Comparing the Nidek MP-1 and Humphrey field analyzer in normal subjects.
To compare visual fields on the Nidek MP-1 to those obtained on the Humphrey field analyzer (HFA) in healthy volunteers and assess the effects of differences in stimulus parameters and testing strategies that may influence the interpretation of results in patients. A secondary aim was to establish MP-1 normative data to calculate the total deviation analyses and global indices analogous to those used by the HFA. Fifty healthy volunteers (age 43.5 ± 13.9 years, range, 18 to 68 years) underwent repeat MP-1 and HFA visual field testing, using the 10-2 pattern. MP-1 data were converted to HFA equivalent dB units. Between instrument comparisons of HFA and MP-1 sensitivities, regression of sensitivity with age and examination duration were assessed. Test-retest variability was examined between visits. MP-1 (mean = 32.82 dB, SD = 1.92 dB) and HFA sensitivities (mean = 32.84 dB, SD = 1.83 dB) were not significantly different (p = 0.759). SD values for the HFA (range, 1.11 to 3.30 dB) were similar to the MP-1 (range, 0.14 to 2.75 dB). However, asymmetry comparisons between instruments showed significantly decreased superior rather than inferior retinal values for the MP-1. There was a small but significant difference (p = 0.004) in mean test duration between the MP-1 (mean = 6:11 min, SD = 1:49 min) and the HFA (mean = 5:14 min, SD = 0:42 min). There was also a difference in the decline of mean sensitivity with age, a decline of 0.1 and 0.4 dB per decade was noted in MP-1 and HFA sensitivity, respectively. Test-retest variability was similar between instruments. A small but non-significant increase in mean sensitivity at the second visit for both the MP-1 (p = 0.060) and HFA (p = 0.570) was found. Both instruments showed similar variability and test-retest variability when results were compared using equivalent units. However, there are important differences in sensitivity values, stimulus parameters, and testing strategies that have to be taken into account when comparisons are made.


Independent inactivation of arginine decarboxylase genes by nonsense and missense mutations led to pseudogene formation in Chlamydia trachomatis serovar L2 and D strains.
Chlamydia have reduced genomes that reflect their obligately parasitic lifestyle. Despite their different tissue tropisms, chlamydial strains share a large number of common genes and have few recognized pseudogenes, indicating genomic stability. All of the Chlamydiaceae have homologs of the aaxABC gene cluster that encodes a functional arginine:agmatine exchange system in Chlamydia (Chlamydophila)pneumoniae. However, Chlamydia trachomatis serovar L2 strains have a nonsense mutation in their aaxB genes, and C. trachomatis serovar A and B strains have frameshift mutations in their aaxC homologs, suggesting that relaxed selection may have enabled the evolution of aax pseudogenes. Biochemical experiments were performed to determine whether the aaxABC genes from C. trachomatis strains were transcribed, and mutagenesis was used to identify nucleotide substitutions that prevent protein maturation and activity. Molecular evolution techniques were applied to determine the relaxation of selection and the scope of aax gene inactivation in the Chlamydiales. The aaxABC genes were co-transcribed in C. trachomatis L2/434, during the mid-late stage of cellular infection. However, a stop codon in the aaxB gene from this strain prevented the heterologous production of an active pyruvoyl-dependent arginine decarboxylase. Replacing that ochre codon with its ancestral tryptophan codon rescued the activity of this self-cleaving enzyme. The aaxB gene from C. trachomatis D/UW-3 was heterologously expressed as a proenzyme that failed to cleave and form the catalytic pyruvoyl cofactor. This inactive protein could be rescued by replacing the arginine-115 codon with an ancestral glycine codon. The aaxC gene from the D/UW-3 strain encoded an active arginine:agmatine antiporter protein, while the L2/434 homolog was unexpectedly inactive. Yet the frequencies of nonsynonymous versus synonymous nucleotide substitutions show no signs of relaxed selection, consistent with the recent inactivation of these genes. The ancestor of the Chlamydiaceae had a functional arginine:agmatine exchange system that is decaying through independent, parallel processes in the C. trachomatis lineage. Differences in arginine metabolism among Chlamydiaceae species may be partly associated with their tissue tropism, possibly due to the protection conferred by a functional arginine-agmatine exchange system against host nitric oxide production and innate immunity. The independent loss of AaxB activity in all sequenced C. trachomatis strains indicates continual gene inactivation and illustrates the difficulty of recognizing recent bacterial pseudogenes from sequence comparison, transcriptional profiling or the analysis of nucleotide substitution rates.


Interpenetrated biosurfactant-silk fibroin networks - a SANS study.
Silk fibroin (SF) based hydrogels have been exploited for years for their inherent biocompatibility and favorable mechanical properties which makes them interesting for biotechnology applications. In this study we investigate silk based composite hydrogels where pH-sensitive, anionic biosurfactant assemblies (sophorolipids SL-C18 : 1 and SL-C18 : 0), are employed to improve the present properties of SF. Results suggest that the presence of SL surfactant assemblies leads to faster gelling of SF by accelerating the refolding from random coil to β-sheet as shown by infrared and UV-visible spectroscopy. Small angle neutron scattering (SANS) including contrast matching studies show that SF and SL assemblies coexist in a fibrillary network that is, in the case of SL-C18 : 0, interpenetrating. The resulting overall network structure in composite gels is slightly more affected by SL-C18 : 1 than by SL-C18 : 0, whereas the structure of both SF and surfactant assemblies remains unchanged. No disassembly of SL surfactant structures is observed, which gives a new perspective on SF-surfactant interactions. The hydrophobic effect within SF is favored in the presence of SL, leading to faster refolding of SF into β-sheet conformation. The presented composite gels, being an interpenetrating network of which one compound (SL-C18 : 0) can be tweaked by pH, open an interesting option towards improved workability and stimuli responsive mechanical properties of SF based hydrogels with possible applications in controlled cell culture and tissue engineering or drug delivery. The presented SANS analysis approach has the potential to be expanded to other protein-surfactant systems and composite hydrogels.


Phytoplasma effector SAP54 hijacks plant reproduction by degrading MADS-box proteins and promotes insect colonization in a RAD23-dependent manner.
Pathogens that rely upon multiple hosts to complete their life cycles often modify behavior and development of these hosts to coerce them into improving pathogen fitness. However, few studies describe mechanisms underlying host coercion. In this study, we elucidate the mechanism by which an insect-transmitted pathogen of plants alters floral development to convert flowers into vegetative tissues. We find that phytoplasma produce a novel effector protein (SAP54) that interacts with members of the MADS-domain transcription factor (MTF) family, including key regulators SEPALLATA3 and APETALA1, that occupy central positions in the regulation of floral development. SAP54 mediates degradation of MTFs by interacting with proteins of the RADIATION SENSITIVE23 (RAD23) family, eukaryotic proteins that shuttle substrates to the proteasome. Arabidopsis rad23 mutants do not show conversion of flowers into leaf-like tissues in the presence of SAP54 and during phytoplasma infection, emphasizing the importance of RAD23 to the activity of SAP54. Remarkably, plants with SAP54-induced leaf-like flowers are more attractive for colonization by phytoplasma leafhopper vectors and this colonization preference is dependent on RAD23. An effector that targets and suppresses flowering while simultaneously promoting insect herbivore colonization is unprecedented. Moreover, RAD23 proteins have, to our knowledge, no known roles in flower development, nor plant defence mechanisms against insects. Thus SAP54 generates a short circuit between two key pathways of the host to alter development, resulting in sterile plants, and promotes attractiveness of these plants to leafhopper vectors helping the obligate phytoplasmas reproduce and propagate (zombie plants).


Improving the efficiency of feed utilization in poultry by selection. 1. Genetic parameters of anatomy of the gastro-intestinal tract and digestive efficiency.
Feed costs represent about 70% of the costs of raising broilers. The main way to decrease these costs is to improve feed efficiency by modification of diet formulation, but one other possibility would be to use genetic selection. Understanding the genetic architecture of the gastro-intestinal tract (GIT) and the impact of the selection criterion on the GIT would be of particular interest. We therefore studied the genetic parameters of AMEn (Apparent metabolisable energy corrected for zero nitrogen balance), feed efficiency, and GIT traits in chickens.Genetic parameters were estimated for 630 broiler chickens of the eighth generation of a divergent selection experiment on AMEn. Birds were reared until 23 d of age and fed a wheat-based diet. The traits measured were body weight (BW), feed conversion ratio (FCR), AMEn, weights of crop, liver, gizzard and proventriculus, and weight, length and density of the duodenum, jejunum and ileum. The heritability estimates of BW, FCR and AMEn were moderate. The heritability estimates were higher for the GIT characteristics except for the weights of the proventriculus and liver. Gizzard weight was negatively correlated with density (weight to length ratio) of duodenum, jejunum and ileum. Proventriculus and gizzard weights were more strongly correlated with AMEn than with FCR, which was not the case for intestine weight and density. GIT traits were largely dependent on genetics and that selecting on AMEn or FCR would modify them. Phenotypic observations carried out in the divergent lines selected on AMEn were consistent with estimated genetic correlations between AMEn and GIT traits.


[Correlates of smoking in pregnant women in six Brazilian cities].
To evaluate sociodemographic and lifestyle correlates of smoking in pregnant women sampled from hospitals. A cross-sectional study was conducted in 5,539 pregnant women aged 20 or more who sought medical attention in prenatal clinics of affiliate hospitals of the Brazilian National Health System in the cities of Manaus, Fortaleza, Salvador, Rio de Janeiro, São Paulo, and Porto Alegre from 1991 to 1995. Interviews were conducted using a standardized questionnaire that covered sociodemographics and smoking habits before and during pregnancy. Current smoking was defined as smoking at least one cigarette/day, former smoking as reporting having smoked at least one cigarette/day but having quit, and never smoking as never having smoked one cigarette/day. Smoking during pregnancy was associated with lower education (OR=2.13; CI 95%: 1.76-2.57) and greater parity (OR=1.84; CI 95%: 1.53-2.21). Positive associations were also found with increased gestational age and alcohol consumption. No significant association was found with skin color or occupation status. A protective effect was observed for women married or living with a partner (OR=0.55 CI 95%: 0.42-0.72). Having Manaus' women as a reference, Porto Alegre's women showed the greatest risk for smoking in pregnancy (OR=5.00; CI 95%: 3.35-7.38), followed by São Paulo's (OR=3.42; CI 95%: 2.25-5.20), Rio de Janeiro (OR=2.53; CI 95%: 1.65-3.88) and Fortaleza's (OR=2.56; CI 95%: 1.74-3.78). The study findings are similar to those described in the literature regarding education, parity, and marital status. However, no association with skin color was seen in the multivariate analysis. Former smokers had sociodemographic characteristics more similar to non-smokers than former smokers.


A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT).
Glioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intracerebral tumors in NOD-SCID-IL2Rγ (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplantations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor.


High-throughput cell transplantation establishes that tumor-initiating cells are abundant in zebrafish T-cell acute lymphoblastic leukemia.
Self-renewal is a feature of cancer and can be assessed by cell transplantation into immune-compromised or immune-matched animals. However, studies in zebrafish have been severely limited by lack of these reagents. Here, Myc-induced T-cell acute lymphoblastic leukemias (T-ALLs) have been made in syngeneic, clonal zebrafish and can be transplanted into sibling animals without the need for immune suppression. These studies show that self-renewing cells are abundant in T-ALL and comprise 0.1% to 15.9% of the T-ALL mass. Large-scale single-cell transplantation experiments established that T-ALLs can be initiated from a single cell and that leukemias exhibit wide differences in tumor-initiating potential. T-ALLs also can be introduced into clonal-outcrossed animals, and T-ALLs arising in mixed genetic backgrounds can be transplanted into clonal recipients without the need for major histocompatibility complex matching. Finally, high-throughput imaging methods are described that allow large numbers of fluorescent transgenic animals to be imaged simultaneously, facilitating the rapid screening of engrafted animals. Our experiments highlight the large numbers of zebrafish that can be experimentally assessed by cell transplantation and establish new high-throughput methods to functionally interrogate gene pathways involved in cancer self-renewal.


Deep microbial proliferation at the basalt interface in 33.5-104 million-year-old oceanic crust.
The upper oceanic crust is mainly composed of basaltic lava that constitutes one of the largest habitable zones on Earth. However, the nature of deep microbial life in oceanic crust remains poorly understood, especially where old cold basaltic rock interacts with seawater beneath sediment. Here we show that microbial cells are densely concentrated in Fe-rich smectite on fracture surfaces and veins in 33.5- and 104-million-year-old (Ma) subseafloor basaltic rock. The Fe-rich smectite is locally enriched in organic carbon. Nanoscale solid characterizations reveal the organic carbon to be microbial cells within the Fe-rich smectite, with cell densities locally exceeding 1010 cells/cm3. Dominance of heterotrophic bacteria indicated by analyses of DNA sequences and lipids supports the importance of organic matter as carbon and energy sources in subseafloor basalt. Given the prominence of basaltic lava on Earth and Mars, microbial life could be habitable where subsurface basaltic rocks interact with liquid water.


ADRENAL CARCINOMA IN CHILDREN: LONGITUDINAL STUDY IN MINAS GERAIS, BRAZIL.
To analyze clinical, laboratory and histopathological features and the path to diagnosis establishment and treatment of patients with adrenal carcinoma (AC). Retrospective study with 13 patients assisted at the pediatric oncology service of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, between 2004 and 2015. Age at diagnosis ranged from 1.0 to 14.8 years (median: 2.0 years). Manifestations of hypercortisolism were identified in all cases and virilization in all girls. All patients met the Weiss criteria to AC histopathological diagnosis. Immunohistochemistry was performed in 61.5% of the cases. Most patients had stage I disease (76.9%). All subjects were submitted to total tumor resection. Two patients (stages III and IV disease) received chemotherapy associated to mitotane. The only death case was that of a patient with stage IV disease. The probability of overall survival for the entire group up to 5.0 years was 92.3±7.4%. The median time between the onset of symptoms and diagnosis was 9.5 months, and 6.0 months between first visit and start of treatment. Low age at diagnosis, predominance of cases with localized disease and complete tumor resection - with only one case of tumor capsule rupture - can possibly explain the favorable evolution of the studied population. The long period between onset of symptoms and diagnosis highlights the importance of training pediatricians for early recognition of AC signs and symptoms.


Management of Patients With Pancreatic Cysts: Analysis of Possible False-Negative Cases of Malignancy.
To examine the utility of integrated molecular pathology (IMP) in managing surveillance of pancreatic cysts based on outcomes and analysis of false negatives (FNs) from a previously published cohort (n=492). In endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of cyst fluid lacking malignant cytology, IMP demonstrated better risk stratification for malignancy at approximately 3 years' follow-up than International Consensus Guideline (Fukuoka) 2012 management recommendations in such cases. Patient outcomes and clinical features of Fukuoka and IMP FN cases were reviewed. Practical guidance for appropriate surveillance intervals and surgery decisions using IMP were derived from follow-up data, considering EUS-FNA sampling limitations and high-risk clinical circumstances observed. Surveillance intervals for patients based on IMP predictive value were compared with those of Fukuoka. Outcomes at follow-up for IMP low-risk diagnoses supported surveillance every 2 to 3 years, independent of cyst size, when EUS-FNA sampling limitations or high-risk clinical circumstances were absent. In 10 of 11 patients with FN IMP diagnoses (2% of cohort), EUS-FNA sampling limitations existed; Fukuoka identified high risk in 9 of 11 cases. In 4 of 6 FN cases by Fukuoka (1% of cohort), IMP identified high risk. Overall, 55% of cases had possible sampling limitations and 37% had high-risk clinical circumstances. Outcomes support more cautious management in such cases when using IMP. Adjunct use of IMP can provide evidence for relaxed surveillance of patients with benign cysts that meet Fukuoka criteria for closer observation or surgery. Although infrequent, FN results with IMP can be associated with EUS-FNA sampling limitations or high-risk clinical circumstances.


Low serum potassium in mid life associated with decreased cerebrospinal fluid Abeta42 in late life.
Low serum potassium increases risk of hypertension and stroke, and cardiovascular factors increase the risk of Alzheimer disease (AD). We examined the association between serum potassium and the biologic marker cerebrospinal fluid amyloid-beta (Abeta42), which is decreased in Alzheimer disease patients. Psychiatric examinations, laboratory and other tests were conducted on a population-based sample of 1080 women aged 46 to 60 in 1968, with follow-ups in 1974, 1980, and 1992. In 1992, cerebrospinal fluid Abeta42 levels were obtained from 81 women. Increasing serum potassium in 1968 was associated with increasing cerebrospinal fluid Abeta42 (beta = 153.9, P = 0.041) in 1992 using age-adjusted linear regression. Compared with the lowest tertile of potassium, the middle (beta = 95.3, P = 0.138) and highest tertiles (beta = 193.5, P = 0.004) had incrementally increased cerebrospinal fluid Abeta42 levels. Associations remained after controlling for blood pressure and other factors, and were similar among the 17 women in 1974 with available serum potassium. Potassium in 1980 and 1992 was not associated with cerebrospinal fluid Abeta42. Findings suggest low serum potassium in mid life, but not late life, is associated with low cerebrospinal fluid Abeta42 levels in late life. It is possible potassium co-varies with another variable that is associated with cerebrospinal fluid Abeta42. Nonetheless, serum potassium is a modifiable risk factor and further examination of the potassium-dementia relationship is warranted.


Joint mobility with particular reference to racial variation and inherited connective tissue disorders.
Joint mobility scores were compared in 248 normal English Caucasian males and females between the ages of 8 and 70 years. The results were contrasted with those in a group of normal Asian Indians and patients suffering from a variety of inherited disorders including Type II Ehlers-Danlos syndrome (EDS), Type I osteogenesis imperfecta (OI), Marfan syndrome, generalized osteoarthritis (GOA), achondroplasia and pseudoachondroplasia. The first-degree relatives of ten subjects with severe or lethal OI were also examined. Asian Indians were significantly more mobile than English Caucasians. Males and females with EDS were hypermobile but only the females with OI and the female relatives of those with severe or lethal OI showed excess joint laxity. Patients with pseudoachondroplasia exhibited a grosser type of joint laxity than other subjects while those with GOA represented a relatively stiff group. No evidence was found to support the view that hypermobility is associated with particular length variants at the Type II collagen structural gene locus (COL2A1).


Protein kinase C activity is acutely regulated by plasma glucose concentration in human monocytes in vivo.
Activation of protein kinase C (PKC) by hyperglycemia is implicated in the pathogenesis of long-term diabetic complications. Monocyte activation and transformation into macrophages is a key step in the atherosclerotic process. Therefore, in this study, we sought to determine 1) the effect of hyperglycemia on monocyte PKC activity and on the distribution of Ca2+-dependent and diacylglycerol-sensitive PKC isoforms; and 2) whether the effects on these parameters are determined by hyperglycemia per se, independent of the diabetic state. The studies were performed in 19 type 2 diabetic patients and 14 control subjects. Plasma glucose concentration was higher and insulin sensitivity lower (both P < 0.01) in diabetic patients than in control subjects. Monocytes from diabetic patients showed similar cytosol PKC activity to those from control subjects but higher membrane PKC activity (78+/-6 vs. 50+/-5 pmol x min(-1) x mg(-1) protein; P < 0.01). A direct correlation was observed between fasting plasma glucose and membrane PKC activity (r2 = 0.4008, P = 0.0001). In contrast, a reciprocal correlation was observed between membrane PKC activity and insulin sensitivity index (r2 = 0.28, P < 0.05). Using immunoblotting analysis, we found that membrane beta2, but not alpha, isoform of PKC was more abundant in monocytes from diabetic patients. In diabetic patients, when euglycemia was acutely induced, membrane PKC activity decreased by approximately 42% and beta2 isoform by approximately 15%. In two normal subjects in whom hyperglycemia was induced, membrane PKC increased from 63 and 57 to 92 and 128.6 pmol x min(-1) x mg(-1) protein, respectively. This increase was associated with an increase in the membrane isoform beta2; alpha isoform was unchanged. We conclude that 1) monocytes express the glucose-sensitive beta2 isoform of PKC; 2) the prevailing plasma glucose acutely regulates the activity of the membrane PKC and the content of membrane PKC beta2 isoform; and 3) this effect appears to be a direct effect of glucose per se, since the phenomenon was observed in normal control subjects when hyperglycemia was induced. Monocyte PKC activation may account for the accelerated atherosclerosis of patients with type 2 diabetes.


Giving patients a starring role in their own care: a bibliometric analysis of the on-going literature debate.
Patient-centred care has been advocated as a key component of high-quality patient care, yet its meanings and related actions have been difficult to ascertain. To map the use of different terms related to the process of giving patients a starring role in their own care and clarify the possible boundaries between terms that are often mixed. A literature search was conducted using different electronic databases. All records containing the search terms 'patient engagement', 'patient activation', 'patient empowerment', 'patient involvement', 'patient adherence', 'patient compliance' and 'patient participation' were collected. Identified literature was then analysed using the Statistical Package for Social Science (SPSS). The number of yearly publications, most productive countries, cross-concepts articles and various scientific fields dealing with the multidisciplinary concepts were identified. Overall, 58 987 papers were analysed. Correspondence analysis revealed three temporal trends. The first period (2002-2004) focused on compliance and adherence, the second period (2006-2009) focused on the relationship between participation and involvement, and the third one (2010-2013) emphasized empowerment. Patient activation and patient engagement followed the temporal development trend connected to the 'immediate future'. The bibliometric trend suggests that the role of patient in the health-care system is changing. In the last years, the patient was viewed as a passive receptor of medical prescription. To date, the need to consider patients as active partners of health-care planning and delivery is growing. In particular, the term patient engagement appears promising, not only for its increasing growth of interest in the scholarly debate, but also because it offers a broader and better systemic conceptualization of the patients' role in the fruition of health care. To build a shared vocabulary of terms and concepts related to the active role of patients in the health-care process may be envisaged as the first operative step towards a concrete innovation of health-care organizations and systems.


Use of transcriptomic data for extending a model of the AppA/PpsR system in Rhodobacter sphaeroides.
Photosynthetic (PS) gene expression in Rhodobacter sphaeroides is regulated in response to changes in light and redox conditions mainly by PrrB/A, FnrL and AppA/PpsR systems. The PrrB/A and FnrL systems activate the expression of them under anaerobic conditions while the AppA/PpsR system represses them under aerobic conditions. Recently, two mathematical models have been developed for the AppA/PpsR system and demonstrated how the interaction between AppA and PpsR could lead to a phenotype in which PS genes are repressed under semi-aerobic conditions. These models have also predicted that the transition from aerobic to anaerobic growth mode could occur via a bistable regime. However, they lack experimentally quantifiable inputs and outputs. Here, we extend one of them to include such quantities and combine all relevant micro-array data publically available for a PS gene of this bacterium and use that to parameterise the model. In addition, we hypothesise that the AppA/PpsR system alone might account for the observed trend of PS gene expression under semi-aerobic conditions. Our extended model of the AppA/PpsR system includes the biological input of atmospheric oxygen concentration and an output of photosynthetic gene expression. Following our hypothesis that the AppA/PpsR system alone is sufficient to describe the overall trend of PS gene expression we parameterise the model and suggest that the rate of AppA reduction in vivo should be faster than its oxidation. Also, we show that despite both the reduced and oxidised forms of PpsR binding to the PS gene promoters in vitro, binding of the oxidised form as a repressor alone is sufficient to reproduce the observed PS gene expression pattern. Finally, the combination of model parameters which fit the biological data well are broadly consistent with those which were previously determined to be required for the system to show (i) the repression of PS genes under semi-aerobic conditions, and (ii) bistability. We found that despite at least three pathways being involved in the regulation of photosynthetic genes, the AppA/PpsR system alone is capable of accounting for the observed trends in photosynthetic gene expression seen at different oxygen levels.


Social Distancing against COVID-19: Implication for the Control of Influenza.
Social distancing has been adopted as one of basic protective measures against coronavirus disease 2019 (COVID-19). During 2019-2020 season, influenza epidemic period was exceptionally short and epidemic peak was low in comparison with previous seasons in Korea. Influenza epidemic pattern was bimodal in 2016-2017 and 2018-2019 seasons, however, influenza viruses have rarely been circulating in spring, 2020 in Korea. Although multiple factors could affect the size of influenza epidemic, extensive application of nonpharmaceutical interventions including mask wearing and social distancing in response to COVID-19 seems to be a major factor of reduced influenza epidemic. Social distancing measures with high feasibility and high acceptability should be implemented even if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are developed in the future. Establishment of guideline for workplace social distancing is needed and it would contribute to reduce disease burden of influenza, especially in vaccine mismatch year.


Pancreatic amylase secretion and cytoplasmic free calcium. Effects of ionomycin, phorbol dibutyrate and diacylglycerols alone and in combination.
Both protein kinase C and Ca2+ may act in concert to bring about activation of secretion. This study examined the actions on pancreatic acini of ionomycin and phorbol dibutyrate, which selectively stimulate one or the other of these pathways; their stimulatory effects were compared with those of receptor agonists, such as carbachol and caerulein, which activate phospholipase C. The Ca2+ ionophore ionomycin produced a dose-dependent increase in amylase secretion and intracellular free Ca2+ (as measured by quin-2). The increase in amylase secretion elicited by carbachol or caerulein was accompanied by a small sustained increase in intracellular free Ca2+, following an initial peak. However, the elevation in intracellular free Ca2+ produced by these receptor agonists for a given level of amylase secretion was less than that observed with ionomycin. Phorbol dibutyrate stimulated amylase secretion by a mechanism that was independent of extracellular Ca2+, and no change in intracellular free Ca2+ was observed. Synergistic stimulatory effects of phorbol dibutyrate and ionomycin were observed, whether the phorbol ester was present before, or in combination with, ionomycin. Diacylglycerols containing unsaturated fatty acids (1,2-dioleoylglycerol and 1,3-dioleoylglycerol) also stimulated amylase secretion and exhibited synergistic effects on secretion with ionomycin. These findings suggest that complete activation of amylase secretion from the pancreas requires stimulation of both Ca2+-dependent and protein kinase C-activated pathways.


Development of Heavyweight Self-Compacting Concrete and Ambient-Cured Heavyweight Geopolymer Concrete Using Magnetite Aggregates.
Heavyweight self-compacting concrete (HWSCC) and heavyweight geopolymer concrete (HWGC) are new types of concrete that integrate the advantages of heavyweight concrete (HWC) with self-compacting concrete (SCC) and geopolymer concrete (GC), respectively. The replacement of natural coarse aggregates with magnetite aggregates in control SCC and control GC at volume ratios of 50%, 75%, and 100% was considered in this study to obtain heavyweight concrete classifications, according to British standards, which provide proper protection from sources that emit harmful radiations in medical and nuclear industries and may also be used in many offshore structures. The main aim of this study is to examine the fresh and mechanical properties of both types of mixes. The experimental program investigates the fresh properties of HWSCC and HWGC through the slump flow test. However, J-ring tests were only conducted for HWSCC mixes to ensure the flow requirements in order to achieve self-compacting properties. Moreover, the mechanical properties of both type of mixes were investigated after 7 and 28 days curing at an ambient temperature. The standard 100 × 200 mm cylinders were subjected to compressive and tensile tests. Furthermore, the flexural strength were examined by testing 450 × 100 × 100 mm prisms under four-point loading. The flexural load-displacement relationship for all mixes were also investigated. The results indicated that the maximum compressive strength of 53.54 MPa was achieved by using the control SCC mix after 28 days. However, in HWGC mixes, the maximum compressive strength of 31.31 MPa was achieved by 25% magnetite replacement samples. The overall result shows the strength of HWSCC decreases by increasing magnetite aggregate proportions, while, in HWGC mixes, the compressive strength increased with 50% magnetite replacement followed by a decrease in strength by 75% and 100% magnetite replacements. The maximum densities of 2901 and 2896 kg/m³ were obtained by 100% magnetite replacements in HWSCC and HWGC, respectively.


Systems biology of robustness and homeostatic mechanisms.
All organisms are subject to large amounts of genetic and environmental variation and have evolved mechanisms that allow them to function well in spite of these challenges. This property is generally referred to as robustness. We start with the premise that phenotypes arise from dynamical systems and are therefore system properties. Phenotypes occur at all levels of the biological organizational hierarchy, from gene products, to biochemical pathways, to cells, tissues, organs, appendages, and whole bodies. Phenotypes at all these levels are subject to environmental and genetic challenges against which their form and function need to be protected. The mechanisms that can produce robustness are diverse and several different kinds often operate simultaneously. We focus, in particular, on homeostatic mechanisms that dynamically maintain form and function against varying environmental and genetic factors. Understanding how homeostatic mechanisms operate, how they reach their set point, and the nature of the set point pose difficult challenges. In developmental systems, homeostatic mechanisms make the progression of morphogenesis relatively insensitive to genetic and environmental variation so that the outcomes vary little, even in the presence of severe mutational and environmental stress. Accordingly, developmental systems give the appearance of being goal-oriented, but how the target phenotype is encoded is not known. We discuss why and how individual variation poses challenges for mathematical modeling of biological systems, and conclude with an explanation of how system population models are a useful method for incorporating individual variation into deterministic ordinary differential equation (ODE) models. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Physiology > Mammalian Physiology in Health and Disease Physiology > Organismal Responses to Environment Biological Mechanisms > Regulatory Biology.


Effects of temperature on escape jetting in the squid Loligo opalescens.
In Loligo opalescens, a sudden visual stimulus (flash) elicits a stereotyped, short-latency escape response that is controlled primarily by the giant axon system at 15 C. We used this startle response as an assay to examine the effects of acute temperature changes down to 6 C on behavioral and physiological aspects of escape jetting. In free-swimming squid, latency, distance traveled and peak velocity for single escape jets all increased as temperature decreased. In restrained squid, intra-mantle pressure transients during escape jets increased in latency, duration and amplitude at low temperature. Recordings of stellar nerve activity revealed repetitive firing of the giant motor axon accompanied by increased activity in the non-giant motor axons that run in parallel. Selective stimulation of giant and non-giant motor axons in isolated nerve-muscle preparations failed to show the effects seen in vivo, i.e. increased peak force and increased neural activity at low temperature. Taken together, these results suggest that L. opalescens is able to compensate escape jetting performance for the effects of acute temperature reduction. A major portion of this compensation appears to occur in the central nervous system and involves alterations in the recruitment pattern of both the giant and non-giant axon systems.


Binocular rivalry with isoluminant stimuli visible only via short-wavelength-sensitive cones.
To test whether the binocular contour rivalry mechanism is tritanopic, we presented isoluminant, rival stimuli visible only via the short-wavelength-sensitive (S) cones. We stimulated only the S cones with violet gratings superimposed on a bright yellow field that adapted the responses of the middle- and long-wavelength-sensitive (M and L) cones. We found that an S-cone grating presented to one eye rivalled with an orthogonal grating presented to the other. Rivalry persisted over a range of luminances and contrasts of the S-cone stimuli, and was greater than could be accounted for by nonrival fading. The spatial spread of rivalry from S-cone stimuli is similar to that for the same stimuli when visible also to the M and L cones (luminance stimuli). We found that an S-cone stimulus would rival with a luminance stimulus, and exploited this to determine the equivalent luminance contrast of S-cone stimuli by putting them in a rivalry competition with luminance stimuli. For rivalry, the equivalent luminance contrast of isoluminant, S-cone stimuli is much less than their S-cone contrast. The existence of rivalry with isoluminant stimuli, along with earlier evidence that such stimuli can support stereopsis, challenges the view that an achromatic channel alone drives certain higher level functions such as depth perception.


An onset advantage without a preview benefit: neuropsychological evidence separating onset and preview effects in search.
Visual search is facilitated if half the distractors are presented as a preview prior to the presentation of the target and second set of distractors--the preview benefit [Watson, D. G., & Humphreys, G. W. Visual marking: Prioritizing selection for new objects by top-down attentional inhibition of old objects. Psychological Review, 104, 90-122, 1997]. On one account, the preview advantage is due to automatic capture of attention by the onsets in the second, search display [Donk, M., & Theeuwes, J. Visual marking beside the mark: Prioritizing selection by abrupt onsets. Perception & Psychophysics, 93, 891-900, 2001]. We provide a neuropsychological test of this assertion. We examined onset capture and preview benefits in search in a group of neuropsychological patients with unilateral parietal damage. We demonstrate a normal pattern of performance when patients detected targets defined by onsets relative to those defined by offsets, irrespective of whether the onset target fell contra- or ipsilateral to the lesion. In contrast, there was a normal preview benefit in search only for ipsilesional targets, and preview search was impaired in the contralesional field. The data demonstrate that the preview benefit can dissociate from the onset advantage in search, and that onsets remain strongly weighted for attention even in the contralesional field of patients with parietal lesions.


A validated tool to predict colorectal neoplasia and inform screening choice for asymptomatic subjects.
We aim to develop and validate a clinical scoring system to predict the risks of colorectal neoplasia to better inform screening participants and facilitate their screening test choice. We recruited 5220 Chinese asymptomatic screening participants who underwent colonoscopy in Hong Kong during 2008-2012. From random sampling of 2000 participants, independent risk factors were evaluated for colorectal neoplasia, defined as adenoma, advanced neoplasia, colorectal cancer or any combination thereof using binary regression analysis. The ORs for significant risk factors were used to develop a scoring system ranging from 0 to 6: 0-2 'average risk' (AR) and 3-6 'high risk' (HR). The other 3220 screening participants prospectively enrolled between 2008 and 2012 for screening colonoscopy formed an independent validation cohort. The performance of the scoring system for predicting colorectal neoplasia was evaluated. The prevalence of colorectal neoplasia in the derivation and validation cohorts was 31.4% and 30.8%, respectively. Using the scoring system developed, 78.9% and 21.1% in the validation cohort were classified as AR and HR, respectively. The prevalence of colorectal neoplasia in the AR and HR groups was 27.1% and 44.6%, respectively. The subjects in the HR group had 1.65-fold (95% CI 1.49 to 1.83) increased prevalence of colorectal neoplasia than the AR group. The scoring system based on age, gender, smoking, family history, Body Mass Index and self-reported diabetes is useful in predicting the risk of colorectal neoplasia.


Clinical analysis of the trigger thumb of childhood.
Trigger thumb of childhood, termed congenital trigger thumb, is a pathology of the flexor pollicis longus tendon with an unknown etiology. In this study, treatment outcomes of 47 trigger thumbs of 36 children were evaluated. There were 18 males and 18 females with a mean age of 34 months (9 months-13 years). Average age of recognition of pathology by the family was 20.5 months (0-8 years). In seven of 11 bilateral cases pathology was recognized simultaneously while in the other four, diagnosis was made at different times. We used conservative treatment for all patients under three years of age, which was unsuccessful. Thus, surgical relase was performed in all cases. In the mean follow-up of seven years (range 5-15), contracture and palpable nodules disappeared. In conclusion, we believe trigger thumb in childhood should be treated surgically and that the term "congenital trigger thumb" should be changed to "developmental trigger thumb".


Correlation between biofilm formation and the hypoxic response in Candida parapsilosis.
The ability of Candida parapsilosis to form biofilms on indwelling medical devices is correlated with virulence. To identify genes that are important for biofilm formation, we used arrays representing approximately 4,000 open reading frames (ORFs) to compare the transcriptional profile of biofilm cells growing in a microfermentor under continuous flow conditions with that of cells in planktonic culture. The expression of genes involved in fatty acid and ergosterol metabolism and in glycolysis, is upregulated in biofilms. The transcriptional profile of C. parapsilosis biofilm cells resembles that of Candida albicans cells grown under hypoxic conditions. We therefore subsequently used whole-genome arrays (representing 5,900 ORFs) to determine the hypoxic response of C. parapsilosis and showed that the levels of expression of genes involved in the ergosterol and glycolytic pathways, together with several cell wall genes, are increased. Our results indicate that there is substantial overlap between the hypoxic responses of C. parapsilosis and C. albicans and that this may be important for biofilm development. Knocking out an ortholog of the cell wall gene RBT1, whose expression is induced both in biofilms and under conditions of hypoxia in C. parapsilosis, reduces biofilm development.


The FPR2-induced rise in cytosolic calcium in human neutrophils relies on an emptying of intracellular calcium stores and is inhibited by a gelsolin-derived PIP2-binding peptide.
The molecular basis for neutrophil recognition of chemotactic peptides is their binding to specific G-protein-coupled cell surface receptors (GPCRs). Human neutrophils express two pattern recognition GPCRs, FPR1 and FPR2, which belong to the family of formyl peptide receptors. The high degree of homology between these two receptors suggests that they share many functional and signal transduction properties, although they exhibit some differences with respect to signaling. The aims of this study were to determine whether FPR2 triggers a unique signal that allows direct influx of extracellular calcium without the emptying of intracellular calcium stores, and whether the gelsolin-derived PIP2-binding peptide, PBP10, selectively inhibits FPR2-mediated transient rise in intracellular Ca2+. The transient rise in intracellular Ca2+ induced by agonists for FPR1 or FPR2 in human neutrophils occurred also in the presence of a chelator of Ca2+ (EGTA). PBP10 inhibited not only FPR2-induced oxidase activity, but also the transient rise in intracellular Ca2+. Ca2+ signaling mediated via FPR2 follows the same route as FPR1, which involves initial emptying of the intracellular stores. PBP10 inhibits selectively the signals generated by FPR2, both with respect to NADPH-oxidase activity and the transient rise in intracellular Ca2+ induced by agonist exposure.


Visual Event-Related Potentials in Mild Cognitive Impairment and Alzheimer's Disease: A Literature Review.
Cognitive deficits are correlated with increasing age and become more pronounced for people with mild cognitive impairment (MCI) and dementia caused by Alzheimer's disease (AD). Conventional methods to diagnose cognitive decline (i.e., neuropsychological testing and clinical judgment) can lead to false positives. Tools such as electroencephalography (EEG) offer more refined, objective measures that index electrophysiological changes associated with healthy aging, MCI, and AD. We sought to review the EEG literature to determine whether visual event-related potentials (ERPs) can distinguish between healthy aging, MCI, and AD. We searched Medline and PyscInfo for articles published between January 2005 and April 2018. Articles were considered for review if they included participants aged 60+ who were healthy older adults or people with MCI and AD, and examined at least one visually elicited ERP component. Our search revealed 880 records, of which 34 satisfied the inclusion criteria. All studies compared cognitive function between at least two of the three groups (healthy older adults, MCI, and AD). The most consistent findings related to the P100 and the P3b; while the P100 showed no differences between groups, the P3b showed declines in amplitude in MCI and AD. Visually elicited ERPs can offer insight into the cognitive processes that decline in MCI and AD. The P3b may be useful in identifying older adults who may develop MCI and AD, and more research should examine the sensitivity and specificity of this component when diagnosing MCI and AD.


Sinus node dysfunction after surgical atrial fibrillation ablation with concomitant mitral valve surgery: Determinants and clinical outcomes.
We sought to investigate determinants and prognosis of sinus node dysfunction (SND) after surgical ablation of atrial fibrillation (AF) with concomitant mitral valve (MV) surgery. A total of 202 patients who underwent surgical AF ablation with concomitant MV surgery were studied. SND was defined as electrocardiographic manifestations, such as junctional bradycardia, symptomatic sick sinus syndrome, or symptomatic sinus bradycardia, 7 days after surgery. Baseline clinical and echocardiographic characteristics, rhythm outcomes [AF recurrence or permanent pacemaker (PM) implantation] at 6 and 12 months, and clinical outcomes were compared between patients without SND (n = 165) and those with SND (n = 37) after surgery. Patients with SND showed a significantly larger left atrial volume index (LAVI) and a higher right ventricular systolic pressure than those without SND. In addition, there was a higher likelihood for AF recurrence and PM implantation in patients with SND than in those without SND. Although clinical outcomes did not differ between the two groups, patients with SND had a significantly longer length of hospital stay (p<0.001). In a multivariate analysis, preoperative LAVI was a structural risk factor for SND [hazard ratio (HR): 1.126 per 10 mL/m2; 95% confidence interval (CI): 1.0206-1.236; p = 0.001]. An LAVI cut-off value of 105 mL/m2 showed significant predictive power for SND [sensitivity: 62%; specificity: 64%; area under the curve (AUC): 0.678; p = 0.002]. In conclusion, preoperative LA size was a structural risk factor for SND after surgical AF ablation during MV surgery. SND was associated with an increased risk for AF recurrence and implantation of permanent PM in patients undergoing concomitant surgical ablation of AF with MV surgery.


Per-Prescription Drug Expenditure by Source of Payment and Income Level in the United States, 1997 to 2015.
To evaluate expenditures and sources of payment for prescription drugs in the United States from 1997 to 2015. The Medical Expenditures Panel Survey (MEPS) was used for this analysis. Individuals with one or more prescription medicines were eligible for inclusion. Outcomes were the inflation-adjusted cost per prescription across all payment sources (self or family, public, private, and other sources) before and after the Medicare Part D benefit and the Affordable Care Act. The cost per prescription increased from $38.56 in 1997 to $73.34 in 2015. Nevertheless, consumers' out-of-pocket expenditures decreased from $18.19 to $9.61, whereas public program expenditures per prescription increased from $5.61 to $34.43 over this time. Out-of-pocket expenditures of individuals in the low-income group and near-poor group had larger declined percentages from 51.4% to 20.4% and 46.5% to 17.2% relative to individuals in higher-income groups before and after implementation of the Medicare Part D, respectively. Over 90% prescription purchases were covered by medical insurance by 2015. The per-prescription cost for medications consumed by uninsured individuals increased at a lower rate from $31.83 to $54.96 versus $40.12 to $75.58 for privately insured and $36.00 to $70.96 for publicly insured (P < .001). Prescription drugs expenditures have increased over the past 2 decades, but public sources now pay for a growing proportion of prescription drugs cost regardless of health insurance coverage or income level. Out-of-pocket expenditures have significantly decreased for persons with lower incomes since the implementation of Medicare Part D and the Affordable Care Act.


The actions of bradykinin and eledoisin in the canine isolated kidney: relationships to prostaglandins.
1. The effects of two vasodilator polypeptides, bradykinin and eledoisin, were studied in isolated blood-perfused canine kidneys before and after administration of indomethacin, an inhibitor of prostaglandin synthesis, Bradykinin, but not eledoisin, releases renal prostaglandins. 2. Before administration of indomethacin, bradykinin decreased urinary osmolality and increased free qater clearance, whereas eledoisin did not affect the excretion of solute-free water. After administration of indomethacin, the renal vasodilator action of bradykinin was reduced but the vasodilator action of eledoisin was unaffected. 3. Fractional excretion of sodium was not affected by bradykinin before but was increased after administration of indomethacin. Reduction in glomerular filtration rate contributed to changes in sodium excretion produced by bradykinin and eledoisin. 4. The release of prostaglandins from the kidney by bradykinin amplifies the renal vasodilator action of the kinin and possibly mediates its effect on excretion of solute-free water.


Factors Associated With Psychological Readiness to Return to Sport After Anterior Cruciate Ligament Reconstruction Surgery.
Anterior cruciate ligament (ACL) injury has a significant psychological effect, and a negative psychological state is a commonly cited reason for a reduction or cessation of sports participation after ACL reconstruction (ACLR) surgery. To identify factors that contribute to an athlete's psychological readiness to return to sport (RTS) after ACLR. Cross-sectional study; Level of evidence, 3. A cohort of 635 athletes (389 male, 246 female) who underwent ACLR and had been cleared to RTS completed the Anterior Cruciate Ligament-Return to Sport After Injury (ACL-RSI) scale at an average 12 months (range, 11-24 months) after surgery. Demographics (age, sex), sporting outcomes (preinjury frequency), surgical timing (injury to surgery interval), clinical factors (laxity), functional measures (single-limb hop symmetry), and symptoms of pain and function (International Knee Documentation Committee subjective) were also taken, and univariate and multiple regression models were used to determine the association between these and the psychological readiness of the athlete to RTS (ACL-RSI scores). Data for the entire cohort were initially analyzed; then, patients were grouped according to whether they had returned to competitive sport, and the analysis repeated for each group (return/nonreturn). Univariate analysis for the entire group showed that all of the following had a positive effect on psychological readiness: male sex (β = 5.8; 95% CI, 2-10), younger age (β = -0.2; 95% CI, -0.4 to 0.01), a shorter interval between injury and surgery (β = -0.1; 95% CI, -0.1 to -0.02), a higher frequency of preinjury sport participation (β = 5.4; 95% CI, 2-9), greater limb symmetry (β = 0.5; 95% CI, 0.3-0.6), and higher subjective knee scores (β = 1.3; 95% CI, 1.1-1.4). In the multivariate model, subjective knee scores and age significantly accounted for 37% of the variance in psychological readiness ( r2 = 0.37, P < .0001). The only difference between the groups who had and had not returned to sport was that female sex was a significant contributor for the nonreturn group. Self-reported symptoms and function were most associated with psychological readiness to RTS after ACLR surgery. Male patients who participated frequently in sport before ACL injury had higher psychological readiness. Conversely, female patients had a more negative outlook and may therefore benefit more from interventions designed to facilitate a smooth transition back to sport.


An evaluation of physician predictions of discharge on a general medicine service.
The goal of this study was to evaluate general medicine physicians' ability to predict hospital discharge. We prospectively asked study subjects to predict whether each patient under their care would be discharged on the next day, on the same day, or neither. Discharge predictions were recorded at 3 time points: mornings (7-9 am), midday (12-2 pm), or afternoons (5-7 pm), for a total of 2641 predictions. For predictions of next-day discharge, the sensitivity (SN) and positive predictive value (PPV) were lowest in the morning (27% and 33%, respectively), but increased by the afternoon (SN 67%, PPV 69%). Similarly, for same-day discharge predictions, SN and PPV were highest at midday (88% and 79%, respectively). We found that although physicians have difficulty predicting next-day discharges in the morning prior to the day of expected discharge, their ability to correctly predict discharges continually improved as the time to actual discharge decreased. Journal of Hospital Medicine 2015;10:808-810. © 2015 Society of Hospital Medicine.


More appreciation of life or regretting the test? Experiences of living as a mutation carrier of Huntington's disease.
Little is known about how the knowledge of being a mutation carrier for Huntington's disease (HD) influences lives, emotionally and socially. In this qualitative study 10 interviews were conducted to explore the long term (>5 years) experiences of being a mutation carrier. The results showed a broad variety of both positive and negative impact on the carriers' lives. The most prominent positive changes reported were a greater appreciation of life and a tendency to bring the family closer together. On the other hand, some participants expressed decisional regrets and discussed the negative impact this knowledge had on their psychological well-being. The knowledge variously served as either a motivator or an obstacle in pursuing further education, career or investment in personal health. Deeper understanding of people's reactions to the certainty of knowing they will become affected with HD is essential for the genetic counseling team in order to provide appropriate support.


The Interleaved Genome.
Eukaryotic genomes are pervasively transcribed but until recently this noncoding transcription was considered to be simply noise. Noncoding transcription units overlap with genes and genes overlap other genes, meaning genomes are extensively interleaved. Experimental interventions reveal high degrees of interdependency between these transcription units, which have been co-opted as gene regulatory mechanisms. The precise outcome depends on the relative orientation of the transcription units and whether two overlapping transcription events are contemporaneous or not, but generally involves chromatin-based changes. Thus transcription itself regulates transcription initiation or repression at many regions of the genome.


Ordering Protein Contact Matrices.
Numerous biophysical approaches provide information about residues spatial proximity in proteins. However, correct assignment of the protein fold from this proximity information is not straightforward if the spatially close protein residues are not assigned to residues in the primary sequence. Here, we propose an algorithm to assign such residue numbers by ordering the columns and lines of the raw protein contact matrix directly obtained from proximity information between unassigned amino acids. The ordering problem is formatted as the search of a trail within a graph connecting protein residues through the nonzero contact values. The algorithm performs in two steps: (i) finding the longest trail of the graph using an original dynamic programming algorithm, (ii) clustering the individual ordered matrices using a self-organizing map (SOM) approach. The combination of the dynamic programming and self-organizing map approaches constitutes a quite innovative point of the present work. The algorithm was validated on a set of about 900 proteins, representative of the sizes and proportions of secondary structures observed in the Protein Data Bank. The algorithm was revealed to be efficient for noise levels up to 40%, obtaining average gaps of about 20% at maximum between ordered and initial matrices. The proposed approach paves the ways toward a method of fold prediction from noisy proximity information, as TM scores larger than 0.5 have been obtained for ten randomly chosen proteins, in the case of a noise level of 10%. The methods has been also validated on two experimental cases, on which it performed satisfactorily.


SNPs in Sites for DNA Methylation, Transcription Factor Binding, and miRNA Targets Leading to Allele-Specific Gene Expression and Contributing to Complex Disease Risk: A Systematic Review.
The complex genetic diversity among human populations results from an assortment of factors acting at various sequential levels, including mutations, population migrations, genetic drift, and selection. Although there are a plethora of DNA sequence variations identified through genome-wide association studies (GWAS), the challenge remains to explain the mechanisms underlying interindividual phenotypic disparity accounting for disease susceptibility. Single nucleotide polymorphisms (SNPs) present in the sites for DNA methylation, transcription factor (TF) binding, or miRNA targets can alter the gene expression. The systematic review aimed to evaluate the complex crosstalk among SNPs, miRNAs, DNA methylation, and TFs for complex multifactorial disease risk. PubMed and Scopus databases were used from inception until May 15, 2019. Initially, screening of articles involved studies assessing the interaction of SNPs with TFs, DNA methylation, or miRNAs resulting in allele-specific gene expression in complex multifactorial diseases. We also included the studies which provided experimental validation of the interaction of SNPs with each of these factors. The results from various studies on multifactorial diseases were assessed. A total of 11 articles for SNPs interacting with DNA methylation, 30 articles for SNPs interacting with TFs, and 11 articles for SNPs in miRNA binding sites were selected. The interactions of SNPs with epigenetic factors were found to be implicated in different types of cancers, autoimmune diseases, cardiovascular diseases, diabetes, and asthma. The systematic review provides evidence for the interplay between genetic and epigenetic risk factors through allele-specific gene expression in various complex multifactorial diseases.


A pilot for a computer-based simulation system for risk estimation and treatment of mentally disordered offenders.
Risk/need analysis and treatment of mentally disordered offenders (MDOs) take place in constrained clinical settings, but violence has to be considered in a context where both social and cultural factors are of significance. One way to improve treatment and risk/need analysis of MDOs could be to develop simulation systems where users interact with video-based scenarios. The objective of this study was to develop and pilot test a simulation system to be used as a tool to study MDOs and possibly also to play a part in their rehabilitation. Collaboration between simulation and forensic psychiatry experts and a professional film team was set up. A simulation system called 'Reactions on Display' (RoD) was developed and a pilot study with eight patients and 13 staff members was carried out. Results from the study showed that RoD's interface and design were well received by patients and staff. Participants indicated that they found the video sequences realistic and the system enjoyable to use. The pilot study of RoD was positive, but further research should study possible clinical outcomes of the system. However, we believe that RoD could provide an advance in treatment and risk/need analysis of MDOs.


Actions of angiotensin peptides after partial denervation of the solitary tract nucleus.
We determined the excitatory effects of direct nucleus tractus solitarii injection of angiotensin peptides after the sinoaortic nerves were cut unilaterally in rats under halothane anesthesia. Twenty-four hours later, recordings of mean arterial pressure and heart rate were obtained during injections of 2.5 ng angiotensin II or angiotensin-(1-7) in chloralose-urethane-anesthetized rats. Both peptides caused reductions in pressure and heart rate after nucleus tractus solitarii injections. In unilateral sinoaortic denervated rats, the hypotension and bradycardia produced with angiotensin II injections in either the ipsilateral (denervated) or contralateral (nondenervated) nucleus tractus solitarii were comparable. Angiotensin-(1-7), however, produced a larger decrease in pressure on the denervated side when compared with the nondenervated side. There were no differences in baseline pressure or heart rate between control rats and those with unilateral sinoaortic denervations. The effects of both angiotensin II and angiotensin-(1-7) were blocked by previous administration of the angiotensin II antagonist [Sar1,Thr8]angiotensin II into the nucleus tractus solitarii. Assessment of angiotensin II binding sites in the solitary-vagal complex 24 hours after denervation showed a 13% reduction in angiotensin receptors. These findings confirm that both angiotensin II and angiotensin-(1-7) express biological activity through receptor-mediated actions in the dorsal medulla oblongata. That the effects produced by angiotensin II do not require the integrity of baroreceptor input further suggests that the receptors responsible for the acute cardiovascular actions of this peptide reside on postsynaptic elements in the vagal-solitary complex.


Management of anti-Rhesus-D antibodies in pregnancy: a review from 1994 to 1998.
To review our management of anti-Rhesus-D antibodies in pregnancy over a 5-year period in order to assess possible changes in the management or prognosis which may have developed with time. Retrospective analysis of prospectively collected data from 31 pregnancies with maternal anti-D levels >4 IU/ml and in which the fetus was Rhesus positive. There were a total of 30 amniocenteses, 8 cordocenteses, and 54 fetal blood transfusions performed. When undertaken as the first procedure, the mean gestational age at amniocentesis was 30 weeks as compared with 25 weeks for fetal blood sampling/transfusion (p < 0.05). The median anti-D level at the first procedure was 24 IU/ml for amniocentesis and 64 IU/ml for fetal blood sampling. Of the 54 blood transfusions, 43 were intravascular, 4 were intraperitoneal, and 7 transfusions were both intravascular and intraperitoneal. Intravascular as opposed to intraperitoneal transfusions were found to be the main method of transfusion in the later years in this study, a finding which was expected with improved sonographic equipment. Apart from this, management and prognosis of anti-D red cell isoimmunisation in pregnancy have remained relatively stable since the 1980s. Amniocentesis was useful in the management of such pregnancies, especially as an initial procedure in the cases with a lower initial anti-D level. In this series 90% of the fetuses requiring blood transfusion, but were without hydrops, survived, whereas this was about 70%, if they had become hydropic (this latter figure was reduced by 2 hydropic deaths before 20 weeks' gestation in the same very severely affected woman).


Impact of brief exercise on circulating monocyte gene and microRNA expression: implications for atherosclerotic vascular disease.
Physical activity can prevent and/or attenuate atherosclerosis, a disease clearly linked to inflammation. Paradoxically, even brief exercise induces a stress response and increases inflammatory cells like monocytes in the circulation. We hypothesized that exercise would regulate the expression of genes, gene pathways, and microRNAs in monocytes in a way that could limit pro-inflammatory function and drive monocytes to prevent, rather than contribute to, atherosclerosis. Twelve healthy men (22-30year old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 82% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise. Monocytes were isolated from peripheral blood mononuclear cells. Flow cytometry was used to identify monocyte subtypes. We used Affymetrix U133 + 2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (FDR <0.05) was used to determine that exercise significantly altered the expression of 894 annotated genes and 19 miRNAs. We found distinct gene alterations that were likely to direct monocytes in an anti-inflammatory, anti-atherogenic pathway, including the downregulation of monocyte TNF, TLR4, and CD36 genes and the upregulation of EREG and CXCR4. Exercise significantly altered a number of microRNAs that likely influence monocytes involvement in vascular health. Exercise leads to a novel genomic profile of circulating monocytes, which appears to promote cardiovascular health despite the overall stress response.


Photodynamic action of porphyrin on Ca2+ influx in endoplasmic reticulum: a comparison with mitochondria.
We have studied the distribution properties of haematoporphyrin (HP) and protoporphyrin (PP) in mitochondria and endoplasmic reticulum after isolation from rat liver. The photosensitizing efficiency of porphyrin on the Ca2+ influx function of microsomes has been compared with that obtained on Ca2+ uptake in mitochondria. HP and PP are accumulated in microsomes to a greater extent than in mitochondria, both porphyrins binding to membrane protein sites. The Ca2+ influx functions of mitochondria and microsomes, before and after irradiation in the presence of HP or PP, were studied by following the changes in the free Ca2+ concentration in the medium as revealed by the variations in fluorescence intensity of the Ca2+ indicator Calcium Green-1. For the same amount of incorporated porphyrin, the Ca2+ influx function of microsomes is degraded by irradiation more rapidly than that of mitochondria. The protective effect of dithiothreitol suggests that thiol groups in the Ca2+-transporting enzyme are the preferential targets of the photodynamic effect. These results suggest that intracellular Ca2+ movements are altered primarily by the endoplasmic reticulum rather than by mitochondrial damage, in good agreement with other observations made in porphyrin-loaded irradiated cells.


Supercontinuum generation in planar glass membrane fibers: comparison with bulk media.
Planar glass membrane fibers (PGMFs) are of current interest owing to the fact that they combine the interesting dispersive properties of fibers with diffraction in one unbound transverse dimension. We study supercontinuum (SC) spectra generated in PGMFs and show that the underlying dynamics has similarities to bulk medium. At the same time, the rich dispersion properties of PGMFs open up new possibilities, including SC spectral shapes that do not occur in natural bulk media. In all cases, the SC spectra in PGMFs can be interpreted in detail using the effective-three-wave-mixing model originally developed for bulk media.


Interobserver variability in the assessment of aneurysm occlusion with the WEB aneurysm embolization system.
The WEB (WEB aneurysm embolization system, Sequent Medical, Aliso Viejo, California, USA) is a self-expanding, nitinol, mesh device designed to achieve aneurysm occlusion after endosaccular deployment. The WEB Occlusion Scale (WOS) is a standardized angiographic assessment scale for reporting aneurysm occlusion achieved with intrasaccular mesh implants. This study was performed to assess the interobserver variability of the WOS. Seven experienced neurovascular specialists were trained to apply the WOS. These physicians independently reviewed angiographic image sets from 30 patients treated with the WEB under blinded conditions. No additional clinical information was provided. Raters graded each image according to the WOS (complete occlusion, residual neck or residual aneurysm). Final statistics were calculated using the dichotomous outcomes of complete occlusion or incomplete occlusion. The interobserver agreement was measured by the generalized κ statistic. In this series of 30 test case aneurysms, observers rated 12-17 as completely occluded, 3-9 as nearly completely occluded, and 9-11 as demonstrating residual aneurysm filling. Agreement was perfect across all seven observers for the presence or absence of complete occlusion in 22 of 30 cases. Overall, interobserver agreement was substantial (κ statistic 0.779 with a 95% CI of 0.700 to 0.857). The WOS allows a consistent means of reporting angiographic occlusion for aneurysms treated with the WEB device.


Psychiatric Disorders and Psychopharmacologic Treatment as Risk Factors in Elective Fast-track Total Hip and Knee Arthroplasty.
Psychiatric disorder (PsD) is rarely considered when evaluating perioperative risk factors. Studies on PsD are often limited by use of administrative coding, incomplete follow-up, and lack of preoperative data on psychopharmacological treatment. A multicenter study with prospective registration on preoperative comorbidity, complete 90-day follow-up, and information on dispensed prescriptions on psychopharmacological treatment (excluding benzodiazepines). All departments used similar fast-track approaches and discharge to home. Evaluation of postoperative morbidity was based on discharge records. Odds ratios for length of stay (LOS) more than 4 days and surgery-related readmissions were calculated using multiple logistic regression adjusting for potential confounders. Of 8,757 procedures, 1,001 (11.4%) were in PsD patients. Of these, 43.4% used selective serotonin inhibitors (SSRIs), 31.6% used other antidepressants, 8.5% used a combination, and 16.5% used antipsychotics. PsD was associated with increased risk of LOS more than 4 days (16.5 vs. 7.3%; odds ratio, 1.90; 95% CI, 1.52 to 2.37), regardless of treatment with SSRIs (2.19; 1.62 to 2.97), other antidepressants (1.81; 1.25 to 2.61), or antipsychotics (1.90; 1.62 to 3.16). PsD was associated with increased 30- (9.9 vs. 5.1%; 1.93; 1.49 to 2.49) and 90-day surgery-related readmissions (12.8 vs. 7.4%; 1.68; 1.34 to 2.10), significant for SSRIs (1.97; 1.38 to 2.82 and 1.77; 1.29 to 2.43), other antidepressants (2.24; 1.51 to 3.32 and 1.82; 1.27 to 2.61), and antipsychotics (1.85; 1.03 to 3.31, 30 days only). In PsD patients, pain (1.4%), postoperative anemia (1.1%), and pulmonary complications (1.1%) were the most frequent causes of LOS more than 4 days. Hip displacements (2.8%) and falls (1.9%) were the most frequent readmissions, and 90-day surgery-related mortality was 0.7% with and 0.2% without PsD. Psychopharmacologically treated PsD is a risk factor for postoperative morbidity after fast-track arthroplasty, regardless of treatment type. This may be due to PsD per se and/or drug-related side effects.


Organizational participatory research: a systematic mixed studies review exposing its extra benefits and the key factors associated with them.
In health, organizational participatory research (OPR) refers to health organization members participating in research decisions, with university researchers, throughout a study. This non-academic partner contribution to the research may take the form of consultation or co-construction. A drawback of OPR is that it requires more time from all those involved, compared to non-participatory research approaches; thus, understanding the added value of OPR, if any, is important. Thus, we sought to assess whether the OPR approach leads to benefits beyond what could be achieved through traditional research. We identified, selected, and appraised OPR health literature, and at each stage, two team members independently reviewed and coded the literature. We used quantitative content analysis to transform textual data into reliable numerical codes and conducted a logistic regression to test the hypothesis that a co-construction type OPR study yields extra benefits with a greater likelihood than consultation-type OPR studies. From 8873 abstracts and 992 full text papers, we distilled a sample of 107 OPR studies. We found no difference between the type of organization members' participation and the likelihood of exhibiting an extra benefit. However, the likelihood of an OPR study exhibiting at least one extra benefit is quadrupled when the impetus for the study comes from the organization, rather than the university researcher(s), or the organization and the university researcher(s) together (OR = 4.11, CI = 1.12-14.01). We also defined five types of extra benefits. This review describes the types of extra benefits OPR can yield and suggests these benefits may occur if the organization initiates the OPR. Further, this review exposes a need for OPR authors to more clearly describe the type of non-academic partner participation in key research decisions throughout the study. Detailed descriptions will benefit others conducting OPR and allow for a re-examination of the relationship between participation and extra benefits in future reviews.


α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.
Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug target, we show that the repurposed α2-adrenergic antagonist yohimbine potently reversed the depressant effect of REM sleep on baseline hypoglossal motoneuron activity (a first-line motor defense against OSA) in rats. Remarkably, yohimbine also restored the obstructive apnea-induced long-term facilitation of hypoglossal motoneuron activity (hLTF), a much-neglected form of noradrenergic-dependent neuroplasticity that could provide a second-line motor defense against OSA but was also depressed during REM sleep. Corroborating immunohistologic, optogenetic, and pharmacologic evidence confirmed that yohimbine's beneficial effects on baseline hypoglossal motoneuron activity and hLTF were mediated mainly through activation of pontine A7 and A5 noradrenergic neurons. Our results suggest a 2-tier (impaired first- and second-line motor defense) mechanism of noradrenergic-dependent pathogenesis of OSA and a promising pharmacotherapy for rescuing both these intrinsic defenses against OSA through disinhibition of A7 and A5 neurons by α2-adrenergic blockade.


Deep drilling into the Chesapeake Bay impact structure.
Samples from a 1.76-kilometer-deep corehole drilled near the center of the late Eocene Chesapeake Bay impact structure (Virginia, USA) reveal its geologic, hydrologic, and biologic history. We conducted stratigraphic and petrologic analyses of the cores to elucidate the timing and results of impact-melt creation and distribution, transient-cavity collapse, and ocean-water resurge. Comparison of post-impact sedimentary sequences inside and outside the structure indicates that compaction of the crater fill influenced long-term sedimentation patterns in the mid-Atlantic region. Salty connate water of the target remains in the crater fill today, where it poses a potential threat to the regional groundwater resource. Observed depth variations in microbial abundance indicate a complex history of impact-related thermal sterilization and habitat modification, and subsequent post-impact repopulation.


Effect of cochlear implantation on nasality in children.
Hypernasality is a commonly perceived characteristic of speech in deaf adults and children, but the mechanism of this abnormal nasal resonance is poorly understood. The impact of cochlear implantation on nasalance measures in children with severe auditory deprivation has not been previously reported. We conducted a study of nasality in 6 deaf children who had undergone cochlear implantation. Voice recordings were obtained before surgery and 6 months after activation of the implants. The MacKay-Kummer SNAP Test--which consists of a syllable-repetition subtest and a picture-cued subtest--was used to obtain nasalance scores for oral (bilabial, alveolar, velar, and sibilant) and nasal phonemes. Before cochlear implantation, mean nasalance scores were significantly higher than normal during the production of oral phonemes for both subtests (p < or = 0.05). Six months after activation, the nasalance measures for all components of the syllable-repetition subtest had been restored to within 1 standard deviation of normal. For all oral phonemes of the picture-cued subtest, the elevated nasalance scores were consistently lower after cochlear implant activation, although the difference was statistically significant only for velar tasks. Nasalance scores for nasal phonemes were within 1 standard deviation of normal both before and after implant activation. Our study showed that cochlear implantation partially corrects elevated nasalance measures. Disturbances in nasal resonance may be caused in part by the inability of deaf speakers to monitor velopharyngeal valving with auditory feedback. The trend toward improved nasalance scores after implantation highlights the role of auditory feedback in monitoring velopharyngeal function. Visual biofeedback may be required to further normalize hypernasal speech in profoundly deaf children.


Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone.
Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level-dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 years completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence.


Overlapping role of dynamin isoforms in synaptic vesicle endocytosis.
The existence of neuron-specific endocytic protein isoforms raises questions about their importance for specialized neuronal functions. Dynamin, a GTPase implicated in the fission reaction of endocytosis, is encoded by three genes, two of which, dynamin 1 and 3, are highly expressed in neurons. We show that dynamin 3, thought to play a predominantly postsynaptic role, has a major presynaptic function. Although lack of dynamin 3 does not produce an overt phenotype in mice, it worsens the dynamin 1 KO phenotype, leading to perinatal lethality and a more severe defect in activity-dependent synaptic vesicle endocytosis. Thus, dynamin 1 and 3, which together account for the overwhelming majority of brain dynamin, cooperate in supporting optimal rates of synaptic vesicle endocytosis. Persistence of synaptic transmission in their absence indicates that if dynamin plays essential functions in neurons, such functions can be achieved by the very low levels of dynamin 2.


From cancer screening to treatment: service delivery and referral in the National Breast and Cervical Cancer Early Detection Program.
The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides breast and cervical cancer screening and diagnostic services to low-income and underserved women through a network of providers and health care organizations. Although the program serves women 40-64 years old for breast cancer screening and 21-64 years old for cervical cancer screening, the priority populations are women 50-64 years old for breast cancer and women who have never or rarely been screened for cervical cancer. From 1991 through 2011, the NBCCEDP provided screening and diagnostic services to more than 4.3 million women, diagnosing 54,276 breast cancers, 2554 cervical cancers, and 123,563 precancerous cervical lesions. A critical component of providing screening services is to ensure that all women with abnormal screening results receive appropriate and timely diagnostic evaluations. Case management is provided to assist women with overcoming barriers that would delay or prevent follow-up care. Women diagnosed with cancer receive treatment through the states' Breast and Cervical Cancer Treatment Programs (a special waiver for Medicaid) if they are eligible. The NBCCEDP has performance measures that serve as benchmarks to monitor the completeness and timeliness of care. More than 90% of the women receive complete diagnostic care and initiate treatment less than 30 days from the time of their diagnosis. Provision of effective screening and diagnostic services depends on effective program management, networks of providers throughout the community, and the use of evidence-based knowledge, procedures, and technologies.


A modulated closed form solution for quantitative susceptibility mapping--a thorough evaluation and comparison to iterative methods based on edge prior knowledge.
The aim of this study is to perform a thorough comparison of quantitative susceptibility mapping (QSM) techniques and their dependence on the assumptions made. The compared methodologies were: two iterative single orientation methodologies minimizing the l2, l1TV norm of the prior knowledge of the edges of the object, one over-determined multiple orientation method (COSMOS) and a newly proposed modulated closed-form solution (MCF). The performance of these methods was compared using a numerical phantom and in-vivo high resolution (0.65 mm isotropic) brain data acquired at 7 T using a new coil combination method. For all QSM methods, the relevant regularization and prior-knowledge parameters were systematically changed in order to evaluate the optimal reconstruction in the presence and absence of a ground truth. Additionally, the QSM contrast was compared to conventional gradient recalled echo (GRE) magnitude and R2* maps obtained from the same dataset. The QSM reconstruction results of the single orientation methods show comparable performance. The MCF method has the highest correlation (corr MCF=0.95, r(2)MCF=0.97) with the state of the art method (COSMOS) with additional advantage of extreme fast computation time. The L-curve method gave the visually most satisfactory balance between reduction of streaking artifacts and over-regularization with the latter being overemphasized when the using the COSMOS susceptibility maps as ground-truth. R2* and susceptibility maps, when calculated from the same datasets, although based on distinct features of the data, have a comparable ability to distinguish deep gray matter structures.


Reactive Oxygen Species in Chronic Obstructive Pulmonary Disease.
Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema. Environmental exposure, primarily cigarette smoking, can cause high oxidative stress and is the main factor of COPD development. Cigarette smoke also contributes to the imbalance of oxidant/antioxidant due to exogenous reactive oxygen species (ROS). Moreover, endogenously released ROS during the inflammatory process and mitochondrial dysfunction may contribute to this disease progression. ROS and reactive nitrogen species (RNS) can oxidize different biomolecules such as DNA, proteins, and lipids leading to epithelial cell injury and death. Various detoxifying enzymes and antioxidant defense systems can be involved in ROS removal. In this review, we summarize the main findings regarding the biological role of ROS, which may contribute to COPD development, and cytoprotective mechanisms against this disease progression.


Classification of scalar and dyadic nonlocal optical response models.
Nonlocal optical response is one of the emerging effects on the nanoscale for particles made of metals or doped semiconductors. Here we classify and compare both scalar and tensorial nonlocal response models. In the latter case the nonlocality can stem from either the longitudinal response, the transverse response, or both. In phenomenological scalar models the nonlocal response is described as a smearing out of the commonly assumed infinitely localized response, as characterized by a distribution with a finite width. Here we calculate explicitly whether and how tensorial models, such as the hydrodynamic Drude model and generalized nonlocal optical response theory, follow this phenomenological description. We find considerable differences, for example that nonlocal response functions, in contrast to simple distributions, assume negative and complex values. Moreover, nonlocal response regularizes some but not all diverging optical near fields. We identify the scalar model that comes closest to the hydrodynamic model. Interestingly, for the hydrodynamic Drude model we find that actually only one third (1/3) of the free-electron response is smeared out nonlocally. In that sense, nonlocal response is stronger for transverse and scalar nonlocal response models, where the smeared-out fractions are 2/3 and 3/3, respectively. The latter two models seem to predict novel plasmonic resonances also below the plasma frequency, in contrast to the hydrodynamic model that predicts standing pressure waves only above the plasma frequency.


Multiple hippocampal transections for refractory pediatric mesial temporal lobe epilepsy: seizure and neuropsychological outcomes.
Temporal lobe epilepsy (TLE) is the most common focal epilepsy across adult and pediatric age groups. It is also the most amenable to surgery, with excellent long-term seizure outcome. Most TLE cases have an epileptogenic zone in the mesial temporal structures, namely the hippocampus. Resecting the dominant hippocampus has been shown to be associated with significant verbal memory deficits, especially in patients with intact verbal memory scores presurgically. Multiple hippocampal transection (MHT) is a relatively new surgical technique designed to interrupt the longitudinal hippocampal circuitry involved in seizure propagation yet preserve the circular fibers involved in memory function. This technique has been used to treat mesial TLE in both dominant- and nondominant-hemisphere cases, almost exclusively in adults. It has been applied to normal and sclerotic hippocampi. In this study, information on 3 pediatric patients who underwent MHT for mesial TLE at Children's Wisconsin between 2017 and 2018 is included. Clinical, electroencephalographic, and neuropsychological features and outcomes are described in detail. MRI revealed a tumor in the amygdala with a normal hippocampus in 1 patient and hippocampal sclerosis in 2 patients. All patients underwent stereoelectroencephalography confirming the involvement of the hippocampus in seizure onset. MHTs were completed under intraoperative monitoring, with amygdala and temporal tip resection in all patients due to early spread to these regions. All patients had excellent seizure outcomes at 1 year, and 2 of the 3 patients remain seizure free at last follow-up (range 20-36 months), all with stable or improved neuropsychological profiles, including verbal memory. MHT is a relatively new surgical procedure designed to preserve essential memory circuitry while disrupting seizure propagation pathways in the hippocampus. A growing body of literature shows good seizure and neuropsychological results, but mainly in adults. This is the first series of MHTs used exclusively in children at one medical center, showcasing excellent seizure control and preservation of neuropsychological functioning. One of the patients is also the first described to have MHT in the setting of an amygdalar tumor abutting the hippocampus, further expanding the pathological setting in which MHT can be used effectively.


Pattern of attendance and predictors of default among Nigerian outpatients with schizophrenia.
To assess the pattern of and factors associated with outpatient clinic attendance among patients diagnosed with schizophrenia at a Nigerian psychiatric hospital. This was a cross-sectional descriptive study of 313 consecutive outpatients with diagnosis of schizophrenia confirmed with the Structured Clinical Interview for Diagnosis (SCID). Data was collected on sociodemographics, clinic attendance, perceived social support, perceived satisfaction with hospital care and illness severity (assessed using the Brief Psychiatric Rating Scale, BPRS). Logistic regression analysis was used to identify factors associated with outpatient clinic default. Overall, 20.4% respondents were defaulters, with a median duration of clinic non-attendance of 8 weeks. Outpatient clinic defaulters had significantly higher BPRS scores and had missed more outpatient clinic appointments compared with non-defaulters. A significantly higher proportion of defaulters resided more than 20 km away from the hospital and reported "not satisfied" with their outpatient care. Being financially constrained was the commonest reason given by defaulters for missing their clinic appointments. The significant predictors of outpatient clinic default included residing more than 20 km from the hospital, missing previous appointments and dissatisfaction with outpatient care. Outpatient clinic non-attendance is common among patients with schizophrenia, and is significantly associated with demographic, clinical and service related factors. Interventions targeted at addressing the risk factors for defaulting peculiar to developing country settings similar to the location of this study, could significantly improve treatment outcome.


Immunization with different formulations of Mycobacterium tuberculosis antigen 85A induces immune responses with different specificity and protective efficacy.
To test the relative efficacy of CD4 and CD8T cells in mediating protective immunity to Mycobacterium tuberculosis (Mtb), we compared three immunization regimes designed to induce preferentially each subset. BALB/c mice were immunized intranasally (i.n.) or parenterally with antigen 85A either in a recombinant Adenoviral vector (Ad85A), as recombinant protein (r85A) or as a set of overlapping 15mer peptides (p85A). For the first time we show that i.n. immunization with overlapping 85A synthetic peptides as well as Ad85A or r85A can provide protection against Mtb challenge. For all forms of the antigen, i.n. induces greater protection against Mtb challenge than parenteral immunization. Ad85A induces a predominantly CD8T cell response against the 85A(70-78) epitope, r85A a CD4 response to 85A(99-118) and p85A a balanced CD4/CD8 response to the CD4 85A(99-118 )and CD8 85A(145-152) epitopes. Immune responses to CD4 85A(99-118) and CD8 85A(70-78) but not CD8 85A(145-152) are protective. Although Ad85A induces a strong response to the protective CD8 85A(70-78) epitope, we could not induce any response to this epitope by peptide immunization. These results show that although peptide immunization can induce protective immunity to Mtb challenge, it can also induce a response to a non-protective epitope in antigen 85A, indicating that the specificity of an immune response may be more important for protection against Mtb than its magnitude. These findings have important implications for the application of such vaccines in humans.


Preferences for end-of-life care among community-dwelling older adults and patients with advanced cancer: A discrete choice experiment.
Singapore is in the midst of several healthcare reforms in efforts to finance and deliver health services for a rapidly aging population. The primary focus of these reforms is to make healthcare services, including those at the end of life (EOL), affordable. Given the increasingly high health care costs at the EOL, policy makers need to consider how best to allocate resources. One strategy is to allocate resources based on the preferences of sub-populations most likely to be affected. This paper thus aims to quantify preferences for EOL care both among community dwelling older adults (CDOAs) and among patients with a life-limiting illness. A discrete choice experiment was administered to CDOAs and advanced cancer patients in Singapore and willingness to pay (WTP) for specific EOL improvements was estimated. We find that patients have a higher WTP for nearly all EOL attributes compared with CDOAs. We also show that, for both groups, moderate life extension is not the most important consideration; WTP for one additional life year is lower than common thresholds for cost-effectiveness. Irrespective of whose preference are considered, the results highlight the importance of pain management and supporting home deaths at the EOL, perhaps at the expense of public funding for costly but only marginally effective treatments.


Complete Genome Sequence of Achromobacter spanius UQ283, a Soilborne Isolate Exhibiting Plant Growth-Promoting Properties.
Achromobacter spanius UQ283 is a soilborne bacterium found to exhibit plant growth-promoting and disease-suppressing attributes in several plant species. Accordingly, we used long-read sequencing to determine its complete genome sequence. The assembled genome will aid in understanding the multifaceted interactions between plant growth-promoting rhizobacteria, pathogens, and plants.