt PRRSV-specific antibodies. Furthermore, inoculation of pigs with the mutant viruses induced significantly higher levels of neutralizing antibodies against the mutant as well as the wt PRRSV, suggesting that the loss of glycan residues in the ectodomain of GP5 enhances both the sensitivity of these viruses to in vitro neutralization and the immunogenicity of the nearby neutralization epitope. These results should have great significance for development of PRRSV vaccines of enhanced protective efficacy.


Modifications of adiposity in school-age children according to nutritional status: a 20-year analysis.
To analyze adiposity changes in school-age children over a 20 year-period, according to nutritional status. The study is part of the Ilhabela Longitudinal Mixed Project on Growth, Development and Physical Fitness. A sample of 1,095 school students of both sexes, from 7 to 10 years, met the following inclusion criteria: (a) at least one complete assessment in one of the analyzed periods; (b) to be in prepubertal stage of sexual maturation; (c) to be apparently healthy. The periods analyzed were 1990/1991 (initial), 2000/2001 (10 years) and 2010/2011 (20 years). The variables analyzed were: body weight, height and adiposity through individual analysis of each skinfold. Children were classified as eutrophic, overweight and obese, according to the curves of body mass index for age and sex proposed by the World Health Organization. The statistical analysis used was one-way ANOVA, followed by Scheffé's post-hoc test, with p < 0.01. In boys, the largest increase occurred in the overweight group, followed by the obese and eutrophic groups. In girls, the largest increases occurred in the groups with overweight and eutrophic children, followed by the obese group. During the 20-year period analyzed, there were changes in adiposity, even when the nutritional status was controlled, showing that individuals who have similar body mass indexes may vary in proportion and distribution of subcutaneous adipose tissue. In both sexes, the increase was higher in the overweight group, and mainly in central skinfolds.


Catalyzing Technology-Based Innovation in Teen Pregnancy Prevention: an Implementation Model and Findings from a Human-Centered Design Initiative.
From 2015 to 2021, the US Department of Health and Human Services' Teen Pregnancy Prevention (TPP) program funded Power to Decide, a national reproductive health nonprofit organization, to catalyze innovation in adolescent sexual and reproductive health through the development of technology-based interventions. Power to Decide's initiative, Innovation Next, supported twenty innovation teams in using human-centered design (HCD) to develop new products, services, and programs. We describe the Innovation Next implementation model, which can inform future efforts to develop innovative, technology-based TPP programs using HCD. To that end, we draw on quantitative and qualitative data collected for program improvement to summarize key implementation findings.


How prepared are foundation dentists in England and Wales for independent general dental practice?
Introduction The Graduate Assessment of Preparedness for Practice (GAPP) questionnaire has been shown to be valid and reliable in assessing the preparedness of foundation dentists (FDs) for independent general dental practice (GDP). In this study it is used to establish preparedness at six weeks of dental foundation training (DFT) across England and Wales.Method GAPP questionnaires were sent to all FDs and ESs in England and Wales in mid-September 2012. Part 1 of the GAPP questionnaire collected the descriptive data of respondents. Part 2 comprised 34 'competence areas' designed to reflect the breadth of Preparing for Practice allowing respondents a 7-category Likert style response. Part 3 comprised open questions designed to allow respondents to expand on their views. Quantitative categorical data from Part 2 was analysed using IBM SPSS (version 20). Median scores were analysed and mean rank scores were generated in order to compare FD and ES responses. Part 2 results were cross-tabulated with the Part 1 descriptors and analysed using the Mann Whitney U and Kruskal Wallis H non-parametric tests. Mean rank scores were considered to be statistically significant if P ≤0.05. Part 3 data was analysed thematically using NVivo (version 10).Results FDs and ESs felt that FDs were generally well prepared for independent GDP, although FDs rated their preparedness significantly higher than ESs in all areas. FDs who graduated from 4-year courses felt significantly more prepared across most of the curriculum than those from 5-year courses, and graduates from outside the UK felt less prepared for GDP than those from a UK school.Conclusions FDs appear to be well prepared for independent GDP at six weeks of DFT. FDs rated their preparedness significantly higher than ESs across the curriculum. Coupled with the finding that the more experienced ESs felt their FDs were less well prepared, that may indicate FDs potentially overstate their level of preparedness. FDs who completed 4-year courses were generally more prepared across a range of curricular areas, some of which may reflect differences in the courses they completed, while others may relate to the individual being a graduate on entry to the course. Distribution of questionnaires through DFT schemes has resulted in a large number of respondents which may allow valuable generalisations to be made about the preparedness of graduates entering DFT in the UK.


Modelling testing and response strategies for COVID-19 outbreaks in remote Australian Aboriginal communities.
Remote Australian Aboriginal and Torres Strait Islander communities have potential to be severely impacted by COVID-19, with multiple factors predisposing to increased transmission and disease severity. Our modelling aims to inform optimal public health responses. An individual-based simulation model represented SARS-CoV2 transmission in communities ranging from 100 to 3500 people, comprised of large, interconnected households. A range of strategies for case finding, quarantining of contacts, testing, and lockdown were examined, following the silent introduction of a case. Multiple secondary infections are likely present by the time the first case is identified. Quarantine of close contacts, defined by extended household membership, can reduce peak infection prevalence from 60 to 70% to around 10%, but subsequent waves may occur when community mixing resumes. Exit testing significantly reduces ongoing transmission. Concurrent lockdown of non-quarantined households for 14 days is highly effective for epidemic control and reduces overall testing requirements; peak prevalence of the initial outbreak can be constrained to less than 5%, and the final community attack rate to less than 10% in modelled scenarios. Lockdown also mitigates the effect of a delay in the initial response. Compliance with lockdown must be at least 80-90%, however, or epidemic control will be lost. A SARS-CoV-2 outbreak will spread rapidly in remote communities. Prompt case detection with quarantining of extended-household contacts and a 14 day lockdown for all other residents, combined with exit testing for all, is the most effective strategy for rapid containment. Compliance is crucial, underscoring the need for community supported, culturally sensitive responses.


Losing the rose tinted glasses: neural substrates of unbiased belief updating in depression.
Recent evidence suggests that a state of good mental health is associated with biased processing of information that supports a positively skewed view of the future. Depression, on the other hand, is associated with unbiased processing of such information. Here, we use brain imaging in conjunction with a belief update task administered to clinically depressed patients and healthy controls to characterize brain activity that supports unbiased belief updating in clinically depressed individuals. Our results reveal that unbiased belief updating in depression is mediated by strong neural coding of estimation errors in response to both good news (in left inferior frontal gyrus and bilateral superior frontal gyrus) and bad news (in right inferior parietal lobule and right inferior frontal gyrus) regarding the future. In contrast, intact mental health was linked to a relatively attenuated neural coding of bad news about the future. These findings identify a neural substrate mediating the breakdown of biased updating in major depression disorder, which may be essential for mental health.


Deaths from recreational use of propofol in Korea.
Propofol, a short-acting and sedative-hypnotic agent, induces and maintains anesthesia. Since it is known to produce mild euphoria and hallucinations, the recreational use of propofol has been a big issue in Korea. Furthermore, many deaths have occurred due to its abuse and misuse. In order to study the prevalence of abuse and deaths due to propofol, all autopsy cases conducted between 2005 and 2010 at the NFS (National Forensic Service, Korea) were monitored by checking its concentrations in the blood. Propofol was detected in 131 cases (0.88%) out of 14,673 autopsied cases within 6 years. Propofol alone was detected in 49 of 131 fatal cases, while the combination of drugs was detected with propofol in the remaining 82 cases. The concentrations of propofol from autopsied cases ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05) in the heart (n=31) and the femoral blood (n=32), respectively. The investigation of the ratio of heart to femoral blood and the difference between the concentrations in heart and femoral blood (n=15) from the same body revealed the ratio from 0.45 to 3.66 (mean 1.53; median 1.40). The autopsy resulted in accidental death after self-administration in 16 autopsied cases among 131 autopsied cases. In 16 cases, their ages ranged from 17 to 56 and 75% of them were in their 20's and 30's and 75% were female. Half of them were medical personnel including 19% of doctors and 38% of nurses. The combination of drugs was detected in 6 cases. Fluoxetine was detected in three and vecuronium was detected in two along with propofol. The cause of death in 14 cases was drug intoxication, while that in 2 cases was hanging. Due to its prevalence, Korea has become the first country that regulates propofol as a psychotropic substance.


Sodium intake and blood pressure in children and adolescents: a systematic review and meta-analysis of experimental and observational studies.
High sodium intake is a cause of elevated blood pressure in adults. In children and adolescents, less evidence is available and findings are equivocal. We systematically reviewed the evidence from experimental and observational studies on the association between sodium intake and blood pressure in children and adolescents. A systematic search of the Medline, Embase, CINAHL and CENTRAL databases up to March 2017 was conducted and supplemented by a manual search of bibliographies and unpublished studies. Experimental and observational studies involving children or adolescents between 0 and 18 years of age were included. Random-effects meta-analyses were performed by pooling data across all studies, separately for experimental and observational studies, and restricting to studies with sodium intake and blood pressure measurement methods of high quality. Subgroup meta-analyses, sensitivity analyses and meta-regressions were conducted to investigate sources of heterogeneity and confounding. The dose-response relationship was also investigated. Of the 6572 publications identified, 85 studies (14 experimental; 71 observational, including 60 cross-sectional, 6 cohort and 5 case-control studies) with 58 531 participants were included. In experimental studies, sodium reduction interventions decreased systolic blood pressure by 0.6 mm Hg [95% confidence interval (CI): 0.5, 0.8] and diastolic blood pressure by 1.2 mm Hg (95% CI: 0.4, 1.9). The meta-analysis of 18 experimental and observational studies (including 3406 participants) with sodium intake and blood pressure measurement methods of high quality showed that, for every additional gram of sodium intake per day, systolic blood pressure increased by 0.8 mm Hg (95% CI: 0.4, 1.3) and diastolic blood pressure by 0.7 mm Hg (95% CI: 0.0, 1.4). The association was stronger among children with overweight and with low potassium intake. A quasi-linear relationship was found between sodium intake and blood pressure. Sodium intake is positively associated with blood pressure in children and adolescents, with consistent findings in experimental and observational studies. Since blood pressure tracks across the life course, our findings support the reduction of sodium intake during childhood and adolescence to lower blood pressure and prevent the development of hypertension.


Lipidbook: a public repository for force-field parameters used in membrane simulations.
Lipidbook is a public database for force-field parameters with a special emphasis on lipids, detergents and similar molecules that are of interest when simulating biological membrane systems. It stores parameter files that are supplied by the community. Topologies, parameters and lipid or whole bilayer structures can be deposited in any format for any simulation code, preferably under a license that promotes "open knowledge." A number of mechanisms are implemented to aid a user in judging the appropriateness of a given parameter set for a project. For instance, parameter sets are versioned, linked to the primary citation via PubMed identifier and digital object identifier (DOI), and users can publicly comment on deposited parameters. Licensing and, hence, the conditions for use and dissemination of academically generated data are often unclear. In those cases it is also possible to provide a link instead of uploading a file. A snapshot of the linked file is then archived using the WebCite(®) service without further involvement of the user or Lipidbook, thus ensuring a transparent and permanent history of the parameter set. Lipidbook can be accessed freely online at http://lipidbook.bioch.ox.ac.uk. Deposition of data requires online registration.


Promotive effects of far-infrared ray on full-thickness skin wound healing in rats.
The biological effects of far-infrared ray (FIR) on whole organisms remain poorly understood. The aim of our study was to investigate not only the hyperthermic effect of the FIR irradiation, but also the biological effects of FIR on wound healing. To evaluate the effect of FIR on a skin wound site, the speed of full-thickness skin wound healing was compared among groups with and without FIR using a rat model. We measured the skin wound area, skin blood flow, and skin temperature before and during FIR irradiation, and we performed histological inspection. Wound healing was significantly more rapid with than without FIR. Skin blood flow and skin temperature did not change significantly before or during FIR irradiation. Histological findings revealed greater collagen regeneration and infiltration of fibroblasts that expressed transforming growth factor-beta1 (TGF-beta1) in wounds in the FIR group than in the group without FIR. Stimulation of the secretion of TGF-beta1 or the activation of fibroblasts may be considered as a possible mechanisms for the promotive effect of FIR on wound healing independent of skin blood flow and skin temperature.


Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children.
Major gaps in our understanding of Plasmodium vivax biology and the acquisition of immunity to this parasite hinder vaccine development. P. vivax merozoites exclusively invade reticulocytes, making parasite proteins that mediate reticulocyte binding and/or invasion potential key vaccine or drug targets. While protein interactions that mediate invasion are still poorly understood, the P. vivax Reticulocyte-Binding Protein family (PvRBP) is thought to be involved in P. vivax restricted host-cell selectivity. We assessed the binding specificity of five members of the PvRBP family (PvRBP1a, PvRBP1b, PvRBP2a, PvRBP2b, PvRBP2-P2 and a non-binding fragment of PvRBP2c) to normocytes or reticulocytes. PvRBP2b was identified as the only reticulocyte-specific binder (P<0.001), whereas the others preferentially bound to normocytes (PvRBP1a/b P≤0.034), or showed comparable binding to both (PvRBP2a/2-P2, P = 0.38). Furthermore, we measured levels of total and IgG subclasses 1, 2, 3 and 4 to the six PvRBPs in a cohort of young Papua New Guinean children, and assessed their relationship with prospective risk of P. vivax malaria. Children had substantial, highly correlated (rho = 0.49-0.82, P<0.001) antibody levels to all six PvRBPs, with dominant IgG1 and IgG3 subclasses. Both total IgG (Incidence Rate Ratio [IRR] 0.63-0.73, P = 0.008-0.041) and IgG1 (IRR 0.56-0.69, P = 0.001-0.035) to PvRBP2b and PvRBP1a were strongly associated with reduced risk of vivax-malaria, independently of age and exposure. These results demonstrate a diversity of erythrocyte-binding phenotypes of PvRBPs, indicating binding to both reticulocyte-specific and normocyte-specific ligands. Our findings provide further insights into the naturally acquired immunity to P. vivax and highlight the importance of PvRBP proteins as targets of naturally acquired humoral immunity. In-depth studies of the role of PvRBPs in P. vivax invasion and functional validation of the role of anti-PvRBP antibodies in clinical immunity against P. vivax are now required to confirm the potential of the reticulocyte-binding PvRBP2b and PvRBP1a as vaccine candidate antigens.


A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension.
Clinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients. We searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects. Of 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01). Current evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.


Concentration of the macrolide antibiotic tulathromycin in broncho-alveolar cells is influenced by comedication of rifampicin in foals.
Macrolide antibiotics penetrate in the lung against steep concentration gradients into the epithelial lining fluid (ELF) and broncho-alveolar cells (BAC). Since they interact with ABCB1, ABCC2, and organic anion transporting proteins (OATPs), which are localized to lung tissue, pulmonary concentration may be influenced by rifampicin (RIF), an inducer and modulator of efflux and uptake transporters. We measured concentrations of tulathromycin (TM) in plasma, ELF and BAC in 21 warm-blooded foals 24 and 192 h after first and last intramuscular injection of 2.5 mg/kg TM once weekly for 6 weeks. In 11 foals, TM was combined with RIF (10 mg/kg twice daily), and mRNA expression of ABCB1 and ABCC2 in BAC was assessed before and after RIF. Affinity of TM to ABCB1 and ABCC2 was measured by transport assays using cell monolayers and membrane vesicles of MDCKII and 2008 cells transfected with ABCB1 and ABCC2, respectively. At steady state, TM concentrated manifold in ELF and BAC. Comedication of RIF significantly decreased the AUC of TM (18.5 +/- 4.0 versus 24.4 +/- 3.7 microg x h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 +/- 0.05 versus 0.24 +/- 0.05 microg/ml; 192 h, 0.05 +/- 0.01 versus 0.06 +/- 0.01 microg/ml) and BAC (24 h, 0.84 +/- 0.36 versus 1.56 +/- 1.02 microg/ml; 192 h, 0.60 +/- 0.23 versus 1.23 +/- 0.90 microg/ml, all p < 0.05). Treatment with rifampicin did not markedly induce ABCB1 and ABCC2 expression. TM had no affinity to ABCB1 and ABCC2 in vitro. Concentration of TM in the lung of foals was significantly lowered by comedication of rifampicin most likely caused by extrapulmonary mechanisms leading to lower plasma concentrations.


Team Leader Structuring for Team Effectiveness and Team Learning in Command-and-Control Teams.
Due to their crucial and highly consequential task, it is of utmost importance to understand the levers leading to effectiveness of multidisciplinary emergency management command-and-control (EMCC) teams. We argue that the formal EMCC team leader needs to initiate structure in the team meetings to support organizing the work as well as facilitate team learning, especially the team learning process of constructive conflict. In a sample of 17 EMCC teams performing a realistic EMCC exercise, including one or two team meetings (28 in sum), we coded the team leader's verbal structuring behaviors (1,704 events), rated constructive conflict by external experts, and rated team effectiveness by field experts. Results show that leaders of effective teams use structuring behaviors more often (except asking procedural questions) but decreasingly over time. They support constructive conflict by clarifying and by making summaries that conclude in a command or decision in a decreasing frequency over time.


Deceiving others: distinct neural responses of the prefrontal cortex and amygdala in simple fabrication and deception with social interactions.
Brain mechanisms for telling lies have been investigated recently using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. Although the advent of these techniques has gradually enabled clarification of the functional contributions of the prefrontal cortex in deception with respect to executive function, the specific roles of subregions within the prefrontal cortex and other brain regions responsible for emotional regulation or social interactions during deception are still unclear. Assuming that the processes of falsifying truthful responses and deceiving others are differentially associated with the activities of these regions, we conducted a positron emission tomography experiment with 2 (truth, lie) x 2 (honesty, dishonesty) factorial design. The main effect of falsifying the truthful responses revealed increased brain activity of the left dorsolateral and right anterior prefrontal cortices, supporting the interpretation of previous studies that executive functions are related to making untruthful responses. The main effect of deceiving the interrogator showed activations of the ventromedial prefrontal (medial orbitofrontal) cortex and amygdala, adding new evidence that the brain regions assumed to be responsible for emotional processing or social interaction are active during deceptive behavior similar to that in real-life situations. Further analysis revealed that activity of the right anterior prefrontal cortex showed both effects of deception, indicating that this region has a pivotal role in telling lies. Our results provide clear evidence of functionally dissociable roles of the prefrontal subregions and amygdala for human deception.


The Quest for Accurate Liquid Water Properties from First Principles.
Developing accurate ab initio molecular dynamics (AIMD) models that capture both electronic reorganization and nuclear quantum effects associated with hydrogen bonding is key to quantitative understanding of bulk water and its anomalies as well as its role as a universal solvent. For condensed phase simulations, AIMD has typically relied on the generalized gradient approximation (GGA) of density functional theory (DFT) as the underlying model chemistry for the potential energy surface, with nuclear quantum effects (NQEs) sometimes modeled by performing classical molecular dynamics simulations at elevated temperatures. Here we show that the properties of liquid water obtained from the meta-GGA B97M-rV functional, when evaluated using accelerated path integral molecular dynamics simulations, display accuracy comparable to a computationally expensive dispersion-corrected hybrid functional, revPBE0-D3. We show that the meta-GGA DFT functional reproduces bulk water properties including radial distribution functions, self-diffusion coefficients, and infrared spectra with comparable accuracy of a much more expensive hybrid functional. This work demonstrates that the underlying quality of a good DFT functional requires evaluation with quantum nuclei and that high-temperature simulations are a poor proxy for properly treating NQEs.


HIV-infected cells are killed by rCD4-ricin A chain.
The gp120 envelope glycoprotein of the human immunodeficiency virus (HIV), which is expressed on the surface of many HIV-infected cells, binds to the cell surface molecule CD4. Soluble derivatives of recombinant CD4 (rCD4) that bind gp120 with high affinity are attractive vehicles for targeting a cytotoxic reagent to HIV-infected cells. Soluble rCD4 was conjugated to the active subunit of the toxin ricin. This conjugate killed HIV-infected H9 cells but was 1/1000 as toxic to uninfected H9 cells (which do not express gp120) and was not toxic to Daudi cells (which express major histocompatibility class II antigens, the putative natural ligand for cell surface CD4). Specific killing of infected cells can be blocked by rgp120, rCD4, or a monoclonal antibody to the gp120 binding site on CD4.


Nutritional and management methods to decrease nitrogen losses from beef feedlots.
Nitrogen losses from open beef feedlots are a concern. Methods that decrease volatilization losses will lead to greater manure N, which is likely to be beneficial in open lot beef operations. Twelve or more pens were dedicated to N research whereby N intake, retention, and excretion were quantified and a mass balance conducted using manure, runoff, soil balance, and loss quantities. The objective was to decrease N volatilization losses or increase manure N or both. Dietary CP affects N excretion and N volatilization losses. Four experiments across 2 yr compared industry average CP (13%) to diets that were phase-fed to not exceed protein requirements (12.1 to 10.9%). Phase-fed cattle excreted 12 to 21% less N (P < 0.01), and N volatilization losses were reduced 15 to 33% (P < 0.01). In 2 other experiments, phase-fed diets were formulated to recycle undegradable intake protein. Steer G:F was similar (P = 0.18) or improved (P = 0.09), whereas N excretion and N volatilization losses tended to be reduced (P < 0.11) and N in manure was not affected (P > 0.35) compared with cattle fed 13% CP. Feeding less protein did not affect manure N, indicating manure N from open lots is related to other factors. A series of experiments evaluated increasing OM on the pen surface to increase N in manure. Feeding less digestible diets using fiber increased manure N (P < 0.01) and decreased (P < 0.10) N volatilization losses in 2 experiments conducted from November to May, but did not affect (P > 0.30) manure N or volatilization losses during 2 summer experiments. Adding bedding (i.e., OM) increased manure N in the winter as well. Another method evaluated was increasing pen cleaning frequency, which decreased N volatilization losses by 19 to 44% and increased manure N by 26 to 41% across 3 experiments. Other methods, such as acidifying manure by manipulating dietary cation anion difference, clinoptilite zeolite clay addition, and feeding different amounts of by-products had variable impacts on N volatilization losses. No treatments markedly affected runoff N, which is <5% of excreted N. Dietary protein affects N volatilization losses but not manure N. Other factors, such as OM on the pen surface, affect manure N. Cleaning manure frequently, which decreases exposure of manure N to air, decreases volatilization losses. Treatments should be evaluated across seasons due to seasonal effects.


Hybrid silica/polymer long period gratings for wavelength filtering and power distribution.
We report long period grating (LPG) devices based on a hybrid architecture incorporating photopatternable fluorinated poly(aryl ether ketone) and silica layers for applications in wavelength filtering and power distribution. The grating structure was implemented using a periodic corrugation on a thermally oxidized silica lower cladding layer, a photopatterned fluorinated polymer ridge waveguide, and a similar polymer top cladding. In this design, the corrugated silica layer allows a highly stable grating structure, while the fluorinated polymer offers a low propagation loss and easy processability. Strong rejection bands have been demonstrated in the C+L wavelength band, in good agreement with theoretical calculations. The fabricated LPG devices show a thermal dependence of 1.5 nm/ degrees C. Based on this design, an array of waveguides incorporating LPGs has also been fabricated. Distribution of light at the resonance wavelength across all the channels from a single input has been demonstrated. These results are promising for power distribution in photonic network applications or on-chip sensors.


No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans.
In rodent and primate studies, urotensin II is an extremely potent vasoconstrictor peptide with effects in the central aortic and arterial vasculature as well as on cardiac function. The aim of the present study was to assess systemic haemodynamic responses to intravenous urotensin II infusion in humans. In 10 healthy male volunteers, intravenous urotensin II (3, 30 and 300 pmol min-1) and saline placebo were given on separate occasions in a single-blind randomized manner. Systemic haemodynamics and arterial stiffness were assessed by sphygmomanometry, transthoracic bioimpedance, and pulse wave analysis. Plasma urotensin II immuno-reactivity was measured by radio-immunoassay. Intravenous urotensin II infusions were well tolerated with no adverse clinical effects and no electrocardiographic changes. Circulating plasma urotensin II immuno-reactivity increased from baseline of 16 +/- 1 to 1460 +/- 82 pmol l-1 (mean +/- s.e. mean) during infusion of urotensin II at 300 pmol min-1 (P < 0.001). However, there were no significant placebo adjusted changes in heart rate (95% confidence intervals: -3.6, + 4.4 min-1), mean arterial pressure (-5.8, + 1.7 mmHg) or cardiac index (-0.1, + 0.4 l min-1 m-2). There were also no changes in augmentation index (-4.1, + 5.2%) or pulse wave velocity (-1.3, + 0.3 m s-1). Intravenous urotensin II infusion did not affect systemic haemodynamics or arterial stiffness, despite achieving an approximately 100-fold increase in plasma immuno-reactivity. We conclude that urotensin II is unlikely to have a physiological role in the short term regulation of vascular tone or blood pressure in man. Further confirmatory studies with urotensin II receptor antagonists are required.


Feasibility, reliability, and validity of adolescent health status measurement by the Child Health Questionnaire Child Form (CHQ-CF): internet administration compared with the standard paper version.
In this study we evaluated indicators of the feasibility, reliability, and validity of the Child Health Questionnaire-Child Form (CHQ-CF). We compared the results in a subgroup of adolescents who completed the standard paper version of the CHQ-CF with the results in another subgroup of adolescents who completed an internet version, i.e., an online, web-based CHQ-CF questionnaire. Under supervision at school, 1,071 adolescents were randomized to complete the CHQ-CF and items on chronic conditions by a paper questionnaire or by an internet administered questionnaire. The participation rate was 87%; age range 13-17 years. The internet administration resulted in fewer missing answers. All but one multi-item scale showed internal consistency reliability (Cronbach's alpha > 0.70). All scales clearly discriminated between adolescents with no, a few, or many self-reported chronic conditions. The paper administration resulted in statistically significant, higher scores on 4 of 10 CHQ-CF scales compared with the internet administration (P < 0.05), but Cohen's effect sizes d were </= 0.21. Mode of administration interacted significantly with age (P < 0.05) on four CHQ-CF scales, but Cohen's effect sizes for these differences were also </= 0.21. This study supports the feasibility, internal consistency reliability of the scales, and construct validity of the CHQ-CF administered by either a paper questionnaire or online questionnaire. Given Cohen's suggested guidelines for the interpretation of effect sizes, i.e., 0.20-0.50 indicates a small effect, differences in CHQ-CF scale scores between paper and internet administration can be considered as negligible or small.


Antidepressant response and the serotonin transporter gene-linked polymorphic region.
The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been proposed as a predictor of antidepressant response. Insertion or deletion of a 44-base pair-long region gives rise to short "S" and long "L" forms of the promoter region, the "S" form being associated with reduced serotonin transporter expression. A systematic review and meta-analysis was performed to clarify the effect of 5-HTTLPR on antidepressant response and remission rates. Data were obtained from 28 studies with 5408 participants. Three genotype comparisons were tested-SS versus (SL or LL), (SS or SL) versus LL, and SS versus LL. There was no statistically significant effect on antidepressant response. Compared with L carriers, there was an apparent effect of the SS genotype on remission rate (relative risk: .88; 95% confidence interval: .79-.98; p = .02). However, after trim and fill correction for missing data, the effect disappeared (relative risk: .92; 95% confidence interval: .81-1.05; p = .23), indicating that the initial significant effect was likely the result of publication bias. No significant effect on remission rate was seen for SS versus LL and SS/SL versus LL. Substantial unexplained heterogeneity of effect sizes was observed between studies, pointing to additional interacting factors contributing to an association in some cases. The 5-HTTLPR biallelic short/long polymorphism by itself does not seem to usefully predict antidepressant response.


The not guilty verdict: psychological reactions to a diagnosis of Asperger syndrome in adulthood.
Asperger syndrome is a relatively new diagnostic classification. A number of factors make receiving a diagnosis of Asperger syndrome in adulthood a unique experience. This study used a phenomenological approach to examine the experiences of 10 adults receiving such a diagnosis. Results suggested that six major themes were associated with receiving a diagnosis of Asperger syndrome. Individuals discussed their negative life experiences and their experience of services prior to diagnosis, which led to individuals holding certain beliefs about the symptoms of Asperger syndrome. These beliefs had an effect on the formation of each individual's perceived self-identity. Participants made links between how they felt when they received the diagnosis and their current beliefs about both their ;symptoms' and themselves. Finally, participants highlighted the importance of the societal view of Asperger syndrome. The implications of these findings are reappraised in the context of previous research and the wider literature on identity formation.


Antifungal skin bacteria, embryonic survival, and communal nesting in four-toed salamanders, Hemidactylium scutatum.
We examined a novel hypothesis for the maintenance of communal nesting in the salamander, Hemidactylium scutatum, namely that communal nests are more likely than solitary nests to be associated with cutaneous antifungal bacteria, which can inhibit fungal infections of embryos. A communal nest contains eggs of two or more females of the same species. The nesting behavior of H. scutatum females and survival of embryos were determined by frequent nest surveys at three ponds. For communal nests, embryonic survival tended to be higher and catastrophic nest failure was lower. Pure bacterial cultures of resident species were obtained from the salamanders' skins by swabbing and tested against a fungal pathogen of embryos (Mariannaea sp.) in laboratory assays. We found that 27% of females had skin bacteria inhibitory to Mariannaea sp. Communal nests were more likely to have at least one female with antifungal bacteria than were solitary nests. Using a culture-independent assay (denaturing gradient gel electrophoresis of 16S rRNA gene fragments), we found that bacterial species on females and embryos were more similar to each other than they were to bacterial species found in soil within the nest, suggesting that females transmitted skin bacteria to embryos. The presence of anti-Mariannaea skin bacteria identified from the laboratory assays did not prevent fungal presence in field nests. However, once a nest was visibly infected with fungi, presence of anti-Mariannaea bacteria was positively correlated with survival of embryos. Microbe transmission is usually thought to be a cost of group living, but communal nesting in H. scutatum may facilitate the transmission of antifungal bacteria to embryos.


Expression of bovine Mx1 protein inhibits the replication of foot-and-mouth disease virus in BHK-21 cells.
Mx proteins belonging to the dynamin superfamily of large GTPases inhibit replication of a wide range of RNA viruses. In this study, we examined whether bovine Mx1 protein could interfere with the replication of foot-and-mouth disease virus (FMDV). For this purpose we established cloned BHK-21 cells expressing bovine Mx1 protein (BM1 cells) and infected them with FMDV serotype O. Cloned BHK-21 cells expressing neomycin resistance instead of Mx1 protein (BH1 cells) and original BHK-21 cells served as negative controls. The results showed that the expression of bovine Mx1 protein reduced viral yields by 90% and levels of viral VP1 mRNA by 60%. These findings correlated with a significant reduction of viral antigen detectable in infected cells by immunofluorescent assay. These results demonstrate that bovine Mx1 protein interferes with the replication of FMDV.


Extracorporeal treatment for carbamazepine poisoning: systematic review and recommendations from the EXTRIP workgroup.
The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence and consensus-based recommendations on the use of extracorporeal treatments (ECTRs) in poisoning. To perform a systematic review and provide clinical recommendations for ECTR in carbamazepine poisoning. After a systematic literature search, the subgroup extracted the data and summarized the findings following a pre-determined format. The entire workgroup voted via a two-round modified Delphi method to reach a consensus on voting statements, using a RAND/UCLA Appropriateness Method to quantify disagreement. Anonymous votes were compiled, returned, and discussed in person. A second vote determined the final recommendations. Seventy-four articles met inclusion criteria. Articles included case reports, case series, descriptive cohorts, pharmacokinetic studies, and in-vitro studies; two poor-quality observational studies were identified, yielding a very low quality of evidence for all recommendations. Data on 173 patients, including 6 fatalities, were reviewed. The workgroup concluded that carbamazepine is moderately dialyzable and made the following recommendations: ECTR is suggested in severe carbamazepine poisoning (2D). ECTR is recommended if multiple seizures occur and are refractory to treatment (1D), or if life-threatening dysrhythmias occur (1D). ECTR is suggested if prolonged coma or respiratory depression requiring mechanical ventilation are present (2D) or if significant toxicity persists, particularly when carbamazepine concentrations rise or remain elevated, despite using multiple-dose activated charcoal (MDAC) and supportive measures (2D). ECTR should be continued until clinical improvement is apparent (1D) or the serum carbamazepine concentration is below 10 mg/L (42 the μ in μmol/L looks weird.) (2D). Intermittent hemodialysis is the preferred ECTR (1D), but both intermittent hemoperfusion (1D) or continuous renal replacement therapies (3D) are alternatives if hemodialysis is not available. MDAC therapy should be continued during ECTR (1D). Despite the low quality of the available clinical evidence and the high protein binding capacity of carbamazepine, the workgroup suggested extracorporeal removal in cases of severe carbamazepine poisoning.