Electron distributions in peptides and related molecules. 1. An experimental and theoretical study of N-acetyl-L-tryptophan methylamide.
The thermal vibrations and electron density of N-Ac-L-Trp-NHMe have been analyzed using single-crystal X-ray diffraction data measured at 103 K with Mo K alpha radiation to a resolution corresponding to (sin theta max)/ lambda = 1.17 A-1. Measurements of 10,527 reflections gave 4913 unique data [R(int)(magnitude of F2) = 0.019] of which 2641 had I greater than 3 sigma (I). A multipolar atomic density model was fitted [R(magnitude of F) = 0.028] in order to calculate phases for the crystal structure factors and map the valence-electron distribution. The phase problem for determining deformation densities by Fourier synthesis for noncentrosymmetric crystals is discussed. The experimental density agrees well with the theoretical density from an ab initio SCF molecular wave function calculated at the crystallographic molecular geometry with a split-valence basis set. Both the experimental and theoretical analyses confirm that the electron distribution is the same in the two different peptide groups in the molecule. Crystal data: C14H17N3O2, Mr = 259.31, orthorhombic, P2(1)2(1)2(1), Z = 4, F(000) = 522 e from 295 to 103 K; at 295 K, a = 8.152(2), b = 11.170 (2), c = 15.068 (3) A, V = 1372 A3, Dx = 1.26 mg mm-3; at 103 K, a = 8.209 (3), b = 11.016 (2), c = 14.760 (4) A, V = 1135 A3, Dx = 1.29 mg mm-3, mu = 0.083 mm-1 for lambda = 0.7107 A.


Structure and dynamics of methyl cis-3,4-diamino-2,3,4,6-tetradeoxy-alpha-L-lyxo-hexopyranoside complexes with PtCl(2) and PdCl(2), by (1)H, (2)H, (13)C, (15)N and (195)Pt NMR spectroscopy in DMSO, CD(3)CN and H(2)O.
Pd(II) and Pt(II) chloride complexes with LL = methyl cis-3,4-diamino-2,3,4,6-tetradeoxy-alpha-l-lyxo-hexopyranoside of the formulae [Pd(LL)Cl(2)] and [Pt(LL)Cl(2)], 1, were studied by (1)H, (2)H, (13)C, (15)N and (195)Pt NMR spectroscopy. These techniques were applied for characterization of the structure and ligand exchange dynamics, in case of diastereomeric species formed from 1 in DMSO-d(6), DMSO-h(6) and H(2)O; their general formula was [Pt(LL)XY](+) (X = Cl, Y = DMSO-d(6), 2a; X = DMSO-d(6), Y = Cl, 2b; X = Cl, Y = DMSO-h(6), 2a'; X = DMSO-h(6), Y = Cl, 2b'; X = Cl, Y = H(2)O, 3a; X = H(2)O, Y = Cl, 3b). Their theoretical structures and NMR parameters, calculated at the level of DFT approach, were also presented and compared to the experimental data. The model complex [Pt(trans-diaminocyclohexane)Cl(2)], 4, was studied as well. To the best of our knowledge, this work is the first account dealing with the detailed analysis of structure and dynamics of ligand exchange processes in organic solvents and water, performed for a PtCl(2) complex containing a diaminosugar moiety. The kinetic behavior of the studied coordination compounds suggests that some of them may be potentially active in bioassays against cancer cells. Compound 1 exhibits noticeable versatile ligand exchange possibilities in DMSO and H(2)O. Particularly, it undergoes solvolysis in DMSO-d(6), exchanging one chloride atom and yielding two diastereomers 2a and 2b; the former, being the kinetically favored species, has the DMSO-d(6) ligand syn to the N(3) atom. The lyophilisate of the respective 2a + 2b mixture, earlier equilibrated in DMSO-d(6), after dissolving in H(2)O yields only the latter isomer, which is thermodynamically favored. The solvolysis of 1 in H(2)O yields instantaneously two diastereomeric monoaquated species, 3a and 3b, amounting to 10% of each.


Deformation behavior of low-carbon Co-Cr-Mo alloys for low-friction implant applications.
The plastic flow behavior of wrought Co-27Cr-5Mo-0.05C alloy was investigated at 298 K as a function of grain size using uniaxial tension testing. The microstructures produced by deformation were characterized using X-ray diffraction, reflected light, and scanning electron microscopy. This study revealed that material with initially coarse face-centered cubic (fcc) grains exhibits larger uniform ductility than material with fine grain size. Typically, increasing the grain size from 7 to 70 microns reduces the yield strength by about 50% and increases the elongation to fracture from 12 to 30% with a small effect on the tensile strength. The material is capable of deforming uniformly to large strains without developing plastic instabilities until the point of fracture. This effect was found to be associated with the occurrence of transformation-induced plasticity (TRIP) in the coarse-grained material. TRIP enhances the material's ability to deform uniformly by maintaining a high rate of strain hardening during deformation. Smaller fcc initial grain size inhibits the transformation kinetics of the fcc-hexagonal close-packed phase transition according to the Olson-Cohen model.


[Prevalence of diabetes and impaired glucose regulation in Chengdu populations and associated dietary risk factors].
To determine the prevalence of type 2 DM and impaired glucose regulation (IGR) in Chengdu populations and to identify dietary risk factors associated with DM and IGR. Two communities in Chengdu were selected for this study. Fasting blood-glucose (FBG) and 2-hour post-meal blood glucose (2 hGlu) tests were performed in the community residents. The participants were asked to complete a questionair recording their daily food intaking. The total calorie of food, percentage of different kinds of food, and intake of electrolyte, vietamine and micro minerals were calculated and compared between those with and without type 2 DM or IGR. Of the study participants, 18.59% had type 2 DM and 24.22% had IGR. Those with DM had higher levels of intake of calorie,fat,protein and sodium, and lower levels of intake of cellulose, carbohydrates, Iron, zinc, selenium,manganese and vietamine C and E compared with those without DM/IGR (P < 0.05). The participants with IGR had higher levels of intake of calorie and sodium and lower levels of intake of cellulose, zinc, selenium, manganese and vitamine C and E compared with those without DM/IGR (P < 0.05). Percentage of dietary fat was identified as an independent risk factor of type 2 DM (OR = 1.609); whearaus Vitamine E was identified as a protective factor of type 2 DM (OR = 0.733) and IGR (OR = 0.990). Chengdu has a higher than national average prevalence of type 2 DM and IGR. The high percentage of dietary fat and low levels of Vitamine E are major risk factors of type 2 DM and IGR.


p70 S6 kinase and tau in Alzheimer's disease.
The 70-kDa S6 kinase (p70S6K) is a Ser/Thr (S/T)-directed kinase that plays a crucial role in cell growth, cell differentiation, and cell cycle control. This article presented evidence that supports both toxic and protective roles of p70S6K activity towards tau in Alzheimer's disease (AD) brains. The p70S6K can phosphorylate tau at S262, S214, and T212 sites. Phosphorylation at these sites might release tau from microtubules, resulting in microtubule disruption. Evidence also suggests that p70S6K regulates the translation of tau mRNA by phosphorylating the 40S ribosomal protein S6. The extracellular amyloid-beta deposition in AD brains could be a causative factor that activates p70S6K. We hypothesized that amyloid-beta deposition activates p70S6K whose anti-apoptotic property subsequently keeps neurons from entering into the apoptotic process. This process provides the opportunity for the newly synthesized tau to be phosphorylated by p70S6K and by other tau kinases. This hyperphosphorylated tau then aggregates and is progressively deposited in neurons.


Idiopathic inflammatory myopathies - myositis.
The inflammatory myopathies - myositis - encompass a heterogeneous group of chronic muscle disorders of unknown origin and with varying prognoses. New clinical phenotypes of myositis have been identified since the most widely used classification criteria were proposed in 1975. Based on clinical and histopathological features, inclusion body myositis was identified. Furthermore, the myositis-specific autoantibodies may also identify different clinical phenotypes and serve as prognostic markers. The different classifications and inclusion criteria that have been used in different studies make some epidemiological data uncertain. In order to improve our knowledge of causative factors, as well as of pathogenic mechanisms, there is a need for revision and also for an international acceptance of the classification criteria. During recent years, our knowledge has increased regarding the role of some genetic and environmental factors that could affect susceptibility for developing myositis as well as the prognosis. Whether there is an association between myositis and malignancies has been a subject of controversy for many years and recent epidemiological data have brought some clarification on this issue.


Ascertaining the true incidence of stroke: experience from the Perth Community Stroke Study, 1989-1990.
To determine the age and sex specific incidence, and case fatality of stroke in Perth, Western Australia. A population-based descriptive epidemiological study. All residents of a geographically defined segment of the Perth metropolitan area (population 138,708) who had a stroke or transient ischaemic attack between 20 February 1989 and 19 August 1990, inclusive. Definite acute "first-ever-in-a-lifetime" (first-ever) and recurrent stroke classified according to standard definitions and criteria. During the 18-month study period, 536 stroke events occurred among 492 patients, 69% of which were first-ever strokes. The crude annual event rate for all strokes was 258 (95% confidence interval 231-285) per 100,000, and the overall case fatality at 28 days was 24% (95% CI, 20%-28%). The crude annual incidence for first-ever strokes was 178 (95% CI, 156-200) per 100,000; 189 (95% CI, 157-221) per 100,000 in males and 166 (95% CI, 136-196) per 100,000 in females. The corresponding rates, age-adjusted to the "world" population, were 132 (95% CI, 109-155) for males and 77 (95% CI, 60-94) for females. In contrast to mortality rates for ischaemic heart disease, the incidence of stroke in Australia appears little different from that for several other Western countries. For both males and females the incidence of stroke rises exponentially with increasing age. Although the sex-dependent difference in the risk of stroke is greatest in middle age, males are at greater risk of stroke even among the most elderly. To determine the incidence of stroke accurately, population-based studies of stroke need exhaustive and overlapping sources of case ascertainment. If only cases admitted to hospital had been used, we would have underestimated the rate of stroke among the most elderly by almost 40%. We estimate that approximately 37,000 people, about 50% of whom are over the age of 75, suffer a stroke each year in Australia.


Identification of gene expression patterns using planned linear contrasts.
In gene networks, the timing of significant changes in the expression level of each gene may be the most critical information in time course expression profiles. With the same timing of the initial change, genes which share similar patterns of expression for any number of sampling intervals from the beginning should be considered co-expressed at certain level(s) in the gene networks. In addition, multiple testing problems are complicated in experiments with multi-level treatments when thousands of genes are involved. To address these issues, we first performed an ANOVA F test to identify significantly regulated genes. The Benjamini and Hochberg (BH) procedure of controlling false discovery rate (FDR) at 5% was applied to the P values of the F test. We then categorized the genes with a significant F test into 4 classes based on the timing of their initial responses by sequentially testing a complete set of orthogonal contrasts, the reverse Helmert series. For genes within each class, specific sequences of contrasts were performed to characterize their general 'fluctuation' shapes of expression along the subsequent sampling time points. To be consistent with the BH procedure, each contrast was examined using a stepwise Studentized Maximum Modulus test to control the gene based maximum family-wise error rate (MFWER) at the level of alphanew determined by the BH procedure. We demonstrated our method on the analysis of microarray data from murine olfactory sensory epithelia at five different time points after target ablation. In this manuscript, we used planned linear contrasts to analyze time-course microarray experiments. This analysis allowed us to characterize gene expression patterns based on the temporal order in the data, the timing of a gene's initial response, and the general shapes of gene expression patterns along the subsequent sampling time points. Our method is particularly suitable for analysis of microarray experiments in which it is often difficult to take sufficiently frequent measurements and/or the sampling intervals are non-uniform.


Ricin RCA60: evidence of its phospholipase activity.
The present work documents, on a qualitative and quantitative basis, the lipolytic activity of ricin protein RCA60 on glycerophospholipids. RCA60 demonstrates a low level of hydrolysis towards radioactive dipalmitoyl-glycerophosphatidylcholine. This observation was confirmed on a better substrate, palmitoyl-oleoyl-glycerophosphatidylcholine, after analysis of the reaction products by thin-layer and gas chromatography. A comparable hydrolytic activity was observed when palmitoyl-oleoyl-glycerophosphatidylethanolamine was used as substrate. The nature of the hydrolysis products supports the conclusion that RCA60 demonstrates phospholipase A1 and A2 activities as well as a lysophospholipase activity of A1 and A2 type. The insensitivity of this lipolytic activity towards calcium ions and the presence of the already described consensus sequence of lipases, Gly-Xaa-Ser-Xaa-Gly, in the primary sequence of the B-chain of RCA60 support the idea that the lipolytic activity of RCA60 is more related to the lipase family than to the phospholipases A. We hypothesize that such activity contributes to the mechanism which underlies the expression of the cytotoxicity of RCA60.


Evaluation of polyurethane dressing with ibuprofen in the management of split-thickness skin graft donor sites.
The authors investigated the possible effect of ibuprofen when included in polyurethane dressing foam in the management of pain and healing related to split-thickness skin graft (STSG) donor sites. The study focused on the use of a foam dressing, Biatain-Ibu, the combination of an absorbent hydrophilic polyurethane foam, Biatain, and the active ingredient ibuprofen as an integral part of the matrix. A prospective study was conducted from October 2006 to April 2007 and included 40 patients undergoing surgery for any reconstructive purposes with the use of STSG. The patients were divided into two groups in a randomized fashion. In the first group of 20 patients, the donor sites were covered using Biatain-Ibu foam dressing. In the second group of 20 patients, the donor sites were closed intra-operatively with a standard dressing which did not contain any known healing promoting agent. To evaluate the extent and quality of the pain experienced by the patients and to score pain over time, the patients in the study were asked to complete a form containing a visual analogue scale and answer questions on the quality of pain and the way normal daily activities were affected. The combined use of ibuprofen with bio-occlusive dressings accelerated wound healing compared to fine-mesh gauze dressings and almost eliminated pain and discomfort in all patients treated. In patients receiving topical ibuprofen, itch did not present a major problem. This study demonstrates that the Biatain-Ibu dressing is a useful tool in the management of STSG donor sites by providing an optimal environment for wound healing due to its bio-occlusive properties and by minimizing pain and discomfort.


Nutraceuticals for the Treatment of Diabetic Retinopathy.
Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and is characterized by degeneration of retinal neurons and neoangiogenesis, causing a severe threat to vision. Nowadays, the principal treatment options for DR are laser photocoagulation, vitreoretinal surgery, or intravitreal injection of drugs targeting vascular endothelial growth factor. However, these treatments only act at advanced stages of DR, have short term efficacy, and cause side effects. Treatment with nutraceuticals (foods providing medical or health benefits) at early stages of DR may represent a reasonable alternative to act upstream of the disease, preventing its progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DR, reducing both the neural and vascular damage typical of DR. Although most studies are limited to animal models and there is the problem of low bioavailability for many nutraceuticals, the use of these compounds may represent a natural alternative method to standard DR treatments.


Role of the N-terminus in the interaction of pancreatic phospholipase A2 with aggregated substrates. Properties and crystal structure of transaminated phospholipase A2.
A free N-terminal alpha-NH3+ group is absolutely required for full catalytic activity of phospholipase A2 on aggregated substrates. To elucidate how this alpha-NH3+ group triggers catalytic activity, we specifically transaminated this group in various pancreatic phospholipases A2. Porcine, porcine iso-, equine, human, ovine, and bovine phospholipases A2 all loose catalytic activity on micellar substrates due to the inability of the transaminated proteins to bind to neutral micellar substrate analogues, as was found for the zymogens. Loss of activity is pseudo first order, the rate constants being different for the enzymes studied. The transaminated phospholipases A2 have an intact active site, as catalytic activities on monomeric substrates are comparable to those of the respective zymogens. The X-ray structure of transaminated bovine phospholipase A2 at 2.1-A resolution shows that the N-terminal region and the sequence 63-72 in this protein are more flexible than in the native enzyme. Also, in this respect, the transaminated enzyme very much resembles the zymogen structure. In good agreement with this, it was found by photochemically induced dynamic nuclear polarization 1H NMR that aromatic resonances of Trp-3 and Tyr-69 are affected by transamination. In addition, fluorescence spectroscopy of the unique Trp-3 in transaminated bovine phospholipase A2 revealed a red shift of the emission maximum indicative of a more polar environment of Trp-3 in the transaminated phospholipase A2 as compared to the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)


Using psychological theory and qualitative methods to develop a new evidence-based website about acupuncture for back pain.
Potential acupuncture patients seek out information about acupuncture from various sources including websites, many of which are unreliable. We aimed to create an informative, scientifically accurate and engaging website to educate patients about acupuncture for back pain and modify their beliefs in a way that might enhance its clinical effects. We used psychological theory and techniques to design an evidence-based website, incorporating multimedia elements. We conducted qualitative "think aloud" audio-recorded interviews to elicit user views of the website. A convenience sample of ten participants (4 male; aged 21-64 years from the local community) looked at the website in the presence of a researcher and spoke their thoughts out loud. Comments were categorised by topic. The website comprises 11 main pages and addresses key topics of interest to potential acupuncture patients, including beneficial and adverse effects, mechanisms of action, safety, practicalities, and patients' experiences of acupuncture. It provides information through text, evidence summaries and audio-clips of four patients' stories and two acupuncturists' descriptions of their practice, and three short films. Evidence from the think aloud study was used to identify opportunities to make the website more informative, engaging, and user-friendly. Using a combination of psychological theory and qualitative interviews enabled us to produce a user-friendly, evidence-based website that is likely to change patients' beliefs about acupuncture for back pain. Before using the website in clinical settings it is necessary to test its effects on key outcomes including patients' beliefs and capacity for making informed choices about acupuncture.


Screening of poplar clones for cadmium phytoremediation using photosynthesis, biomass and cadmium content analyses.
Variability of cadmium tolerance and distribution in plant organs was investigated in ten selected poplar clones from different species, hybrids and genotypes. To this end, plants were exposed for three weeks to 50 microM CdSO4 in hydroponics. Cadmium accumulation in roots, stem and leaves as well as biomass production and photosynthesis maintenance varied greatly among clones. The metal mostly accumulated in roots, up to 80% in some clones, and interestingly, only 50% in some others. In general, metal tolerance reflected the degree of photosynthesis inhibition, which was higher in clones with high cadmium accumulation in leaves. Biomass production, net photosynthesis, transpiration, and pigment content were differently reduced in cadmium-treated clones with respect to control. The variability of cadmium distribution among leaves, stem, and roots provides candidate poplars for specific phytoremediation processes of contaminated waters and soils.


Genome-wide gene responses in a transgenic rice line carrying the maize resistance gene Rxo1 to the rice bacterial streak pathogen, Xanthomonas oryzae pv. oryzicola.
Non-host resistance in rice to its bacterial pathogen, Xanthomonas oryzae pv. oryzicola (Xoc), mediated by a maize NBS-LRR type R gene, Rxo1 shows a typical hypersensitive reaction (HR) phenotype, but the molecular mechanism(s) underlying this type of non-host resistance remain largely unknown. A microarray experiment was performed to reveal the molecular mechanisms underlying HR of rice to Xoc mediated by Rxo1 using a pair of transgenic and non-transgenic rice lines. Our results indicated that Rxo1 appeared to function in the very early step of the interaction between rice and Xoc, and could specifically activate large numbers of genes involved in signaling pathways leading to HR and some basal defensive pathways such as SA and ET pathways. In the former case, Rxo1 appeared to differ from the typical host R genes in that it could lead to HR without activating NDR1. In the latter cases, Rxo1 was able to induce a unique group of WRKY TF genes and a large set of genes encoding PPR and RRM proteins that share the same G-box in their promoter regions with possible functions in post-transcriptional regulation. In conclusion, Rxo1, like most host R genes, was able to trigger HR against Xoc in the heterologous rice plants by activating multiple defensive pathways related to HR, providing useful information on the evolution of plant resistance genes. Maize non-host resistance gene Rxo1 could trigger the pathogen-specific HR in heterologous rice, and ultimately leading to a localized programmed cell death which exhibits the characteristics consistent with those mediated by host resistance genes, but a number of genes encoding pentatricopeptide repeat and RNA recognition motif protein were found specifically up-regulated in the Rxo1 mediated disease resistance. These results add to our understanding the evolution of plant resistance genes.


Incidence rates and risk factors for asthma among school children: a 2-year follow-up report from the obstructive lung disease in Northern Sweden (OLIN) studies.
Studies of incidence of asthma are still limited. A longitudinal study of asthma in school children was started in 1996 in Northern Sweden. The incidence of asthma and the associated risk factors have been studied over a 2 years period. The study started with a parental questionnaire, the ISAAC questionnaire with additional questions, and a skin-prick test. The cohort, 3,525 children, 7 and 8 years old at start, was followed after 1 and 2 years by using the same questions, Each year responded 97%. The cumulative incidence of physician-diagnosed asthma was 1.7%, 0.9/1,000/year the first year, and 0.8/1,000/year the second year. The cumulative incidence of wheezing was 6.3%, and of frequent or daily users of asthma medicines 2.1%. Significant risk factors for incident asthma were a positive skin test, OR 5.64 (3.10-10.25); rhinitis,OR 3.53 (1.80-6.90); eczema, OR 2.19 (1.26-3.82); a family history of asthma, OR 2.83 (1.75-4.56); low birth weight, OR 3.38 (1.61-754); respiratory infections, OR 2.12 (1.24-3.63); male gender, OR 1.71 (1.06-2.81); and a smoking mother OR 2.00 (1.07-3.73). In summary the incidence of asthma during 2 years after age 7 was high, almost 1/100/year. Allergy was the most important risk factor, but other factors were influential.


Primary Membranous Glomerulonephritis-associated with Schistosomal Nephropathy.
The association of bilharziasis with membranous nephropathy (MN) has long been debated. The relatively recent use of antibodies against the M-type phospholipase A2 receptor (PLA2R) has been proposed as a valuable tool to discriminate the idiopathic from secondary MNs. Anti-PLA2R antibodies are found in sera from about 70% of iMN patients, in contrast to patients with secondary MN, in whom serum anti-PLA2R antibodies could not be detected. In the current case report, we detected anti-PLA2R antibodies both in serum and renal biopsy from a patient with MN associated with Schistosoma mansoni. This finding confirms the idiopathic nature of the MN and excludes schistosomiasis as the triggering agent of MN. After treating bilharziasis, Ponticelli regimen was initiated without a significant improvement.


Systemic mediators released from the gut in critical illness.
To discuss the mediators released from the gut in critical states, with emphasis on the intestinal mucosal barrier function, mediators of bacterial origin, and myocardial depressant factors. Relevant articles that have been published in the English language literature. No special study has been carried out for the present discussion. Information from the literature has been used to illustrate important points in the discussion. Due to decreased mucosal blood flow, increased short-circuiting of oxygen in the mucosal countercurrent exchanger, and increased oxygen demand in sepsis mucosal injury develops rapidly in the gut after various forms of shock and splanchnic ischemia. In addition, due to increased generation of oxygen-derived radicals, injury may also occur with reperfusion. As a consequence of increased permeability of the intestinal mucosal barrier between the luminal content and the sterile interior milieu, increased translocation of bacteria and bacterial endotoxin occurs. In addition, cardiodepressant factors are released, as is evident from in vivo and in vitro studies. No such factor has been fully identified chemically. Intestinal mucosal injury, as seen in critical illness, may induce increased translocation of bacteria and endotoxin and release of myocardial depressant factors into the circulation.


An androgen receptor gene mutation (E653K) in a family with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency as well as in partial androgen insensitivity.
An androgen receptor (AR) variant (E653K) was found in two unrelated Swedish families. One family had two girls affected with congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. The girls, who showed mild virilization in relation to their CYP21 genotype, had inherited the AR gene mutation from their father, who showed no symptoms of androgen insensitivity. The other family had a boy with partial androgen insensitivity and ambiguous genitalia, and he had inherited the AR gene mutation from his mother. The mutant receptor showed a transactivating capacity in the same range as the normal receptor at high concentrations of ligand (1 and 10 nM dihydrotestosterone), but absent or reduced transactivation at low levels (0.01 and 0.1 nM). The receptor variant was not found among 250 additional unselected Swedish men. Sequencing of the AR gene in five unrelated CAH girls with the I172N mutation in CYP21 and minimal virilization did not reveal any additional deviations from the normal reference sequence. In addition, there was no difference in lengths of the polymorphic CAG repeat in the AR gene between CAH girls with the I172N mutation who showed minimal and severe virilization, and we found no evidence of skewed X-inactivation. We conclude that AR gene mutations or polymorphisms are not a common factor influencing the degree of hyperandrogenic symptoms displayed by CAH girls, and that the AR E653K mutation is compatible with normal genital development, although it can cause genital malformations in susceptible individuals.


Regulation of the tryptophan biosynthetic genes in Bacillus halodurans: common elements but different strategies than those used by Bacillus subtilis.
In Bacillus subtilis, an RNA binding protein called TRAP regulates both transcription and translation of the tryptophan biosynthetic genes. Bacillus halodurans is an alkaliphilic Bacillus species that grows at high pHs. Previous studies of this bacterium have focused on mechanisms of adaptation for growth in alkaline environments. We have characterized the regulation of the tryptophan biosynthetic genes in B. halodurans and compared it to that in B. subtilis. B. halodurans encodes a TRAP protein with 71% sequence identity to the B. subtilis protein. Expression of anthranilate synthetase, the first enzyme in the pathway to tryptophan, is regulated significantly less in B. halodurans than in B. subtilis. Examination of the control of the B. halodurans trpEDCFBA operon both in vivo and in vitro shows that only transcription is regulated, whereas in B. subtilis both transcription of the operon and translation of trpE are controlled. The attenuation mechanism that controls transcription in B. halodurans is similar to that in B. subtilis, but there are some differences in the predicted RNA secondary structures in the B. halodurans trp leader region, including the presence of a potential anti-antiterminator structure. Translation of trpG, which is within the folate operon in both bacilli, is regulated similarly in the two species.


Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma.
Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test. Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study. Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate. These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.


Making a case for the teaching scholar.
Medical schools are increasingly cognizant of their inability to critically evaluate faculty who support the core mission of education. To address this need, the Project on Scholarship was initiated by the Group on Educational Affairs (GEA) of the Association of American Medical Colleges. Building on and expanding previous definitions of scholarship and the associated criteria emerging in higher education, the project developed a set of "teacher as scholar" scenarios. These scenarios contained varied types of evidence for teaching scholarship and were discussed at the 1999 GEA regional meetings. Two major conclusions/recommendations emerged from these discussions: (1) the use of commonly accepted scholarship criteria (clear goals, appropriate methods, significant results, effective communication) provides a framework for identifying the types of evidence needed to document teaching scholarship, and (2) medical schools must create an infrastructure for promoting educational scholarship. This infrastructure must support the reliable and valid collection of evidence of educational scholarship and the continuous development of faculty as teaching scholars.


Characterizing protein-glycosaminoglycan interactions using solution NMR spectroscopy.
Solution nuclear magnetic resonance (NMR) spectroscopy and, in particular, chemical shift perturbation (CSP) titration experiments are ideally suited for characterizing the binding interface of macromolecular complexes. (1)H-(15) N-HSQC-based CSP studies have become the method of choice due to their simplicity, short time requirements, and not requiring high-level NMR expertise. Nevertheless, CSP studies for characterizing protein-glycosaminoglycan (GAG) interactions have been challenging due to binding-induced aggregation/precipitation and/or poor quality data. In this chapter, we discuss how optimizing experimental variables such as protein concentration, GAG size, and sensitivity of NMR instrumentation can overcome these roadblocks to obtain meaningful structural insights into protein-GAG interactions.


Imaging of a glucose analog, calcium and NADH in neurons and astrocytes: dynamic responses to depolarization and sensitivity to pioglitazone.
Neuronal Ca(2+) dyshomeostasis associated with cognitive impairment and mediated by changes in several Ca(2+) sources has been seen in animal models of both aging and diabetes. In the periphery, dysregulation of intracellular Ca(2+) signals may contribute to the development of insulin resistance. In the brain, while it is well-established that type 2 diabetes mellitus is a risk factor for the development of dementia in the elderly, it is not clear whether Ca(2+) dysregulation might also affect insulin sensitivity and glucose utilization. Here we present a combination of imaging techniques testing the disappearance of the fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as an indication of glycolytic activity in neurons and astrocytes. Our work shows that glucose utilization at rest is greater in neurons compared to astrocytes, and ceases upon activation in neurons with little change in astrocytes. Pretreatment of hippocampal cultures with pioglitazone, a drug used in the treatment of type 2 diabetes, significantly reduced glycolytic activity in neurons and enhanced it in astrocytes. This series of experiments, including Fura-2 and NADH imaging, provides results that are consistent with the idea that Ca(2+) levels may rapidly alter glycolytic activity, and that downstream events beyond Ca(2+) dysregulation with aging, may alter cellular metabolism in the brain.


[Delayed hypersensitivity to Trypanosoma cruzi antigen. II--Use of the skin test with T12E antigen for the diagnosis of Chagas disease].
Delayed-type skin reactivity against a Trypanosoma cruzi antigen was elicited in 35.7 percent of the individuals living in the country of Mambaí, state of Goiás, Brazil. The specificity of this skin reaction was shown in 93 out of 94 (98.7%) chagasic patients, in whom the parasitemias were detected by xenodiagnosis. In these patients, however, the hemagglutination, immunofluorescence and complement fixation assays were positive in respectively, 100, 97.8 and 80.6 per cent. The relationship between the combined positive results by hemagglutination and immunofluorescence with that obtained with skin testings was 0.897, in the overall population in this study. The quantity of 50 micrograms of protein in 100 microliters of the T12E antigen did not produce undesired effects, and did not shift the immunologic assays, when healthy volunteers were skin tested five times within 15-day intervals. Also, the potency of this antigen remained unaltered after 24 months at -10 degrees C.


Senescence of Rice Leaves : VII. PROLINE ACCUMULATION IN SENESCING EXCISED LEAVES.
Proline content increased greatly in detached rice (Oryza sativa cv. Taichung Native 1) leaves during senescence. There was a slight but significant increase in proline level after one day of incubation, and, subsequently, proline accumulated relatively rapidly. By 4 days after excision, the level of proline had increased 30- to 50-fold, which is similar to the level seen in the water-stressed detached rice leaves. It is unlikely that the proline accumulation in detached leaves is to be derived solely from protein hydrolysis, since the addition of l-glutamic acid increased the proline level during senescence. The proline analog, 3,4-dehydroproline, did not affect the level of proline during senescence. It seems that accumulation of proline may, at least in part, result from an increased rate of synthesis, possibly due to a disruption of the normal feedback inhibition of proline synthesis. Potassium cyanide and 2,4-dinitrophenol strongly inhibited proline accumulation, indicating that some energy compound(s) may participate in proline accumulation during senescence of excised rice leaves.


Political unification and regional consequences of German East-West migration.
"The purpose of this paper is to evaluate the impact of the post-unification East to West transfer of the German population on levels of spatial concentration and deconcentration in Eastern and Western Germany. Using 1991 internal migration data, it was found that German East-to-West migration served to deconcentrate regional population in the West, but concentrate population in the East. Regional variations in German East-to-West migration during 1991 can be explained by the availability of employment and housing, a distance-minimisation effect, and the location of relatives and friends."


Efficient prediction of temperature-dependent elastic and mechanical properties of 2D materials.
An efficient automated toolkit for predicting the mechanical properties of materials can accelerate new materials design and discovery; this process often involves screening large configurational space in high-throughput calculations. Herein, we present the ElasTool toolkit for these applications. In particular, we use the ElasTool to study diversity of 2D materials and heterostructures including their temperature-dependent mechanical properties, and developed a machine learning algorithm for exploring predicted properties.


Probable secondary transmission of antimicrobial-resistant Escherichia coli between people living with and without pets.
Companion animals are considered as one of the reservoirs of antimicrobial-resistant (AR) bacteria that can be cross-transmitted to humans. However, limited information is available on the possibility of AR bacteria originating from companion animals being transmitted secondarily from owners to non-owners sharing the same space. To address this issue, the present study investigated clonal relatedness among AR E. coli isolated from dog owners and non-owners in the same college classroom or household. Anal samples (n=48) were obtained from 14 owners and 34 non-owners; 31 E. coli isolates were collected (nine from owners and 22 from non-owners). Of 31 E. coli, 20 isolates (64.5%) were resistant to at least one antimicrobial, and 16 isolates (51.6%) were determined as multi-drug resistant E. coli. Six isolates (19.4%) harbored integrase genes (five harbored class I integrase gene and one harbored class 2 integrase gene, respectively). Pulsed-field gel electrophoretic analysis identified three different E. coli clonal sets among isolates, indicating that cross-transmission of AR E. coli can easily occur between owners and non-owners. The findings emphasize a potential risk of spread of AR bacteria originating from pets within human communities, once they are transferred to humans. Further studies are needed to evaluate the exact risk and identify the risk factors of secondarily transmission by investigating larger numbers of isolates from pets, their owners and non-owners in a community.


The effect of immune therapy on surgical site infection following Crohn's Disease resection.
Patients with Crohn's disease are increasingly receiving antitumour necrosis factor α (anti-TNF-α) therapy. Whether anti-TNF-α therapy increases the risk of postoperative infectious complications in Crohn's disease is a matter of debate. This was a retrospective study of three referral centres. The charts of patients who underwent ileocaecal or ileocolonic resection for Crohn's disease between 2000 and 2011 were reviewed. The impact of baseline characteristics and Crohn's disease-related medications on the risk of postoperative intra-abdominal infectious complications was investigated by univariable and multivariable analysis. A total of 217 patients were included in the study. Median age at the time of surgery was 36·8 (range 15-78) years. A postoperative intra-abdominal infection occurred in 24 (11·1 per cent) of 217 patients. No deaths were reported. On univariable analysis, age less than 25 years (P = 0·023), steroid use (P = 0·017), anti-TNF-α therapy (P = 0·043) and anti-TNF-α treatment in combination with steroids (P = 0·004) were associated with an increased risk of postoperative intra-abdominal infectious complications. On multivariable analysis, only anti-TNF-α therapy in combination with steroids significantly increased this risk (odds ratio 8·03, 95 per cent confidence interval 1·93 to 33·43; P = 0·035). Combined use of steroids and anti-TNF-α therapy was associated with an increased risk of postoperative intra-abdominal infectious complications.


A Literature Survey and Experimental Evaluation of the State-of-the-Art in Uplift Modeling: A Stepping Stone Toward the Development of Prescriptive Analytics.
Prescriptive analytics extends on predictive analytics by allowing to estimate an outcome in function of control variables, allowing as such to establish the required level of control variables for realizing a desired outcome. Uplift modeling is at the heart of prescriptive analytics and aims at estimating the net difference in an outcome resulting from a specific action or treatment that is applied. In this article, a structured and detailed literature survey on uplift modeling is provided by identifying and contrasting various groups of approaches. In addition, evaluation metrics for assessing the performance of uplift models are reviewed. An experimental evaluation on four real-world data sets provides further insight into their use. Uplift random forests are found to be consistently among the best performing techniques in terms of the Qini and Gini measures, although considerable variability in performance across the various data sets of the experiments is observed. In addition, uplift models are frequently observed to be unstable and display a strong variability in terms of performance across different folds in the cross-validation experimental setup. This potentially threatens their actual use for business applications. Moreover, it is found that the available evaluation metrics do not provide an intuitively understandable indication of the actual use and performance of a model. Specifically, existing evaluation metrics do not facilitate a comparison of uplift models and predictive models and evaluate performance either at an arbitrary cutoff or over the full spectrum of potential cutoffs. In conclusion, we highlight the instability of uplift models and the need for an application-oriented approach to assess uplift models as prime topics for further research.


Transient silencing mediated by in vitro synthesized double-stranded RNA indicates that PsCdc14 is required for sporangial development in a soybean root rot pathogen.
In many eukaryotic organisms, Cdc14 phosphatase regulates multiple biological events during anaphase and is essential for mitosis. It has been shown that Cdc14 is required for sporulation in the potato blight pathogen Phytophthora infestans; however, the role that the Cdc14 homolog (PsCdc14) plays in the soil-borne soybean root rot pathogen P. sojae remains ambiguous. PsCdc14 is highly expressed in sporulation, zoospore, and cyst life stages, but not in vegetative mycelia and infection stages, suggesting that it contributes to asexual reproduction and thus the spread of the disease. Double-stranded RNA (dsRNA) mediates gene silencing, a post-transcriptional and highly conserved process in eukaryotes, involving specific gene silencing through degradation of target mRNA. We combined in vitro dsRNA synthesis and a polyethylene glycol-mediated transformation system to construct a dsRNA-mediated transient gene silencing system; and then performed a functional analysis of PsCdc14 in P. sojae. PsCdc14 mRNA was dramatically reduced in transformants after protoplasts were exposed in in vitro synthesized PsCdc14 dsRNA, resulting in low sporangial production and abnormal development in P. sojae silencing lines. Furthermore, dsRNA-mediated transient gene silencing could enable elucidation of P. sojae rapid gene function, facilitating our understanding of the development and pathogenicity mechanisms of this oomycete fungus.


Prenatal LPS increases inflammation in the substantia nigra of Gdnf heterozygous mice.
Prenatal systemic inflammation has been implicated in neurological diseases, but optimal animal models have not been developed. We investigated whether a partial genetic deletion of glial cell line-derived neurotrophic factor (Gdnf(+/-)) increased vulnerability of dopamine (DA) neurons to prenatal lipopolysaccharide (LPS). LPS [0.01 mg/kg intraperitoneal (i.p.)] or saline was administered to wild-type (WT) or Gdnf(+/-) pregnant mice on gestational day 9.5. Male offspring were examined at 3 weeks, 3 and 12 months of age. There was a progressive degeneration of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) with age in Gdnf(+/-) but not in WT mice, with no observed effects on locus coeruleus (LC) noradrenergic neurons or DA neurons of the ventral tegmental area. Inflammatory markers were elevated in SN of LPS treated offspring, with exacerbation in Gdnf(+/-) mice. Intracellular accumulation of α-synuclein (α-syn) immunoreactivity in DA neurons of SN was observed in all groups of Gdnf(+/-) and in WT mice with prenatal LPS, with altered distribution between pars reticulata (pr) and pars compacta (pc). The findings suggest that prenatal LPS leads to accelerated neuropathology in the SN with age, and that a partial loss of GDNF exacerbates these effects, providing a novel model for age-related neuropathology of the nigrostriatal DA system.


Engineering Macrophages for Cancer Immunotherapy and Drug Delivery.
Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while anti-inflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are elaborated. Overall, there is still significant room for development in macrophage-mediated immune modulation and macrophage-mediated drug delivery, which will further enhance current tumor therapies against various malignant solid tumors, including drug-resistant tumors and metastatic tumors.


Treatment of Budd-Chiari syndrome due to inferior vena cava occlusion by combined portal and vena caval decompression.
This study concerns Budd-Chiari syndrome (BCS) caused by occlusion of the subdiaphragmatic inferior vena cava (IVC). It describes the experimental and clinical evaluation of the treatment of this disorder by one-stage combined portal and vena caval decompression with a direct side-to-side portacaval shunt (PCS) and a caval-atrial shunt (CAS) graft. BCS was produced in rats by gradual occlusion of the suprahepatic IVC with an ameroid constrictor. When ascites and portal hypertension were established, 12 control rats survived a sham thoracolaparotomy, 16 rats survived a mesoatrial shunt, and 16 rats survived combined PCS and CAS graft. All control rats re-formed ascites and died within 2 months. Nine of 16 rats with mesoatrial shunt developed graft thrombosis, re-formed ascites, and died within 2 months. In contrast, only 2 of 16 rats that underwent combined PCS and CAS developed graft thrombosis, re-formed ascites, and died. Liver biopsies showed reversal of severe pathologic changes in rats with patent grafts. Clinical evaluation of combined PCS and CAS using a 20-mm ring-reinforced Gore-Tex graft has been undertaken in five patients with BCS and ascites, hepatosplenomegaly, intense hepatic congestion on biopsy, and angiography showing occlusion of both the IVC and hepatic veins. All five patients are alive and well 6 months to 7.5 years postoperatively with patent grafts, no ascites or need for diuretics, no encephalopathy, normal liver function, and reversal of liver pathology. It is concluded that combined PCS and CAS create a high-flow shunt that decompresses both the portal system and IVC, has a low incidence of graft thrombosis, has been consistently effective in relieving BCS caused by IVC occlusion, and appears to be superior to mesoatrial shunt.


[Barrett's esophagus: its diagnosis and management in Japan].
The incidence of adenocarcinoma derived from Barrett's esophagus has been steadily increasing during the past some decades in Western countries. The development of better diagnostic and therapeutic strategies for Barrett's esophagus and Barrett's adenocarcinoma have become an important objective. In Japan, Barrett's adenocarcinoma has been gradually increasing as the results of a high incidence of reflux esophagitis, a decreasing of Helicobacter pylori infection and an increasing of obesity, etc. Subsequently, in recent, the management of Barrett's esophagus has come to be of interest as well as in the Western countries. Many issues found in the pathophysiology and epidemiology of Barrett's esophagus in Japanese patients are required to be clarified and the Japanese maneuvers regarding the diagnostic procedure and clinical management including the surveillance for patients with Barrett's esophagus should be established as soon as possible.


Oral contraceptives in women with diabetes.
We evaluated the association of oral contraceptive use with the presence and severity of diabetic retinopathy, hypertension, and glycosylated hemoglobin in women of childbearing age who have diabetes. Neither current or past use nor number of years of use of oral contraceptives was associated with severity of retinopathy, hypertension, or current glycosylated hemoglobin. In conclusion, further study of various birth control methods in young women of childbearing age should be considered.


Attentional resources in hypnotic responding.
Theories of hypnotic responding differ regarding attentional processes. Predictions derived from neodissociation, dissociation control, response set, and ironic process theory were tested by administering suggestions with and without cognitive load to high suggestible participants and low suggestible simulators. Cognitive load interfered with responses to ideomotor and cognitive suggestions but not with responses to challenge suggestions. The effect of cognitive load on suggested amnesia depended on the assessment of that response. Although cognitive load decreased recall on the amnesia trial, it did so even more on recall trials before the amnesia suggestion was given and after it was canceled. These data indicate that attentional effort is required for both recall and memory suppression. Under conditions of low cognitive load, simulators displayed less recall than did nonsimulating participants during suggested amnesia, and they reported smaller subjective responses to ideomotor and challenge suggestions.


Review: On Segmentation of Nodules from Posterior and Anterior Chest Radiographs.
Lung cancer is one of the major types of cancer in the world. Survival rate can be increased if the disease can be identified early. Posterior and anterior chest radiography and computerized tomography scans are the most used diagnosis techniques for detecting tumor from lungs. Posterior and anterior chest radiography requires less radiation dose and is available in most of the diagnostic centers and it costs less compared to the remaining diagnosis techniques. So PA chest radiography became the most commonly used technique for lung cancer detection. Because of superimposed anatomical structures present in the image, sometimes radiologists cannot find abnormalities from the image. To help radiologists in diagnosing tumor from PA chest radiographic images range of CAD scheme has been developed for the past three decades. These computerized tools may be used by radiologists as a second opinion in detecting tumor. Literature survey on detecting tumors from chest graphs is presented in this paper.


Online Gain Adaptation of Whole-Body Control for Legged Robots with Unknown Disturbances.
This paper proposes an online gain adaptation approach to enhance the robustness of whole-body control (WBC) framework for legged robots under unknown external force disturbances. Without properly accounting for external forces, the closed-loop control system incorporating WBC may become unstable, and therefore the desired task goals may not be achievable. To study the effects of external disturbances, we analyze the behavior of our current WBC framework via the use of both full-body and centroidal dynamics. In turn, we propose a way to adapt feedback gains for stabilizing the controlled system automatically. Based on model approximations and stability theory, we propose three conditions to ensure that the adjusted gains are suitable for stabilizing a robot under WBC. The proposed approach has four contributions. We make it possible to estimate the unknown disturbances without force/torque sensors. We then compute adaptive gains based on theoretic stability analysis incorporating the unknown forces at the joint actuation level. We demonstrate that the proposed method reduces task tracking errors under the effect of external forces on the robot. In addition, the proposed method is easy-to-use without further modifications of the controllers and task specifications. The resulting gain adaptation process is able to run in real-time. Finally, we verify the effectiveness of our method both in simulations and experiments using the bipedal robot Draco2 and the humanoid robot Valkyrie.


Accuracy of shock index versus ABC score to predict need for massive transfusion in trauma patients.
Various scoring systems have been developed to predict need for massive transfusion in traumatically injured patients. Assessments of Blood Consumption (ABC) score and Shock Index (SI) have been shown to be reliable predictors for Massive Transfusion Protocol (MTP) activation. However, no study has directly compared these two scoring systems to determine which is a better predictor for MTP activation. The primary objective was to determine whether ABC or SI better predicted the need for MTP in adult trauma patients with severe hemorrhage. This was a retrospective cohort study which included all injured patients who were trauma activations between January 1, 2009 and December 31, 2013 at an urban Level I trauma center. Patients <18 years old or with traumatic brain injury (TBI) were excluded. ABC and SI were calculated for each patient. MTP was defined as need for >10 units PRBC transfusion within 24h of emergency department arrival. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) were used to evaluate scoring systems' ability to predict effective MTP utilization. A total of 645 patients had complete data for analysis. Shock Index ≥1 had sensitivity of 67.7% (95% CI 49.5%-82.6%) and specificity of 81.3% (95% CI 78.0%-84.3%) for predicting MTP, and ABC score ≥2 had sensitivity of 47.0% (95% CI 29.8%-64.9%) and specificity of 89.8% (95% CI 87.2%-92.1%). AUROC analyses showed SI to be the strongest predictor followed by ABC score with AUROC values of 0.83 and 0.74, respectively. SI had a significantly greater sensitivity (P=0.035), but a significantly weaker specificity (P<0.001) compared to ABC score. ABC score and Shock Index can both be used to predict need for massive transfusion in trauma patients, however SI is more sensitive and requires less technical skill than ABC score.


Characterization of the human plasmalemmal carnitine transporter in cultured skin fibroblasts.
Carnitine is an essential cofactor for long-chain fatty acid oxidation. We characterized the human carnitine transporter in vitro in a cultured skin fibroblast model both at the previously established Km concentration of carnitine uptake in fibroblasts (5 mumol/liter) and at 0.05% Km (0.25 mumol/liter). A rapid exponential dose-dependent decrease in mean percentage of carnitine uptake was demonstrated with increasing concentrations of nigericin, but no significant decrease was found with equimolar amounts of valinomycin. This would suggest that the Na+ gradient is integral to carnitine transport function. Interference of the Na+ (out-in) gradient by nigericin may be secondary to cytoplasmic acidification by this K+ proton ionophore. The rate of uptake was fully saturated at an extracellular Na+ concentration of 150 mmol/liter. Replacement of 150 mmol/liter extracellular Na+ with Li+ resulted in an 80 and a 50% reduction, and replacement with K+ and Rb+ ions resulted in a 100 and an 85 to 90% reduction in carnitine uptake, respectively, at carnitine concentrations of 0.25 and 5 mumol/liter, underlining the specific requirement for the Na+ ion. The effects of different site-specific respiratory chain toxins, namely, rotenone (complex I), antimycin A (complex III), and potassium cyanide (KCN) (complex IV) on carnitine uptake was also examined. A rapid exponential dose-dependent decrease in mean percentage of carnitine uptake with increasing concentrations of inhibitors was demonstrated. These data suggest either a metabolic energy requirement of the carnitine transporter or interference of the Na+ (out-in) gradient by a proton gradient (in-out) secondary to the accumulation of intracellular H+ ions, due to the action of the respiratory chain toxins, further suggesting that the transporter is sensitive to and inhibited by intracellular H+ ions. The effects of several sulfhydryl-binding agents, namely 2,4-dinitrofluorobenzene, N-ethylmaleimide, and mersalyl acid, were examined, and a significant inhibition of carnitine uptake was demonstrated, suggesting that free sulfhydryl groups are also integral to the import function of the human fibroblast transporter.


Dose-response relationship of perineural dexamethasone for interscalene brachial plexus block: a randomised, controlled, triple-blind trial.
Perineural dexamethasone has a ceiling dose of 4 mg for prolongation of analgesia duration after injection of long-acting local anaesthetic for peripheral nerve block, but evidence for doses < 4 mg is lacking. This randomised controlled triple-blind trial tested the hypothesis that increasing doses of perineural dexamethasone between 1 mg and 4 mg would prolong the duration of analgesia in a dose-dependent manner. Eighty ASA physical status 1-2 patients scheduled for shoulder arthroscopy under general anaesthesia with ultrasound-guided interscalene brachial plexus block were randomly allocated to receive saline (control), dexamethasone 1 mg, 2 mg, 3 mg and 4 mg, together with 20 ml ropivacaine 0.5%. Postoperative analgesia consisted of paracetamol, diclofenac and oxycodone on request, using a pre-defined protocol. The primary outcome was the duration of analgesia, defined as the time between the block procedure and the first analgesic request. Secondary outcomes included rest and dynamic pain scores, and analgesic consumption at 2 h, 24 h and 48 h postoperatively. An analysis of the dose-response relationship was performed using multiple comparison procedure-modelling. The median (IQR [range]) duration of analgesia was significantly prolonged in a dose-dependent manner: control 685 (590-860 [453-1272]) min; 1 mg 835 (740-1110 [450-1375]) min; 2 mg 904 (710-1130 [525-1365]) min; 3 mg 965 (875-1025 [730-1390]) min; 4 mg 1023 (838-1239 [518-1500]) min (p = 0.03). There were no significant differences between the secondary outcomes. Perineural administration of dexamethasone with doses between 1 mg and 4 mg, combined with ropivacaine for interscalene brachial plexus block, prolongs duration of analgesia in a dose-dependent manner.


Fibromyalgia: Associations Between Fat Infiltration, Physical Capacity, and Clinical Variables.
Obesity is a risk factor for the development of fibromyalgia (FM) and generally most studies report increased Body Mass Index (BMI) in FM. Obesity in FM is associated with a worse clinical presentation. FM patients have low physical conditioning and obesity further exacerbates these aspects. Hitherto studies of FM have focused upon a surrogate for overall measure of fat content, ie, BMI. This study is motivated by that ectopic fat and adipose tissues are rarely investigated in FM including their relationships to physical capacity variables. Moreover, their relationships to clinical variables including are not known. Aims were to 1) compare body composition between FM and healthy controls and 2) investigate if significant associations exist between body composition and physical capacity aspects and important clinical variables. FM patients (n = 32) and healthy controls (CON; n = 30) underwent a clinical examination that included pressure pain thresholds and physical tests. They completed a health questionnaire and participated in whole-body magnetic resonance imaging (MRI) to determine body composition aspects. Abdominal adipose tissues, muscle fat, and BMI were significantly higher in FM, whereas muscle volumes of quadriceps were smaller. Physical capacity variables correlated negatively with body composition variables in FM. Both body composition and physical capacity variables were significant regressors of group belonging; the physical capacity variables alone showed stronger relationships with group membership. A mix of body composition variables and physical capacity variables were significant regressors of pain intensity and impact in FM. Body composition variables were the strongest regressors of blood pressures, which were increased in FM. Obesity has a negative influence on FM symptomatology and increases the risk for other serious conditions. Hence, obesity, dietary habits, and physical activity should be considered when developing clinical management plans for patients with FM.


Plasma ferritin concentration in relation to vitamin A and E status of children with severe oedematous malnutrition.
The association between plasma ferritin concentration and vitamin A and E status was studied in 17 children aged 15-72 months with severe oedematous malnutrition. The controls were 10 children of similar age who were apparently well and with no obvious signs of clinical malnutrition. Plasma ferritin concentration in the patients was significantly higher than that in the control children. Conversely, the plasma concentrations of beta-carotene, alpha-tocopherol and retinol in patients were significantly lower than those in plasma of control children. The median (interquartile range) plasma alpha-tocopherol concentration of patients, 6.03 (5.29-9.50) mumol/l, is below the threshold of vitamin E deficiency (11.6 mumol/l). Fifteen of 17 (88%) malnourished patients were found to have plasma tocopherol concentrations below the normal threshold. However, all the patients had a tocopherol: cholesterol ratio greater than 2.22, indicating adequate vitamin E status for the level of cholesterol present in plasma. Twelve of 17 patients (70.5%) had plasma retinol concentration less than 0.70 mumol/l, indicative of marginal vitamin A status, while 3 patients had plasma retinol concentrations less than 0.35 mumol/l, indicating vitamin A deficiency. The median (interquartile range) plasma retinol concentration of patients, 0.51 (0.41-0.93) mumol/l, is significantly less than that of control children, 0.96 (0.74-1.09) mumol/l; p less than 0.01 Mann Whitney U test. Furthermore, anaemia (Hb less than 110 g/l) was widespread in the patients. The results also indicate no significant correlation between elevated ferritin concentration and the concentrations of beta-carotene, retinol and alpha-tocopherol in the patients' plasma.(ABSTRACT TRUNCATED AT 250 WORDS)


Esketamine increases neurotransmitter releases but simplifies neurotransmitter networks in mouse prefrontal cortex.
General anesthesia induces a profound but reversible unconscious state, which is accompanied by changes in various neurotransmitters in the cortex. Unlike the "brain silencing" effect of γ-aminobutyric acid (GABA) receptor potentiator anesthesia, ketamine anesthesia leads the brain to a paradoxical active state with higher cortical activity, which is manifested as dissociative anesthesia. However, how the overall neurotransmitter network evolves across conscious states after ketamine administration remains unclear. Using in vivo microdialysis, high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, and electroencephalogram (EEG) recording technique, we continuously measured the concentrations of six neurotransmitters and the EEG signals during anesthesia with esketamine, an S-enantiomer of ketamine racemate. We found that there was an increase in the release of five cortical neurotransmitters after the administration of esketamine. The correlation of cortical neurotransmitters was dynamically simplified along with behavioral changes until full recovery after anesthesia. The esketamine-increased gamma oscillation power was positively correlated only with the concentration of 5-hydroxytryptamine (5-HT) in the medial prefrontal cortex. This study suggests that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.NEW & NOTEWORTHY In this study, we found that esketamine significantly increased the cortical concentration of multiple neurotransmitters in mice. However, esketamine dynamically simplified the overall network of cortical neurotransmitters at different behavioral states during the perianesthesia period. The concentration of 5-HT in the medial prefrontal cortex (mPFC) was highly correlated with the esketamine-increased gamma oscillation. These findings suggested that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.


The hydration of the scandium(III) ion in aqueous solution and crystalline hydrates studied by XAFS spectroscopy, large-angle X-ray scattering and crystallography.
The structures of the hydrated scandium(III) ion and of the hydrated dimeric hydrolysis complex, [Sc2(mu-OH)2]4+, in acidic aqueous solutions have been characterized by X-ray absorption fine structure (XAFS) and large-angle X-ray scattering (LAXS) methods. Comparisons with crystalline reference compounds containing hydrated scandium(III) ions in well characterized six-, seven- and eight-coordinated polyhedra have been used to evaluate the coordination numbers and configurations in aqueous solution. In strongly acidic aqueous solution the structure of the hydrated scandium(III) ion is found to be similar to that of the eight-coordinated scandium(III) ion with distorted bicapped trigonal prismatic coordinating geometry in the crystalline [Sc(H2O)(8.0)](CF3SO3)3 compound. The EXAFS data reveal for the solution, as for the solid, a mean Sc-O bond distance of 2.17(1) Angstrom to six strongly bound prism water molecules, 2.32(4) Angstrom to one capping position, with possibly another capping position at about 2.5 Angstrom. The LAXS study supports this structural model and shows furthermore a second hydration sphere with approximately 12 water molecules at a mean Sc...O(II) distance of 4.27(3) Angstrom. In less acidic concentrated scandium(III) aqueous solutions, the dimeric hydrolysis product, [Sc2(mu-OH)2(H2O)10]4+, is the predominating species with seven-coordinated scandium(III) ions in a double hydroxo bridge and five terminal water molecules at a mean Sc-O bond distance of 2.145 Angstrom. Hexahydrated scandium(III) ions are found in the crystal structure of the double salt [Sc(H2O)6][Sc(CH3SO3)6], which crystallizes in the trigonal space group R3[combining macron] with Z = 6 and the unit cell dimensions a = 14.019(2) and c = 25.3805(5) Angstrom. The Sc-O distances in the two crystallographically unique, but nearly identical, [Sc(H2O)6]3+ entities (both with 3[combining macron] imposed crystallographic symmetry) are 2.085(6) and 2.086(5) Angstrom, while the mean Sc-O distance in the near octahedral [Sc(OSO2CH3)6]3- entities (with three-fold symmetry) is 2.078 Angstrom.


Oligomers: Hidden sources of bisphenol A from reusable food contact materials.
A recent European Regulation further restricted the use of bisphenol A in food-contact materials, reducing its limit of migration. However, all analytical systems of control are aimed at identifying and quantifying the molecules of this monomer without taking in consideration the possible presence of its oligomers, species originating from material degradation and able to follow an in-vivo hydrolysis providing bisphenol A generation. Thus, the presence of oligomers of polycarbonate deriving by unreacted species or polymer degradation can be considered a hidden source of several bisphenol A units, that remains outside the control of legislation and should be considered of high concern. This work was focused on the identification and the description of kinetics of release of different molecules migrating from polycarbonate food contact materials to simulants and to a model food sample such as melted chocolate. Analyses were performed by UHPLC system coupled to a Q-Exactive mass spectrometer. Targeted and untargeted analysis through data dependent acquisition mode allowed to detect the occurrence of several species deriving from polycarbonate, and permitted to investigate the polymer degradation pattern and explore the correlation of the recorded amounts of each product with age, hours of usage, and washing cycles of the plastic items.


Probing arrays of circular magnetic microdots by ferromagnetic resonance.
X-band ferromagnetic resonance (FMR) was used to characterize in-plane magnetic anisotropies in rectangular and square arrays of circular nickel and Permalloy microdots. In the case of a rectangular lattice, as interdot distances in one direction decrease, the in-plane uniaxial anisotropy field increases, in good agreement with a simple theory of magnetostatically interacting uniformly magnetized dots. In the case of a square lattice a four-fold anisotropy of the in-plane FMR field H(r) was found when the interdot distance a gets comparable to the dot diameter D. This anisotropy, not expected in the case of uniformly magnetized dots, was explained by a non-uniform magnetization m(r) in a dot in response to dipolar forces in the patterned magnetic structure. It is well described by an iterative solution of a continuous variation procedure. In the case of perpendicular magnetization multiple sharp resonance peaks were observed below the main FMR peak in all the samples, and the relative positions of these peaks were independent of the interdot separations. Quantitative description of the observed multiresonance FMR spectra was given using the dipole-exchange spin wave dispersion equation for a perpendicularly magnetized film where in-plane wave vector is quantized due to the finite dot radius, and the inhomogenetiy of the intradot static demagnetization field in the nonellipsoidal dot is taken into account. It was demonstrated that ferromagnetic resonance force microscopy (FMRFM) can be used to determine both local and global properties of patterned submicron ferromagnetic samples. Local spectroscopy together with the possibility to vary the tip-sample spacing enables the separation of those two contributions to a FMRFM spectrum. The global FMR properties of circular submicron dots determined using magnetic resonance force microscopy are in a good agreement with results obtained using conventional FMR and with theoretical descriptions.


Effects of taurine supplementation on bone mineral density in ovariectomized rats fed calcium deficient diet.
Taurine supplementation has been shown to have a beneficial effect on femur bone mineral content in ovariectomized rats. It therefore seemed desirable to find out whether the beneficial effect of taurine on ovariectomized rats fed calcium deficient diet could also be reproduced. Forty female Sprague-Dawley rats were divided into two groups. One group was OVX and the other group received sham operation (SHAM), and received either control diet or a taurine supplemented diet for 6 weeks. All rats were fed on calcium deficient diet (AIN-93: 50% level of calcium) and deionized water. Bone mineral density (BMD) and bone mineral content (BMC) were measured in spine and femur. The serum and urine concentrations of calcium and phosphorus were determined. Bone formation was measured by serum osteocalcin and alkaline phosphatase (ALP) concentrations. Bone resorption rate was measured by deoxypyridinoline (DPD) crosslinks immunoassay and corrected for creatinine. Urinary calcium and phosphorus excretion, osteocalcin in blood and cross link value were not significantly different among the groups. Within the OVX group, the taurine supplemented group had not higher femur bone mineral content than the control group. This study established the need for a study on the taurine effect on bone with different calcium levels.


A dynamic model of regional population growth and decline.
"This paper presents a two-sector dynamic model of regional population change. The model contains a migration equation, an earnings equation, and an amenity equation for each region. In the context of this model, migration is seen as a disequilibrium process through which the regional populations move towards equilibrium positions. Migration occurs when one region is perceived to be superior to the other on the basis of its earnings and amenity levels. Equilibrium is achieved when population movements between the regions eliminate any differences in their relative attractiveness. A comparative-static analysis of the model is presented to analyze the effects of policy changes and exogenous shocks on the distribution of population among the regions." The geographical focus is on the United States.


The World Health report 1996--fighting disease, fostering development.
This self-contained, concise and analytical publication is the second in a new series of annual reports. It provides an annual assessment of world health status and needs, and recommends relevant priorities for international health action to meet those needs, as well as reporting on WHO's contribution towards improving the world health situation. The world health report 1996 focuses on infectious diseases and gives an overview of WHO's work during 1995 (1).


Effect of Steam Injection during Carbonation on the Multicyclic Performance of Limestone (CaCO3) under Different Calcium Looping Conditions: A Comparative Study.
This study explores the effect of steam addition during carbonation on the multicyclic performance of limestone under calcium looping conditions compatible with (i) CO2 capture from postcombustion gases (CCS) and with (ii) thermochemical energy storage (TCES). Steam injection has been proposed to improve the CO2 uptake capacity of CaO-based sorbents when the calcination and carbonation loops are carried out in CCS conditions: at moderate carbonation temperatures (∼650 °C) under low CO2 concentration (typically ∼15% at atmospheric pressure). However, the recent proposal of calcium-looping as a TCES system for integration into concentrated solar power (CSP) plants has aroused interest in higher carbonation temperatures (∼800-850 °C) in pure CO2. Here, we show that steam benefits the multicyclic behavior in the milder conditions required for CCS. However, at the more aggressive conditions required in TCES, steam essentially has a neutral net effect as the CO2 uptake promoted by the reduced CO2 partial pressure but also is offset by the substantial steam-promoted mineralization in the high temperature range. Finally, we also demonstrate that the carbonation rate depends exclusively on the partial pressure of CO2, regardless of the diluting gas employed.


Mediation analysis for count and zero-inflated count data without sequential ignorability and its application in dental studies.
Mediation analysis seeks to understand the mechanism by which a treatment affects an outcome. Count or zero-inflated count outcomes are common in many studies in which mediation analysis is of interest. For example, in dental studies, outcomes such as the number of decayed, missing and filled teeth are typically zero inflated. Existing mediation analysis approaches for count data often assume sequential ignorability of the mediator. This is often not plausible because the mediator is not randomized so unmeasured confounders are associated with the mediator and the outcome. We develop causal methods based on instrumental variable approaches for mediation analysis for count data possibly with many 0s that do not require the assumption of sequential ignorability. We first define the direct and indirect effect ratios for those data, and then we propose estimating equations and use empirical likelihood to estimate the direct and indirect effects consistently. A sensitivity analysis is proposed for violations of the instrumental variables exclusion restriction assumption. Simulation studies demonstrate that our method works well for different types of outcome under various settings. Our method is applied to a randomized dental caries prevention trial and a study of the effect of a massive flood in Bangladesh on children's diarrhoea.


A hypothesis: is diverticulitis a type of inflammatory bowel disease?
It is accepted by epidemiologists that diverticula formation in the colon is related to a deficiency in dietary fiber intake, but the cause of acute diverticulitis remains unknown. A hypothesis is presented that acknowledges from the literature that fiber deficiency is also related to an altered intestinal microecology with a change in the bacterial flora. It is hypothesized that the change in the flora with a decrease in their influence on the immune process permits a low-grade chronic inflammation in the mucosa, which is the first step in developing an acute infection of diverticula or diverticulitis. There is some evidence that the low-grade chronic inflammation is present in subjects with diverticula, which is the forerunner of acute diverticulitis. This hypothesis is strengthened by early reports that anti-inflammatory mucosal agents such as mesalamine and immune process regulators such as probiotics may improve diverticulitis.


Evidence for digenic inheritance in a family with both febrile convulsions and temporal lobe epilepsy implicating chromosomes 18qter and 1q25-q31.
We report a clinical and genetic study of a French family among whom febrile convulsions (FC) are associated with subsequent temporal lobe epilepsy (TLE) in the same individual, without magnetic resonance imaging-identifiable hippocampal abnormalities. Linkage analyses excluded the loci FEB1 and FEB2, previously implicated in FC; the GEFS+1 locus responsible for generalized epilepsy with febrile seizures plus; and the locus implicated in lateral temporal lobe epilepsy. After scanning the entire genome, significant lod scores (>3) for markers on 18qter and suggestive lod scores (>2) for markers on 1q25-q31 were obtained. An analysis of the haplotypes at these two loci supported the hypothesis that two genes segregated with the phenotype. All patients shared common haplotypes for both 1q25-q31 and 18qter chromosomes. All but one unaffected at-risk individuals carried only one, or none, of the disease haplotypes. Under the assumption of digenic inheritance, haplotype reconstruction defined a 26 cM interval on chromosome 1 and a 10 cM interval on chromosome 18. This family suggests that the association between FC and TLE may be observed in the absence of hippocampal structural abnormalities and that they may have, in some cases, a common genetic basis.


Aneurysm-express: human abdominal aortic aneurysm wall expression in relation to heterogeneity and vascular events - rationale and design.
Elective repair of abdominal aortic aneurysms (AAA) is associated with significant morbidity and mortality. Large amounts of AAA tissue are necessary to assess heterogeneity among AAA and to correct for potential confounders such as known risk factors. The Aneurysm-express study aims to identify different types of AAA using inflammatory markers in the aneurysm wall that predict postoperative cardiovascular adverse events and mortality, therefore allowing individual risk assessment. The Aneurysm-express is an ongoing prospective cohort study including AAA patients undergoing open repair. At baseline, blood is drawn, relevant clinical data are collected and the standard diagnostic modalities are performed. During surgery a specimen of the ventral AAA wall is collected and processed to study protein expressions and histology. INTERIM RESULTS: The study commenced in 2003 in 2 medical centers and currently holds information and material of >300 AAA patients, making it the largest reported aneurysm biobank. Patients are followed for 3 years after surgery for occurring cardiovascular events. The current mean follow-up is 2.1 ± 1.3 years with an event rate of 27%. The large amount of structurally stored tissue and blood combined with clinical characteristics and follow-up provide an excellent soil for indepth pathophysiological analyses, with assessment of AAA heterogeneity in combination with postoperative clinical outcome.


Docking and molecular dynamics studies of the binding between Peloruside A and tubulin.
The molecular docking, MD simulation and binding free energy calculation were performed to explore the probable binding modes between PLA and tubulin. Through docking study, three possible binding sites for PLA were speculated as follows: the taxane site, the alternative site and a new site in α-tubulin. Then, 12.0 ns MD simulations show that these binding modes predicted by docking have been changed more or less, whereas the MD simulations offer more reliable binding details. The MM-PBSA binding free-energy calculations reasonably identify that the taxane site is the most favorable binding site of PLA and the alternative site is the secondary one, which can be used to explain some experimental facts. These studies theoretically resolve the priority of binding sites for PLA and offer the reliable binding modes between PLA and tubulin, and thus help to understanding the action mechanism for this kind of inhibitor.


Improved detection of in situ hybridization by laser scanning confocal microscopy.
Laser scanning confocal microscopy (LSCM) offers a significant improvement over conventional bright-field and dark-field light microscopy for producing images of silver grains in autoradiograms of specimens prepared by in situ hybridization. The out-of-focus image of the background silver grains present in the emulsion is eliminated from the in-focus image of the radioactive probe associated with the cells by optical sectioning with the LSCM operated in a reflected light mode. The improved images produced by the LSCM provide a significant increase in the sensitivity of detecting positively labeled cells and tissues prepared by in situ hybridization. The power of this detection method is demonstrated using samples of HIV-infected human peripheral blood cells, tissue sections of human placenta and human skin. It is anticipated that the method can be universally applied to samples prepared by in situ hybridization techniques.


Value of NT-ProBNP level and echocardiographic parameters in ST-segment elevation myocardial infarction treated by primary angioplasty: relationships between these variables and their usefulness as predictors of ventricular remodeling.
To assess the value of N-terminal fragment of brain natriuretic peptide (NT-proBNP) measurement and echocardiography for predicting ventricular remodeling after myocardial infarction and to investigate relationships between the NT-proBNP level and echocardiographic parameters at discharge and in the medium term. The study involved 159 patients with myocardial infarction treated by primary coronary angioplasty. The NT-proBNP level was measured on admission, at discharge and after 6 months. Echocardiography was performed at discharge and after 6 months. Overall, 31 patients (19.5%) demonstrated remodeling. At discharge, the variables associated with remodeling were: mitral inflow E-wave-to-A-wave velocity ratio (E/A), systolic mitral annulus velocity (Sm), early diastolic mitral annulus velocity (Em), the mitral inflow E wave to early diastolic mitral annulus velocity ratio (E/ Em), left atrial volume (LAV), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and discharge NT-proBNP level. Only E/Em was an independent predictor of ventricular remodeling (odds ratio [OR]=1.143; 95% confidence interval [CI], 1.039-1.258; P=.006). At discharge, correlations were observed between the NT-proBNP level and LVEDV, LVESV, ejection fraction (EF) and E/Em. At 6 months, correlations with ventricular volumes and EF were unchanged, the correlation with E/Em was better (r=0.47 vs. r=0.69), and a modest correlation with LAV developed (r=0.43; P=.001). The E/Em ratio was the best echocardiographic predictor of left ventricular remodeling after myocardial infarction. The NT-proBNP level had no additional predictive value over echocardiography. Correlations between the NT-proBNP level and ventricular volumes and EF at discharge and 6 months were similar, while correlations with E/Em and LAV were better at 6 months.


Unique temporal change is the key to attentional capture.
Attentional capture refers to the observation that some events break through and attract one's attention even when one is engaged in a task for which these events are irrelevant. Previous research, focusing primarily on spatial factors, has shown that a new object is more salient in this regard than an abrupt change in an object's features. Here we show that feature changes can be as effective as new objects in capturing attention, provided that they occur during a period of temporal calm. Conversely, both feature changes and new objects are far less effective in capturing attention when they occur simultaneously with other display changes, such as coincident with the initial onset of the display or with small visual transients that occur during a display transition. These results highlight the importance of considering both space and time in studies of attentional capture; the most effective stimulus is unique in both dimensions.


Up-regulation of TGF-β via the activation of extracellular signal-regulated kinase 1 and 2 induced by prorenin in human renal mesangial cells.
Prorenin is thought to be an inactive precursor of renin. This study investigated whether human prorenin was capable of activating the (pro)renin receptors [(P)RRs], leading to the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cultured human renal mesangial cells (HRMCs). HRMCs cultured in vitro were pretreated with an AT1 and AT2 blocker prior to stimulation by prorenin, PD98059 (an inhibitor of ERK1/2) and handle-region peptide (HRP). Phosphorylated ERK1/2 was evaluated using Western blot analysis, and the concentration of TGF-β was measured by ELISA. The mRNA of TGF-β was evaluated by RT-PCR. It was found that prorenin activated the (P)RR in cultured HRMCs, which in turn increased p-ERK1/2. Prorenin induced rapid phosphorylation of ERK1/2 and increased p-ERK1/2 in a time- and dose-dependent manner. The protein levels of TGF-β increased significantly with the stimulation of prorenin. PD98059 significantly decreased p-ERK1/2 and then downregulated TGF-β. HRP did not inhibit either ERK1/2 phosphorylation or the increase in TGF-β. ERK1/2 phosphorylation induced by prorenin led to a marked increase in TGF-β. The regulation of TGF-β was highly dependent on ERK1/2. Thus, ERK1/2 may play a key role in the development of kidney disease. HRP neither affects the ERK1/2 signaling nor the level of TGF-β in HRMCs.


Glycogen synthase kinase-3 in the etiology and treatment of mood disorders.
The mood disorders major depressive disorder and bipolar disorder are prevalent, are inadequately treated, and little is known about their etiologies. A better understanding of the causes of mood disorders would benefit from improved animal models of mood disorders, which now rely on behavioral measurements. This review considers the limitations in relating measures of rodent behaviors to mood disorders, and the evidence from behavioral assessments indicating that glycogen synthase kinase-3 (GSK3) dysregulation promotes mood disorders and is a potential target for treating mood disorders. The classical mood stabilizer lithium was identified by studying animal behaviors and later was discovered to be an inhibitor of GSK3. Several mood-relevant behavioral effects of lithium in rodents have been identified, and most have now been shown to be due to its inhibition of GSK3. An extensive variety of pharmacological and molecular approaches for manipulating GSK3 are discussed, the results of which strongly support the proposal that inhibition of GSK3 reduces both depression-like and manic-like behaviors. Studies in human postmortem brain and peripheral cells also have identified correlations between alterations in GSK3 and mood disorders. Evidence is reviewed that depression may be associated with impaired inhibitory control of GSK3, and mania by hyper-stimulation of GSK3. Taken together, these studies provide substantial support for the hypothesis that inhibition of GSK3 activity is therapeutic for mood disorders. Future research should identify the causes of dysregulated GSK3 in mood disorders and the actions of GSK3 that contribute to these diseases.


Fluoroscopically Guided Facet Cyst Rupture: Rate of Conversion to Surgery and Risk Factor Analysis.
Retrospective case series at a single academic medical center. The aim was to determine if specific clinical, radiologic, and procedural factors are associated with conversion to surgery after fluoroscopically guided cyst rupture. Percutaneous fluoroscopic rupture of facet cysts can often be the definitive treatment; however, it is unknown before the procedure who will ultimately proceed to formal surgical decompression. Differences in clinical, radiographic, and procedural factors of facet cysts may relate to the difference in efficacy of fluoroscopically guided cyst rupture. A continuous cohort of 45 patients who underwent fluoroscopically guided cyst rupture was evaluated. The primary outcome measured rate of conversion to surgery and of those that underwent surgery, the rate of decompression and fusion compared with fusion alone was noted. Secondary outcomes included analysis of clinical, radiologic, and procedural variables to determine if there were risk factors associated with conversion to surgery. Twenty-nine percent of patients eventually underwent a surgical procedure with an average interval to surgery of 95 days after attempted rupture. Thirty-eight percent of patients that underwent surgery had a decompression and fusion. Failure of percutaneous cyst rupture trended toward significance for a future surgical decompression (P=0.08). Percutaneous facet cyst rupture is potentially a definitive treatment for this condition; however, it is unknown ahead of time who will proceed to definitive surgical decompression. On the basis of the data in this study, less than one-third of patients who had a fluoroscopically guided facet cyst rupture went on to surgery. There were no clinical, radiographic, or procedural details which could be used to robustly predict failure of percutaneous treatment. At this time, it is recommended to continue to attempt this nonoperative treatment intervention when there is a clinical indication after discussion of the risks and benefits with the patient.


Primate malarias as a model for cross-species parasite transmission.
Parasites regularly switch into new host species, representing a disease burden and conservation risk to the hosts. The distribution of these parasites also gives insight into characteristics of ecological networks and genetic mechanisms of host-parasite interactions. Some parasites are shared across many species, whereas others tend to be restricted to hosts from a single species. Understanding the mechanisms producing this distribution of host specificity can enable more effective interventions and potentially identify genetic targets for vaccines or therapies. As ecological connections between human and local animal populations increase, the risk to human and wildlife health from novel parasites also increases. Which of these parasites will fizzle out and which have the potential to become widespread in humans? We consider the case of primate malarias, caused by Plasmodium parasites, to investigate the interacting ecological and evolutionary mechanisms that put human and nonhuman primates at risk for infection. Plasmodium host switching from nonhuman primates to humans led to ancient introductions of the most common malaria-causing agents in humans today, and new parasite switching is a growing threat, especially in Asia and South America. Based on a wild host-Plasmodium occurrence database, we highlight geographic areas of concern and potential areas to target further sampling. We also discuss methodological developments that will facilitate clinical and field-based interventions to improve human and wildlife health based on this eco-evolutionary perspective.


The effects of phaco-emulsification-aspiration and intra-ocular lens implantation on the pupil: pupillographic and pharmacologic study.
The authors report postoperative change in pupil diameter and pupil dynamics after phaco-emulsification-aspiration and intra-ocular lens implantation by comparing the operated eye and non-operated eye in 20 patients who received unilateral surgery. Miosis was noted in the operated eye throughout the postoperative period in the dark, and also in the light at an early stage after the operation. Both the maximal constriction velocity and maximal dilatation velocity of the light reflex decreased postoperatively, but the constriction velocity alone was accelerated 1 or 2 weeks after the operation. In the drug instillation test, pupillary responses to both neosynephrine and pilocarpine were decreased, indicating damage both to the dilator and sphincter muscles. Since no hypersensitivity of the pupil was noted, lesions in the axonal fibres and denervation were judged to be absent. Postoperative miosis is believed to be explained by irreversible damage to the dilator muscle, as well as by the transient effects of inflammatory substances.