Acetabular retroversion in dysplastic hips is associated with decreased 3D femoral head coverage independently from lateral center-edge angle.
The clinical significance of acetabular retroversion in non-dysplastic hips can be explained as pincer-type femoroacetabular impingement (FAI), whereas that in dysplastic hips is not clarified because FAI normally poses little problems for dysplastic hips. We aimed to evaluate three-dimensional (3D) femoral head coverage in dysplastic hips with and without acetabular retroversion and to elucidate the role of acetabular retroversion on the 3D femoral head coverage. We retrospectively investigated 93 hips in 93 patients (9 males and 84 females) that underwent periacetabular osteotomy for hip dysplasia. Dysplastic hips were divided into anteversion and retroversion groups according to their cranial anteversion, which was measured on the axial section 5 mm caudal to the acetabular roof. The 3D femoral head coverage was provided as a percentage of the acetabulum-covered surface area of the upper femoral hemisphere using a 3D preoperative planning software for total hip arthroplasty. Of the 93 dysplastic hips, 15 hips (16%) were assigned to the retroversion group, which had significantly younger age at surgery (31.9 years versus 39.2 years; p = 0.033). The lateral center-edge angles were comparable between the groups (13.8° versus 12.9°; p = 0.68); however, the hips in the retroversion group had a trend of smaller 3D femoral head coverage than those in the anteversion group (59% versus 63%; p = 0.058). Multivariate analysis using two-way analysis of covariance showed that lateral center-edge angle (partial regression coefficient = 0.83; t value = 17.3; p < 0.001) and acetabular retroversion (partial regression coefficient = - 2.3; t value = - 4.9; p < 0.001) were independent factors that contributed to the 3D femoral head coverage. Acetabular retroversion in dysplastic hips was associated with decreased 3D femoral head coverage independently from lateral center-edge angle. The age at surgery in the retroversion group was significantly younger, suggesting a relationship between decreased 3D coverage and potentially earlier symptom onset.


Tempos and modes of collectivity in the history of life.
Collective integration and processing of information have increased through the history of life, through both the formation of aggregates in which the entities may have very different properties and which jointly coarse-grained environmental variables (ranging from widely varying metabolism in microbial consortia to the ecological diversity of species on reefs) and through collectives of similar entities (such as cells within an organism or social groups). Such increases have been implicated in significant transitions in the history of life, including aspects of the origin of life, the generation of pangenomes among microbes and microbial communities such as stromatolites, multicellularity and social insects. This contribution provides a preliminary overview of the dominant modes of collective information processing in the history of life, their phylogenetic distribution and extent of convergence, and the effects of new modes for integrating and acting upon information on the tempo of evolutionary change.


Multiplex RT-PCR detection of Cucumber mosaic virus subgroups and Tobamoviruses infecting Tomato using 18S rRNA as an internal control.
A multiplex reverse-transcription polymerase chain reaction (RT-PCR) protocol was developed for simultaneous detection and discrimination of subgroups of Cucumber mosaic virus (CMV), including its satellite RNA, Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV), using 18S rRNA as an internal control. Species- and subgroups-specific primers designed to differentiate CMV subgroups I and II, ToMV and TMV, were assessed using the cDNA clones of viral genomes, CMV satellite RNA and 18S rRNA gene from tomato (Solanum lycopersicum L.) or tobacco (Nicotiana tobacum). Using total RNA extracted from artificial mixture of tomato leaf tissues infected by each virus, the reaction components and cycling parameters were optimized and a multiplex RT-PCR procedure was established. Six fragments of 704, 593, 512, 421, 385, 255 bp, specific to CMV subgroup II, CMV subgroup I, ToMV, TMV, satellite RNA and 18S rRNA, respectively, were simultaneously amplified. The sensitivity of the multiplex RT-PCR method for detecting CMV was 100 times higher than that of double-antibody sandwich-enzyme-linked immunosorbent assay (DAS-ELISA). This method was successfully used for field detection. Among 141 samples collected from East China through tomato growth seasons, 106 single infections with one of the above isolates were detected and 13 mixed infections were found. The results showed the potential use of this method for investigating the epidemiology of viral diseases infecting tomato.


Peptide plane can flip in two opposite directions: implication in amyloid formation of transthyretin.
Transthyretin (TTR) is one of the known 20 or so human proteins that form fibrils in vivo, which is a hallmark of amyloid diseases. Recently, molecular dynamics simulations using ENCAD force field have revealed that under low pH conditions, the peptide planes of several amyloidogenic proteins can flip in one direction to form an alpha-pleated structure which may be a common conformational transition in the fibril formation. We performed molecular dynamics simulations with AMBER force fields on a recently engineered double mutant TTR, which was shown experimentally to form amyloid fibrils even under close to physiological conditions. Our simulations have demonstrated that peptide-plane flipping can occur even under neutral pH and room temperature for this amyloidogenic TTR variant. Unlike previously reported peptide-plane flipping of TTR using ENCAD force field, we have found two-way flipping using AMBER force field. We propose a new mechanism of amyloid formation based on the two-way flipping, which gives a better explanation of various experimental and computational results. In principle, the residual dipolar and hydrogen-bond scalar coupling techniques can be applied to the wild-type TTR and the variant to study the peptide-plane flipping of amyloidogenic proteins.


[Optic neuritis in systemic lupus erythematosus: report of 12 cases].
To review the cases of optic neuritis in the population of patients with Systemic Lupus Erythematosus (SLE) who attends to the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. We included 12 patients with optic neuritis who fulfilled the ACR SLE criteria. Age, gender, previous treatment, unilateral or bilateral involvement, recurrence, other concomitant neurologic symptoms, SLE activity, anticardiolipin antibodies and visual outcome were recorded. The female:male ratio was 5:1. The mean age of the study group was 33 +/- 13 years. In two patients the optic neuritis antedated the SLE diagnosis, in one the event presented at the same time of lupus onset, and in the rest of the patients the optic neuritis postdated the diagnosis of SLE. The median SLE duration was three years (1-12). At the optic neuritis onset, four of the patients also presented other lupus manifestations whereas the rest of them were in remission. The event was bilateral in 33% and recurrent in three patients (median two events 2-6). In three cases an event of transverse myelitis was also documented. Only one of the patients had an established diagnosis of antiphospholipid syndrome, however eight were positive for anticardiolipin antibodies. Besides treatment with steroids and in two cases with cyclophosphamide, five of the patients had blindness and only four regained normal visual acuity. Although optic neuritis is a rare manifestation in SLE patients, it is a cause of blindness.


Spatial Variation of Ground Level Ozone Concentrations and its Health Impacts in an Urban Area in India.
The present study was designed to analyze the spatial distributions of ground-level ozone (GLO) concentrations in Ranchi (Jharkhand, India) using geostatistical approaches. From September 2014 to August 2015, monthly GLO concentrations were monitored in 40-identified locations distributed in the region of study. In every month, the monitoring was done at three different time periods of the day; 5.30 AM to 7.30 AM, 11.30 AM to 1.30 PM, and 5.30 PM to 8 PM). The time duration was assigned based on the temporal variations of GLO concentrations. The descriptive statistics indicate that the spatial mean ozone concentrations ranged from 23.45 μg m-3 to 53.91 μg m-3 in morning hours, from 82.50 μg m-3 to 126.66 μg m-3 in the day time and from 40.04 μg m-3 to 71.25 μg m-3 in the evening hours. The higher level of spatial variance observed in the months of December (standard deviation: 24.21), July (standard deviation: 29.59) and November (standard deviation: 19.60) for the morning, noon, and evening time, respectively. The effects of meteorological factors (wind speed and wind direction) on the ozone concentrations were also analysed. The study confirmed that wind speed is not the dominant factor for influencing the GLO concentrations. The study also analysed the ozone air quality index (OZAQI) for assessing the health impacts in the study area. The result suggests that most of the area had the moderate category of OZAQI (101-200) and that leads to breathing discomfort for people with lung and heart disease.


Double aorta artifact in sonography - a diagnostic challenge.
The double aorta artifact was described and studied thoroughly twenty-five years ago. Despite this, it is still not commonly known today and can cause diagnostic difficulty. Total aortic duplication can be considered an anatomic defect whilst partial duplication mimics aortic dissection. In the literature, this artifact has been compared with a very rare anomaly, i.e. the occurrence of two aortas in one patient. Currently, however, the differentiation of this artifact from abdominal aortic dissection seems to be of greater significance. The double aorta image occurs when ultrasound waves encounter prismatic fat tissue of the anterior abdominal wall. This artifact is more frequently observed in children and athletic young adults since the structure of this anatomic region in these individuals is conductive to the occurrence of this phenomenon. Moreover, it can be observed more often when curved transducers are used. Due to all these factors, an ultrasound beam undergoes greater refraction and make the artifact clearer. This phenomenon is usually easily recognizable and avoidable, but it sometimes might cause diagnostic difficulty. Obtaining an image of double abdominal vessels on ultrasound examination in transverse sections requires further inspection of the aorta in a different (sagittal) plane. This is not always possible due to poor patient preparation for scanning. Symmetrical flow on Doppler sonography is a typical feature of this artifact. Finally, magnetic resonance imaging or computed tomography can be considered to rule out a pathology.


Complete Characterization of Cardiac Myosin Heavy Chain (223 kDa) Enabled by Size-Exclusion Chromatography and Middle-Down Mass Spectrometry.
Myosin heavy chain (MHC), the major component of the myosin motor molecule, plays an essential role in force production during muscle contraction. However, a comprehensive analysis of MHC proteoforms arising from sequence variations and post-translational modifications (PTMs) remains challenging due to the difficulties in purifying MHC (∼223 kDa) and achieving complete sequence coverage. Herein, we have established a strategy to effectively purify and comprehensively characterize MHC from heart tissue by combining size-exclusion chromatography (SEC) and middle-down mass spectrometry (MS). First, we have developed a MS-compatible SEC method for purifying MHC from heart tissue with high efficiency. Next, we have optimized the Glu-C, Asp-N, and trypsin limited digestion conditions for middle-down MS. Subsequently, we have applied this strategy with optimized conditions to comprehensively characterize human MHC and identified β-MHC as the predominant isoform in human left ventricular tissue. Full sequence coverage based on highly accurate mass measurements has been achieved using middle-down MS combining 1 Glu-C, 1 Asp-N, and 1 trypsin digestion. Three different PTMs: acetylation, methylation, and trimethylation were identified in human β-MHC and the corresponding sites were localized to the N-terminal Gly, Lys34, and Lys129, respectively, by electron capture dissociation (ECD). Taken together, we have demonstrated this strategy is highly efficient for purification and characterization of MHC, which can be further applied to studies of the role of MHC proteoforms in muscle-related diseases. We also envision that this integrated SEC/middle-down MS strategy can be extended for the characterization of other large proteins over 200 kDa.


[Comparison of physico-chemical properties of two forms of dopamine-beta-hydroxylase from chromaffin granules].
The purification procedures of both soluble and membrane-bound forms of dopamine-beta-hydroxylase have been developed. The membrane-bound form was solubilized by a detergent. Both preparations have been obtained in electrophoretically homogeneous form. The yield of soluble and membrane-bound enzyme forms by a described procedure was 22 mg and 15 mg, correspondingly, from 100 g of chromaffin granules paste. A comparative analysis of the main physico-chemical properties of the two enzyme forms has shown their identity. The effects of pH, ionic strength, oxidants and reducers on the EPR spectra of the two forms of dopamine-beta-hydroxylase have been investigated. A comparison of the EPR spectra of the two forms of the enzyme suggests that the copper environment of soluble and membrane-bound dopamine-beta-hydroxylases is practically identical.


Quantum plexcitonics: strongly interacting plasmons and excitons.
We present a fully quantum mechanical approach to describe the coupling between plasmons and excitonic systems such as molecules or quantum dots. The formalism relies on Zubarev's Green functions, which allow us to go beyond the perturbative regime within the internal evolution of a plasmonic nanostructure and to fully account for quantum aspects of the optical response and Fano resonances in plasmon-excition (plexcitonic) systems. We illustrate this method with two examples consisting of an exciton-supporting quantum emitter placed either in the vicinity of a single metal nanoparticle or in the gap of a nanoparticle dimer. The optical absorption of the combined emitter-dimer structure is shown to undergo dramatic changes when the emitter excitation level is tuned across the gap-plasmon resonance. Our work opens a new avenue to deal with strongly interacting plasmon-excition hybrid systems.


The One-Pot Directed Assembly of Cylinder-Forming Block Copolymer on Adjacent Chemical Patterns for Bimodal Patterning.
The direct self-assembly of cylinder-forming poly(styrene-block-methyl-methacrylate) (PS-b-PMMA) block copolymer is successfully assembled into two orientations, according to the underlying guiding pattern in different areas. Lying-down and perpendicular cylinders are formed, respectively, depending on the design of chemical pattern: sparse line/space pattern or hexagonal dot array. The first chemical pattern composed of prepatterned cross-linked polystyrene (XPS) line/space structure has a period (LS ) equal to twice the intercylinder period of the block copolymer (L0 ). The PS-b-PMMA thin film on the prepared chemical template after thermal annealing forms a lying-down cylinder morphology when the width of the PS strips is less than the width of PS block in the PS-b-PMMA block copolymer. The morphology is only applicable at the discrete thickness of the PS-b-PMMA film. In addition to forming the lying-down cylinders directly on the XPS guiding pattern, the cylinder-forming block copolymer can also be assembled in a perpendicular way on the second guiding pattern (the hexagonal dot array). The block copolymer films are registered into two orientations in a single directed self-assembly process. The features of the assembled patterns are successfully transferred down to the silicon oxide substrate.


Expression of allene oxide synthase determines defense gene activation in tomato.
Allene oxide synthase (AOS; hydroperoxide dehydratase; EC 126.96.36.199) catalyzes the first step in the biosynthesis of jasmonic acid from lipoxygenase-derived hydroperoxides of free fatty acids. Using the AOS cDNA from tomato (Lycopersicon esculentum), in which the role of jasmonic acid in wound-induced defense gene activation has been best described, we examined the kinetics of AOS induction in response to wounding and elicitors, in parallel with that of the wound-inducible PIN II (proteinase inhibitor II) gene. AOS was induced in leaves by wounding, systemin, 12-oxophytodienoic acid, and methyl jasmonate. The levels of AOS mRNA started declining by 4 h after induction, whereas the levels of PIN II mRNA continued to increase up to 20 h after induction. Salicylic acid inhibited AOS and PIN II expression, and the addition of 12-oxophytodienoic acid or methyl jasmonate did not prevent the inhibition of PIN II expression in the presence of salicylic acid. Ethylene induced the expression of AOS, but the presence of ethylene alone did not produce an optimal induction of PIN II. The addition of silver thiosulfate, an ethylene action inhibitor, prevented the wound-induced expression of both AOS and PIN II. Products of hydroperoxide lyase affected neither AOS nor PIN II, but induced expression of prosystemin. Based on these results, we propose an updated model for defense gene activation in tomato.


Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices.
Incidence rates for 27 cancers in 23 countries and mortality rates for 14 cancers in 32 countries have been correlated with a wide range of dietary and other variables. Dietary variables were strongly correlated with several types of cancer, particularly meat consumption with cancer of the colon and fat consumption with cancers of the breast and corpus uteri. The data suggest a possible role for dietary factors in modifying the development of cancer at a number of other sites. The usefulness and limitations of the method are discussed.


Purification and characterization of natural human interferon omega 1. Two alternative cleavage sites for the signal peptidase.
Human interferon omega 1 (IFN-omega 1 = IFN-alpha II1) is a recently discovered protein structurally related to IFN-alpha and -beta; the biological activities of IFN-omega 1 and its physiological role are not known to date. We have purified IFN-omega 1 from preparations of human leukocyte IFN, derived from peripheral blood leukocytes induced with Sendai virus, by two sequential cycles of monoclonal antibody affinity chromatography. The resulting protein was at least 95% pure as determined by reverse-phase high performance liquid chromatography and showed an Mr of 24,500 upon sodium dodecyl sulfate-gel electrophoresis (theoretical Mr, 19,984). Amino acid sequence analysis revealed that only about 40% of the molecules have the NH2 terminus expected on the basis of the sequence similarity to IFN-alpha, whereas the others contain two additional amino acids. This difference probably results from variable cleavage of the pre-protein by the signal peptidase. No evidence for COOH-terminal heterogeneity was found. Essentially all IFN-omega 1 molecules are glycosylated; enzymatic deglycosylation resulted in a reduction of the Mr to 20,500. Experiments using several plant lectins indicated the presence of biantennary complex oligosaccharides containing neuraminic acid. Two major peaks were observed upon chromatofocusing, with isoelectric points of 8.1 and 8.5. The specific antiviral activity of purified IFN-omega 1 assayed on human cells was determined to be 2.7 x 10(8) IU/mg, similar to that of other human class I IFNs; potent antiviral activity was also observed on cells of bovine and ovine but not of equine or murine origin.


[Relation between the renin-angiotensin and kallikrein-kinin systems of the blood during physical loading of hypertension patients].
Blood angiotensin-converting enzyme, renin, kallikrein and prekallikrein ratios were investigated in 61 essentially hypertensive patients at rest and during rationed exercise. Biochemical findings were compared with major parameters of systemic hemodynamics measured under the same conditions. Grouping of patients on the basis of renin activity was mirrored in different levels of the angiotensin-converting enzyme and kallikrein: increased renin activity was accompanied by the activation of the said enzymes, and reduced activity, by their suppression. Rationed exercise did not produce noticeable kallikrein-kinin shifts in hypertensive patients, their renin-angiotensin response depending on the baseline. The markedness of hemodynamic change in response to exercise differed in patients with different humoral background.


Amino Alcohols as Potential Antibiotic and Antifungal Leads.
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.


Brownian motion in a growing population of ballistic particles.
We investigate the motility of a growing population of cells in a idealized setting: We consider a system of hard disks in which new particles are added according to prescribed growth kinetics, thereby dynamically changing the number density. As a result, the expected Brownian motion of the hard disks is modified. We compute the density-dependent friction of the hard disks and insert it in an effective Langevin equation to describe the system, assuming that the intercollision time is smaller than the timescale of the growth. We find that the effective Langevin description captures the changes in motility, in agreement with the simulation results. Our framework can be extended to other systems in which the transport coefficient varies with time.


Hierarchical Phonon Scattering from Nano to Macro Scale in Ag-Nano/TiO2-Micro Particle-Decorated p-type Bismuth Telluride Bulk Composites.
We study the thermoelectric properties of a p-type Bi0.4Sb1.6Te3.4 (BST) composite with Ag nanoparticle-decorated TiO2 microparticles (US-Ag/TiO2). The dispersion of US-Ag/TiO2 particles, synthesized by an ultrasonication (US) method, into the matrix effectively decreases lattice and bipolar thermal conductivity, attributed to the scattering centers formed at nano and micro scales. The electron backscattering diffraction (EBSD) measurements revealed smaller grain sizes within the BST composite when paired with the US-Ag/TiO2 particle dispersion. These reduced grain sizes, alongside nanoparticle-decorated microparticles dispersed throughout the matrix, scatter phonons effectively from long- to short-wavelength phonons and subsequently decrease lattice thermal conductivity. While the power factors of the composites are reduced, significant suppression of lattice and bipolar thermal conductivity has led to an increase in the maximum zT value (1.4 at 325 K) for a 0.9 wt % US-Ag/TiO2 particle dispersion within the BST matrix. This particle dispersion in the BST composite consistently demonstrates a high zT value across an extensive temperature spectrum, leading to an exceptionally high average zTavg value (1.38 up to 400 K), which is superior to the other values from reported BST composites. Thus, this research indicates that the dispersion of nanoparticle-decorated microparticles within a thermoelectric material matrix can significantly improve thermoelectric performance, which has promising implications for practical applications in thermoelectric cooling and sustainable and economical energy harvesting technologies.


Malnutrition in children with ichthyosis: Recommendations for monitoring from a multidisciplinary clinic experience.
Short stature has been reported in congenital ichthyoses (CI), but few data exist on patients' nutritional status. To describe the nutritional status at the first evaluation of children and young adults with CI. Prospective observational study of patients assessed at a multidisciplinary clinic. Clinical variables and ichthyosis severity were collected. Anthropometric assessment was made by measuring weight and height, and nutritional status was classified based on the World Health Organization definitions for malnutrition. Analytical assessment included markers of nutritional status, fat-soluble vitamins, and micronutrients. We included 50 patients with a median age of 5 years (IQR, 1.6-10.3). Undernutrition was found in 32% of patients, and 75% of the undernourished children presented growth impairment. Younger children and those with severe ichthyoses were the most affected. Micronutrient deficiencies were found in 60% of patients. Deficiencies of selenium (34%), iron (28%), vitamin D (22%), and zinc (4%) were the most frequent findings. Our small sample includes a heterogeneous group of ichthyoses. Children with CI appear to be at risk of undernutrition, especially at younger ages. Nutritional deficiencies are common and should be monitored. Growth failure in children with ichthyosis could be caused by undernutrition and aggravated by nutritional deficiencies.


Kinetic studies on reactions of iron-sulphur proteins. Oxidation of the reduced form of Spirulina platensis [2Fe-2S] ferredoxin with inorganic complexes.
Kinetic results are presented for the reaction of reduced [2Fe-2S] ferredoxin from the blue-green alga Spirulina platensis with Co(NH3)6(3+), Co(edta)- and Co(acac)3 as oxidants at pH 8.0 at I0.10 (NaCl). The aim is to compare results obtained with those previously reported for the [2Fe-2S] ferredoxin from parsley, where the two ferredoxins under consideration are in evolutionary terms widely divergent (35% amino acid variations). The three oxidants chosen have different ligand sets and different charges, and are the complexes that in previous studies have given greatest diversity in behaviour. With Co(NH3)6(3+) first-order rate constants (oxidant in large excess) tend to a limiting value with increasing concentration of oxidant. With Co(edta)- and Co(acac)3 there is no similar tendency to limiting behaviour and a first-order dependence on oxidant is observed. The temperature-dependence of the Co(NH3)6(3+) reaction was investigated, and values were obtained for delta H0 [19.8kJ X mol-1 (4.7kcal X mol-1)] and delta S0 [129.3J X K-1 X mol-1 (30.9 cal X K-1 X mol-1)] for the association step that occurs before electron transfer. Whereas redox-inactive Cr(NH3)6(3+) displays competitive inhibition in the reaction of Co(NH3)6(3+), it accelerates the reaction of Co(edta)-, and only partially blocks the reaction with Co(acac)3. Results obtained are similar to those previously reported for parsley (and spinach) ferredoxin. It is concluded that electrostatics play a dominant role and that a negatively charged functional site on the protein common to all three ferredoxins is influential. Conserved negative patches at positions 67-69 and 94-96 within 1.0 nm (10A) of an Fe atom of the active site, as well as the exposed S atoms of cysteine residues 41 and 46, which are a part of the Fe2S*2(SR)4(3-) cluster, are the most likely possibilities. The various effects of Cr(NH3)6(3+) provide a means of testing for utilization of the same site in reactions of the ferredoxins with physiological partners.


Photocycle of the flavin-binding photoreceptor AppA, a bacterial transcriptional antirepressor of photosynthesis genes.
The flavoprotein AppA from Rhodobacter sphaeroides contains an N-terminal domain belonging to a new class of photoreceptors designated BLUF domains. AppA was shown to control photosynthesis gene expression in response to blue light and oxygen tension. We have investigated the photocycle of the AppA BLUF domain by ultrafast fluorescence, femtosecond transient absorption, and nanosecond flash-photolysis spectroscopy. Time-resolved fluorescence experiments revealed four components of flavin adenine dinucleotide (FAD) excited-state decay, with lifetimes of 25 ps, 150 ps, 670 ps, and 3.8 ns. Ultrafast transient absorption spectroscopy revealed rapid internal conversion and vibrational cooling processes on excited FAD with time constants of 250 fs and 1.2 ps, and a multiexponential decay with effective time constants of 90 ps, 590 ps, and 2.7 ns. Concomitant with the decay of excited FAD, the rise of a species with a narrow absorption difference band near 495 nm was detected which spectrally resembles the long-living signaling state of AppA. Consistent with these results, the nanosecond flash-photolysis measurements indicated that formation of the signaling state was complete within the time resolution of 10 ns. No further changes were detected up to 15 micros. The quantum yield of the signaling-state formation was determined to be 24%. Thus, the signaling state of the AppA BLUF domain is formed on the ultrafast time scale directly from the FAD singlet excited state, without any apparent intermediate, and remains stable over 12 decades of time. In parallel with the signaling state, the FAD triplet state is formed from the FAD singlet excited state at 9% efficiency as a side reaction of the AppA photocycle.


Epstein-Barr Virus DNA in Parental Oral Secretions: A Potential Source of Infection for Their Young Children.
A potential source of primary Epstein-Barr virus (EBV) infection for young children is parental oral secretions. If parents who identify with racial/ethnic categories other than white have a higher prevalence of oral EBV DNA, this difference could explain why their children acquire primary EBV infection at an earlier age than white children. To test this hypothesis, we recruited parents who brought their children <8 years old to routine clinic visits, and tested the parents' oral washes for EBV DNA by real-time polymerase chain reaction. Positive samples were assayed for encapsidated EBV DNA, which is potentially infectious, versus naked EBV DNA, which is not infectious. Overall, 221/800 parents (28%) had EBV DNA in their oral washes. Oral EBV DNA was more prevalent in parents who identified as non-white as compared with white parents (P = .0004), and was more prevalent in male vs female parents (P = .04). The mean quantity of EBV DNA in positive samples was 5000 copies/mL. Encapsidated viral DNA comprised 40.3% of the total EBV DNA found in parental oral secretions. Our data support the hypothesis that parents could be a source of virus for their young children, because 28% of parents had a mean of 5000 EBV copies/mL of oral wash and 40.3% of the EBV DNA was encapsidated. The higher prevalence of EBV DNA in non-white parents could explain why their children acquire EBV at an earlier age than children of white parents.


Antiobesity pharmacotherapy: new drugs and emerging targets.
Obesity is a growing pandemic, and related health and economic costs are staggering. Pharmacotherapy, partnered with lifestyle modifications, forms the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing antiobesity therapies, including targets, mechanisms, and developmental status, are highlighted. Progress in this field is underscored by Belviq (lorcaserin) and Qsymia (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic weight management in obese patients. On the horizon, novel insights into metabolism and energy homeostasis reveal guanosine 3',5'-cyclic monophosphate (cGMP) signaling circuits as emerging targets for antiobesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches, leveraging existing approved drugs that modulate cGMP levels for the management of obesity.


A single Danio rerio hars gene encodes both cytoplasmic and mitochondrial histidyl-tRNA synthetases.
Histidyl tRNA Synthetase (HARS) is a member of the aminoacyl tRNA synthetase (ARS) family of enzymes. This family of 20 enzymes is responsible for attaching specific amino acids to their cognate tRNA molecules, a critical step in protein synthesis. However, recent work highlighting a growing number of associations between ARS genes and diverse human diseases raises the possibility of new and unexpected functions in this ancient enzyme family. For example, mutations in HARS have been linked to two different neurological disorders, Usher Syndrome Type IIIB and Charcot Marie Tooth peripheral neuropathy. These connections raise the possibility of previously undiscovered roles for HARS in metazoan development, with alterations in these functions leading to complex diseases. In an attempt to establish Danio rerio as a model for studying HARS functions in human disease, we characterized the Danio rerio hars gene and compared it to that of human HARS. Using a combination of bioinformatics, molecular biology, and cellular approaches, we found that while the human genome encodes separate genes for cytoplasmic and mitochondrial HARS protein, the Danio rerio genome encodes a single hars gene which undergoes alternative splicing to produce the respective cytoplasmic and mitochondrial versions of Hars. Nevertheless, while the HARS genes of humans and Danio differ significantly at the genomic level, we found that they are still highly conserved at the amino acid level, underscoring the potential utility of Danio rerio as a model organism for investigating HARS function and its link to human diseases in vivo.


[Comparative study on the treatment of acromioclavicular joint dislocation: coracoclavicular ligament reconstruction using lateral half of conjoined tendon or tractusiliotibialis with hook plate fixation].
To explore the clinical outcomes of acromioclavicular joint (ACJ) dislocation treated with coracoclavicular ligament (CCL) reconstruction using lateral half of conjoined tendon and tractusiliotibialis with hook plate fixation. Comparative study on their advantages and disadvantages in order to provide the materials for the clinic. From June 2005 to June 2012, the patients with Rockwood type III or severer ACJ dislocation were randomly divided into 2 groups. They underwent CCL reconstruction using lateral half of conjoined tendon (conjoined tendon reconstruction group, n = 36) and tractusiliotibialis (tractusiliotibialis reconstruction group, n = 38) with subsequent fixation of hook plates. During the follow-up, the AC and CC distances were measured on postoperative plain films after a removal of hook plates. And the outcomes were assessed according to Karlsson criteria and Constant-Murley shoulder score. Ranked data were analyzed with the use of χ2 test and measurement date with two-sample t test. Results A total of 74 patients were followed up for an average of 20 (12 - 24) months. No significant inter-group differences existed in age, gender, injured side or classification. And there was no statistical difference in ACor CC distance between two groups within 6 months (P > 0. 05) after a removal of hook plates. The AC and CC distances of conjoined tendon reconstruction group were larger than those of tractusiliotibialis reconstruction group (t = 2. 313, P = 0. 026; t = 2. 114, P = 0. 041) within 12 months. The AC and CC distances of 12 months were both larger than those of 6 months (t =2. 631, P =0. 017; t = 2. 297, P = 0. 032). According to the Constant-Murley shoulder score, conjoined tendon reconstruction group was less than tractusiliotibialis reconstruction group (85. 2 ± 10. 2 vs 93. 1 ± 6. 9, t = 2. 965, P = 0. 006). According to the Karlsson Criteria, the excellent and good rate of functional recovery was 75. 00% in conjoined tendon reconstruction group versus 94. 74% in tractusiliotibialis reconstruction group (χ2 = 8. 111, P = 0. 044). The efficacy of Rockwood type III acromioclavicular joint dislocation for reconstructing coracoclavicular ligament using tractusiliotibialis is better than conjoined tendon. The AC and CC distances increase after a removal of hook plates while it is more obvious for conjoined tendon tractusiliotibialis reconstruction.


Missed epidemics and missing links: international birth cohort trends in multiple sclerosis.
Many hypotheses on the etiopathogenesis of multiple sclerosis (MS) focus on risk factors occurring early in life. This study examined the variability of birth cohort trends in international MS data by means of age-period-cohort (APC) analysis. The data from 25 countries were taken from the WHO mortality database. Data were encoded according to the International Classification of Diseases and covered slightly varying periods between 1951 and 2009. The APC analyses were based on logit models applied to cohort tables with 5-year age- and period intervals. In most countries, the birth cohort estimates peaked in those born in the first half of the 20th century. In countries from Central and Western Europe, the peak concerned those born before and around 1920. A second group of countries (Denmark, Sweden, Italy, Ireland, Scotland) shared a later peak amongst cohorts born in the 1920s and 1930s. Group 3 included Commonwealth countries, the USA and Norway, with a double or extended peak starting in the 1910s or 1920s, and ending by the 1950s. The fourth group, consisting of Mediterranean countries and Finland, was characterized by a steady increase in the birth cohort estimates until the 1950s. The fifth group with countries from Eastern Europe and Japan showed no particular pattern. Birth cohort trends have influenced the change in MS risk across the 20th century in many Western countries. This silent epidemic points to a most important but unknown latent risk factor in MS.


Fecal carriage and shedding density of CTX-M extended-spectrum {beta}-lactamase-producing escherichia coli in cattle, chickens, and pigs: implications for environmental contamination and food production.
The number and proportion of CTX-M positive Escherichia coli organisms were determined in feces from cattle, chickens, and pigs in the United Kingdom to provide a better understanding of the risk of the dissemination of extended-spectrum β-lactamase (ESBL) bacteria to humans from food animal sources. Samples of bovine (n = 35) and swine (n = 20) feces were collected from farms, and chicken cecal contents (n = 32) were collected from abattoirs. There was wide variation in the number of CTX-M-positive E. coli organisms detected; the median (range) CFU/g were 100 (100 × 10(6) to 1 × 10(6)), 5,350 (100 × 10(6) to 3.1 × 10(6)), and 2,800 (100 × 10(5) to 4.7 × 10(5)) for cattle, chickens, and pigs, respectively. The percentages of E. coli isolates that were CTX-M positive also varied widely; median (range) values were 0.013% (0.001 to 1%) for cattle, 0.0197% (0.00001 to 28.18%) for chickens, and 0.121% (0.0002 to 5.88%) for pigs. The proportion of animals designated high-density shedders (≥1 × 10(4) CFU/g) of CTX-M E. coli was 3/35, 15/32, and 8/20 for cattle, chickens, and pigs, respectively. We postulate that high levels of CTX-M E. coli in feces facilitate the dissemination of bla(CTX-M) genes during the rearing of animals for food, and that the absolute numbers of CTX-M bacteria should be given greater consideration in epidemiological studies when assessing the risks of food-borne transmission.


Fruit, vegetables, dietary fiber, and risk of colorectal cancer.
Several recent large prospective cohort studies have failed to demonstrate the presumed protective effect of fruit, vegetable, and dietary fiber consumption on colorectal cancer risk. To further explore this issue, we have examined these associations in a population that consumes relatively low amounts of fruit and vegetables and high amounts of cereals. We examined data obtained from a food-frequency questionnaire used in a population-based prospective mammography screening study of women in central Sweden. Women with colorectal cancer diagnosed through December 31, 1998, were identified by linkage to regional cancer registries. Cox proportional hazards models were used to estimate relative risks. All statistical tests were two-sided. During an average 9.6 years of follow-up of 61 463 women, we observed 460 incident cases of colorectal cancer (291 colon cancers, 159 rectal cancers, and 10 cancers at both sites). In the entire study population, total fruit and vegetable consumption was inversely associated with colorectal cancer risk. Subanalyses showed that this association was due largely to fruit consumption. The association was stronger, however, and the dose-response effect was more evident among individuals who consumed the lowest amounts of fruit and vegetables. Individuals who consumed less than 1.5 servings of fruit and vegetables per day had a relative risk for developing colorectal cancer of 1.65 (95% confidence interval = 1.23 to 2.20; P(trend) =.001) compared with individuals who consumed more than 2.5 servings. We observed no association between colorectal cancer risk and the consumption of cereal fiber, even at amounts substantially greater than previously examined, or of non-cereal fiber. Individuals who consume very low amounts of fruit and vegetables have the greatest risk of colorectal cancer. Relatively high consumption of cereal fiber does not appear to lower the risk of colorectal cancer.


Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells.
How cells degenerate from oxidative stress in aging-related disease is incompletely understood. This study's intent was to identify key cytoprotective pathways activated by oxidative stress and determine the extent of their protection. Using an unbiased strategy with microarray analysis, we found that retinal pigmented epithelial (RPE) cells treated with cigarette smoke extract (CSE) had overrepresented genes involved in the antioxidant and unfolded protein response (UPR). Differentially expressed antioxidant genes were predominantly located in the cytoplasm, with no induction of genes that neutralize superoxide and H2O2 in the mitochondria, resulting in accumulation of superoxide and decreased ATP production. Simultaneously, CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, including CHOP, which was cytoprotective because CHOP knockdown decreased cell viability. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP and developed epithelial-mesenchymal transition, as suggested by decreased LRAT abundance, altered ZO-1 immunolabeling, and dysmorphic cell shape. Mildly degenerated RPE from early age-related macular degeneration (AMD) samples had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling. Although oxidative stress is thought to induce an antioxidant response with cooperation between the mitochondria and the ER, herein we show that mitochondria become impaired sufficiently to induce epithelial-mesenchymal transition despite a protective UPR. With similar responses in early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress despite a protective UPR during the early phases of aging-related disease.


Disseminated Mycobacterium avium complex infection mimicking malignancy in a patient with anti-IFN-γ autoantibodies: a case report.
Disseminated nontuberculous mycobacteria (NTM) infections occur mostly in immunocompromised patients. Therefore, it is difficult to diagnose disseminated NTM infections in patients without history of immunocompromised diseases or using immunosuppressant. Patients with anti-interferon-γ (IFN-γ) autoantibodies are vulnerable to intracellular infections, such as disseminated NTM. Currently, there is no widely used and efficient technique for the detection of anti-IFN-γ autoantibodies. Herein, we report a case of an apparently healthy patient with disseminated Mycobacterium avium complex (MAC) infection who tested positive for anti-IFN-γ autoantibodies. A 64-year-old non-immunocompromised and apparently healthy Asian male presented to the emergency department with complaints of progressive chest pain for about 6 months and weight loss. A bulging tumour was found in the anterior chest wall. Chest computed tomography showed a lung mass over the right lower lobe and an osteolytic lesion with a soft tissue component at the sternum. Sonography-guided biopsies for the osteolytic lesion and sputum culture confirmed the presence of disseminated MAC infection. In addition, positive test result of anti-IFN-γ autoantibodies was noted. The patient was prescribed antibiotics. The lesions over the right lower lobe and sternum attenuated following the antibiotic treatment. Detection of anti-IFN-γ autoantibodies is important among previously healthy people with disseminated NTM infection. Presence of anti-IFN-γ autoantibodies may suggest a high risk of severe intracellular infection, such as disseminated NTM infection.


"On a Positive Path": School Superintendents' Perceptions of and Experiences With Local School Wellness Policy Implementation and Evaluation.
Renewed federal requirements for local school wellness policies highlighted the continued importance of supporting school districts as they implement and evaluate wellness initiatives. Superintendents-as school district leaders-play a critical role in wellness policy implementation and evaluation; however, to our knowledge, no studies examine their perspectives or experiences with the most recent federal rule or wellness initiatives more broadly. This study qualitatively examined superintendents' perspectives, experiences, and recommendations with wellness policy implementation and evaluation. Focus groups (n = 39) and follow-up interviews (n = 14 of the focus group participants) were conducted with superintendents from March to July 2017. Coders organized and coded transcript data using Atlas.ti, Version 8 to facilitate thematic analysis. Superintendents had overall positive perceptions of wellness policies and reported that implementation improved over time. Most described wellness approaches beyond typical wellness policy domains, including social-emotional learning and staff wellness. Evaluation of wellness policies was noted to be a challenge, and superintendents requested more tools and resources, as well as opportunities to learn from "best practices." Increased local and state accountability were recommended to facilitate motivation for other superintendents to engage with wellness. This study adds to the literature on a critical stakeholder in the school wellness field. Advocates and technical assistance providers can apply superintendents' recommendations to engage more district leaders in these initiatives.


Contrast and efficiency enhancement in organic light-emitting devices utilizing high absorption and high charge mobility organic layers.
Organic light-emitting devices utilizing copper phthalocyanine (CuPc) and C(60) as the hole- and electron-injection layers were reported. Compared with a conventional device without CuPc and C(60) layers, the improvement of the contrast is more than 100% under 140-lx ambient lighting at a brightness of 300 cd/m(2). A maximum current efficiency of 3.93 cd/A, which is higher than 3.62 cd/A for a conventional device, was obtained at 9 V. The device has a maximum luminance of 17170 cd/m(2) at 15 V. The high contrast and high efficiency of the device are attributed to the high absorption and high charge mobility of CuPc and C(60) films.


The infection rate of Daphnia magna by Pasteuria ramosa conforms with the mass-action principle.
In simple epidemiological models that describe the interaction between hosts with their parasites, the infection process is commonly assumed to be governed by the law of mass action, i.e. it is assumed that the infection rate depends linearly on the densities of the host and the parasite. The mass-action assumption, however, can be problematic if certain aspects of the host-parasite interaction are very pronounced, such as spatial compartmentalization, host immunity which may protect from infection with low doses, or host heterogeneity with regard to susceptibility to infection. As deviations from a mass-action infection rate have consequences for the dynamics of the host-parasite system, it is important to test for the appropriateness of the mass-action assumption in a given host-parasite system. In this paper, we examine the relationship between the infection rate and the parasite inoculum for the water flee Daphnia magna and its bacterial parasite Pasteuria ramosa. We measured the fraction of infected hosts after exposure to 14 different doses of the parasite. We find that the observed relationship between the fraction of infected hosts and the parasite dose is largely consistent with an infection process governed by the mass-action principle. However, we have evidence for a subtle but significant deviation from a simple mass-action infection model, which can be explained either by some antagonistic effects of the parasite spores during the infection process, or by heterogeneity in the hosts' susceptibility with regard to infection.


Impacts of dyebath auxiliaries on the reductive discoloration of Acid Orange 7 dye by high-carbon iron filings.
This study proposed that the physicochemical effects of common dyebath auxiliaries on the bulk dye solution as well as on the iron surface can influence the reductive discoloration of effluent containing Acid Orange 7 (AO7) dye using high-carbon iron filings. Sodium chloride increased the discoloration rate because of the pitting corrosion on the iron surface, triggered by chloride anion. 'Salting out' effect of ammonium sulfate improved the reaction rate up to a certain concentration, beyond which it could compete with dye molecules for the reactive sites, as revealed by formed sulfite and sulfide. Urea drastically reduced the discoloration rates by its chaotropic effect on the bulk solution and by wrapping around the iron surface. Organic acids, namely acetic acid and citric acid, stimulated iron corrosion to improve the discoloration rates. The discoloration reaction was biphasic with an initial fast reaction phase, where in every case more than 70% discoloration was observed within 5 min of reaction, preceding a slow reaction phase. The experimental data could be well described using biphasic kinetics equation (R(2)> 0.997 in all cases) and a biphasic equation was developed considering the individual impact of co-existing auxiliaries on AO7 discoloration.


Extreme Risk Protection Orders: Legislative Intent and Clinician Guidance.
In this second column of a 2-part series exploring extreme risk protections orders, we utilize recent events in Colorado, including legislative efforts to expand the list of eligible petitioners to include clinicians, as an opportunity to explore questions and challenges faced by mental health and medical professionals serving in this capacity. Clinicians are in need of more clear guidance, given an emerging role that comes without clear evidence or practice standards to inform individualized clinical decision-making, and which potentially pits public safety interests against patient care needs, especially those pertaining to therapeutic relationships. In the interim, clinicians will best serve their patients by continuing to practice in a fashion that is analogous to decision-making around other interventions with serious implications for patient autonomy such as involuntary hospitalization. Ongoing collaboration with legislators is needed to arrive at laws that are informed by the limitations inherent in clinical risk assessment and that can be translated into clinical practices that simultaneously support patient needs and community safety.


Photo-induced radical transformations of tosyl cyanide.
Tosyl cyanide is a commonly used reagent for cyanation and sulfonylation in organic synthesis and pharmaceutical chemistry. The photocatalytic transformations of tosyl cyanide are generally conducted under mild conditions. This minireview summarizes the recent progress of radical-involved transformations of tosyl cyanide via photo-induced cyanation or sulfonylcyanation.


Antimicrobial peptides purified from hydrolysates of kanihua (Chenopodium pallidicaule Aellen) seed protein fractions.
The kanihua (Chenopodium pallidicaule Aellen) Andean grain from the Peruvian Altiplano presents proteins of 15% to 19%. The objective was to obtain purified bioactive antimicrobial peptides (AMPs), hydrolyzed with Alcalase and Pepsin-pancreatin sequential system of protein fractions of kanihua varieties Ramis (KR) and Cupi-Sayhua (KS), and hydrolysates with different degrees of hydrolysis (DH) and percentage inhibition (IP) of the growth of E. coli, S. aureus, and C. albicans. To obtain AMPs, nutraceuticals, bio-preservatives, and novel ingredients in food design. The results showed 216 hydrolysates (1%, w/v), only 28 presented significant difference compared to controls (IP ≥ 45%, p ≤ 0.05), 4 AMPs were purified by chromatography, glutelins KS 4 h (1:10) stood out with DH 40% and IP 52% and 70% of S. aureus and C. albicans, respectively (p ≤ 0.05), showed minimum inhibitory concentration (MIC) of 95% for E. coli (p ≤ 0.05), and presented an anionic charge. In conclusion, the simulated digestion in vitro showed higher DH (7%-67%) than Alcalase (13%-54%); the majority were extensive; of 28 hydrolysates with IP ≥ 45% 4 AMPs with important IPs were obtained, and one was anionic.


Recognition and management of impending vein-graft failure. Importance for long-term patency.
A previous report from this group indicated a very poor long-term patency rate (19%) for occluded femoro-distal vein grafts that require initial thrombectomy prior to patch angioplasty for documented stenosis. Patients with vein grafts were therefore followed up by Doppler pressure determinations of the ankle/brachial index (ABI) postoperatively at three weeks, six weeks, and every four months thereafter for two years in an effort to identify vein-graft failure prior to actual thrombosis. During the past six years we performed 322 vein grafts of which 29 grafts were identified by diminished Doppler ABI and were found to have stenotic segments on subsequent arteriography. Twenty-two of these patients (group 1) underwent reconstruction with patch angioplasty resulting in a five-year cumulative patency rate of 82%. The remaining seven patients (group 2) underwent percutaneous transluminal angioplasty of their stenotic segments yielding a significantly lower five-year patency rate of 43%. These two groups were compared with a third group fo 25 patients with thrombosed grafts mandating initial thrombectomy prior to patch angioplasty. The thrombectomized group 3 patients demonstrated a significantly lower five-year cumulative patency rate of 28%. These data suggest that patients with femoro-distal bypass vein grafts be followed up at frequent intervals early in their postoperative course with determinations of Doppler ABI measurements. Any significant reduction in Doppler ABI compared with the highest postoperative Doppler determination should be aggressively evaluated with digital-subtraction or routine angiography in an effort to locate a stenotic lesion prior to graft thrombosis. Patients found to have such a graft stenosis are then ultimately treated with patch angioplasty in anticipation of satisfactory long-term patency rates.


Theoretical approaches to holistic biological features: Pattern formation, neural networks and the brain-mind relation.
The topic of this article is the relation between bottom-up and top-down, reductionist and holistic approaches to the solution of basic biological problems. While there is no doubt that the laws of physics apply to all events in space and time, including the domains of life, understanding biology depends not only on elucidating the role of the molecules involved, but, to an increasing extent, on systems theoretical approaches in diverse fields of the life sciences. Examples discussed in this article are the generation of spatial patterns in development by the interplay of autocatalysis and lateral inhibition; the evolution of integrating capabilities of the human brain, such as cognition-based empathy; and both neurobiological and epistemological aspects of scientific theories of consciousness and the mind.


Protocol for a systematic review of the effects of interventions to inform or educate caregivers about childhood vaccination in low and middle-income countries.
Despite their proven effectiveness in reducing childhood infectious diseases, the uptake of vaccines remains suboptimal in low and middle-income countries. Identifying strategies for transmitting accurate vaccine information to caregivers would boost childhood vaccination coverage in these countries. The purpose of this review is to assess the effects on childhood vaccination coverage of interventions for informing or educating caregivers about the importance of vaccines in low and middle-income countries, as defined by the World Bank. Eligible study designs include randomised controlled trials (RCTs) as well as non-randomised controlled trials (non-RCTs). We will conduct a comprehensive search of both peer-reviewed and grey literature available up to 31 May 2015. We will search PubMed, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, Cumulative Index of Nursing and Allied Health, prospective trial registries and reference lists of relevant publications. Two authors will independently screen the search output, retrieve full texts of potentially eligible studies and assess the latter against predefined inclusion criteria. Disagreements between the two authors will be resolved through consensus and arbitration by a third author. We will pool data from studies with homogenous interventions and outcomes, using random-effects meta-analysis. We will assess statistical heterogeneity using the χ(2) test of homogeneity (with significance defined at the 10% α-level) and quantify it using Higgins' inconsistency index. We will explore the cause of any observed statistical heterogeneity using subgroup analysis, with subgroups defined by study design (RCTs vs non-RCTs) and type of intervention (information vs educational interventions). The proposed systematic review will collect and analyse secondary data that are not associated with individuals. The review will make a significant contribution to the knowledge base of interventions for improving childhood vaccination coverage in low and middle-income countries. PROSPERO, CRD42014010141.


High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity.
Tissue damage occurs often in the life of mammals and is usually repaired. Dying cells are swiftly phagocytosed, but before disappearing, they alert surrounding cells to activate homeostatic programs. They release signals that recruit inflammatory cells to the site of injury, promote cell migration and cell division to replace dead cells, and activate the immune system in anticipation of microbial invasion. Many of these events involve high-mobility group box 1 protein (HMGB1), a nuclear protein that is released passively when necrotic cells lose the integrity of their membranes. HMGB1 behaves as a trigger of inflammation, attracting inflammatory cells, and of tissue repair, recruiting stem cells and promoting their proliferation. Moreover, HMGB1 activates dendritic cells (DCs) and promotes their functional maturation and their response to lymph node chemokines. Activated leukocytes actively secrete HMGB1 in the microenvironment. Thus, HMGB1 acts in an autocrine/paracrine fashion and sustains long-term repair and defense programs. DCs secrete HMGB1 several hours after contact with the first maturation stimulus; HMGB1 secretion is critical for their ability to reach the lymph nodes, to sustain the proliferation of antigen-specific T cells, to prevent their activation-dependent apoptosis, and to promote their polarization towards a T-helper 1 phenotype. These immune responses will also be directed against self-antigens that DCs process at the time of injury and can lead to autoimmunity.


[Interactive health databases on the Internet].
In order to obtain reliable, comprehensive and current data, information systems which enable flexible presentation or analysis are necessary, as opposed to static tables. On-line and interactive numeric health databases on the Internet are increasingly available. Interactive tables can be produced in many fields, e.g., mortality, hospitalizations, cancer incidence, or motor vehicle accidents. The query screens are user-friendly and they can access remote, computerized data. Thus, it is possible to receive immediate responses to specific questions from national or international datasets, which can then be compared with local data--all without leaving one's chair. The aim of this review is to increase awareness of the existence of numeric health databases on the Internet, and their contribution to epidemiological research.


Evidence of WW and WZ production with lepton + jets final states in pp collisions at square root s=1.96 TeV.
We present first evidence for WW+WZ production in lepton + jets final states at a hadron collider. The data correspond to 1.07 fb-1 of integrated luminosity collected with the D0 detector at the Fermilab Tevatron in pp collisions at square root s=1.96 TeV. The observed cross section for WW+WZ production is 20.2+/-4.5 pb, consistent with the standard model and more precise than previous measurements in fully leptonic final states. The probability that background fluctuations alone produce this excess is <5.4 x 10-6, which corresponds to a significance of 4.4 standard deviations.


Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia.
High levels of erythrocyte destruction in sickle cell anemia (SCA) result in chronic hyperbilirubinemia, with cholelithiasis occurring in a subset of patients. We investigated whether susceptibility to cholelithiasis in SCA was associated with the promoter polymorphism of the 5?-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene encoding a key enzyme in bilirubin catabolism. We determined the frequencies of UGT1A1 promoter alleles in 171 SCA children and 153 SCA adults regularly followed for a number of years at the Guadeloupe sickle cell center. These patients had undergone liver/biliary tree ultrasound scans every year. We analyzed the relationships between the various UGT1A1 promoter alleles and hemoglobin levels, steady-state total and unconjugated bilirubin concentrations and the frequency of cholelithiasis. In both children and adults, (TA)6 was less frequent and (TA)7 more frequent in patients with cholelithiasis than in those without this condition. Total and unconjugated bilirubin levels and the frequency of cholelithiasis were significantly higher in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes than in those with other genotypes. Those homozygous for (TA)6 or carrying at least one (TA)5 allele had the lowest total and unconjugated bilirubin levels and were least likely to have cholelithiasis. Patients with (TA)6/(TA)7 and (TA)6/(TA)8 genotypes presented intermediate values. Kaplan-Meier analysis of cholelithiasis-free survival in children demonstrated an early age-at-onset for cholelithiasis in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes. This study shows that the UGT1A1 gene promoter polymorphism is a major genetic risk factor modifying the frequency and age-at-onset of cholelithiasis in SCA patients.


Airflow resistance measurement for a layer of granular material based on the Helmholtz resonance phenomenon.
A Helmholtz resonance technique was employed to predict the airflow resistance of layers of granular materials, namely glass beads, brown rice, soybean, adzuki beans, and corn kernels. Each granular sample was placed on the tube mouth of an open-type Helmholtz resonator. The resonant frequency was determined by measuring the electric impedance of a loudspeaker that was installed in the resonator and driven by a chirp signal linearly sweeping from 90 to 220 Hz for 6.0 s. For a changing sample layer thickness, the resonant frequency was measured, and the specific airflow resistance was calculated by measuring the static pressure drop required for N2 gas to flow through the layer at a constant velocity of 0.042 m/s. When the thickness of the layer was fixed, the Helmholtz resonant frequency decreased as the specific airflow resistance increased, regardless of the kind of granular material.


[Associated metabolic and nutritional side effects to biological cancer therapy].
The different types of cancer represent one of the main causes of morbimortality worldwide. Classical anti-tumor therapy (surgery, chemotherapy, radiotherapy) has notably increased the survival rate. Biological therapies, with selective and frequently specific mechanisms of action, are a relatively recent acquisition in oncologic therapy; among the most commonly used ones are: cytokines, monoclonal antibodies, tyrosine kinase inhibitors, and mTOR inhibitors. The nutritional and metabolic adverse effects of classical therapy are well documented in the literature and the clinical guidelines, which is not the case for biological therapy. To review the literature in this field and to detail in an organized manner the results obtained. Indexed literature and the technical data sheets of the drugs included in the different families were revised through the Spanish Agency of Medicines and Health Care Products until July of 2013. The symptoms and clinical signs of a theoretical action on the nutritional and metabolic status were recorded. The specific action of each family is described. The possible adverse effects of each one of them on the nutritional and metabolic status are grouped, detailing and differentiating them in tables for easier and more friendly-user consultation. The most prevalent possible side effects observed are those related with the appetite, the gastrointestinal tract, and electrolytic impairments. the possible side effects associated to biological therapies are plenty and occur with different frequency and severity. It is important to know the nutritional and metabolic impact when using these therapies for preventing and managing them.


Fluctuations in classical sum rules.
Classical sum rules arise in a wide variety of physical contexts. Asymptotic expressions have been derived for many of these sum rules in the limit of long orbital period (or large action). Although sum-rule convergence may well be exponentially rapid for chaotic systems in a global phase-space sense with time, individual contributions to the sums may fluctuate with a width which diverges in time. Our interest is in the global convergence of sum rules as well as their local fluctuations. It turns out that a simple version of a lazy baker map gives an ideal system in which classical sum rules, their corrections, and their fluctuations can be worked out analytically. This is worked out in detail for the Hannay-Ozorio sum rule. In this particular case the rate of convergence of the sum rule is found to be governed by the Pollicott-Ruelle resonances, and both local and global boundaries for which the sum rule may converge are given. In addition, the width of the fluctuations is considered and worked out analytically, and it is shown to have an interesting dependence on the location of the region over which the sum rule is applied. It is also found that as the region of application is decreased in size the fluctuations grow. This suggests a way of controlling the length scale of the fluctuations by considering a time dependent phase-space volume, which for the lazy baker map decreases exponentially rapidly with time.


Prevalence and causes of blindness and low vision in leprosy villages of north eastern Nigeria.
To determine the prevalence and spectrum of ocular pathology, and the prevalence and causes of blindness and low vision in leprosy villages of north eastern Nigeria. People affected by leprosy, aged 30 years and above, resident in eight leprosy villages were invited to participate. Ocular examination was undertaken of each consenting individual. 480 people were examined. 456 (48%) of 960 eyes had at least one ocular lesion, but only 37% of all lesions were leprosy related and potentially sight threatening. The prevalence of blindness (VA<3/60 with available correction) was 10.4%. An additional 7.5% of subjects were severely visually impaired (3/60< or =VA<6/60). Cataract was the commonest cause of blindness. Other major causes were non-trachomatous corneal opacity and trachoma. Blindness and low vision are highly prevalent among leprosy patients in this setting. Only a third of the burden of ocular pathology is related to the direct effects of leprosy. Efforts to reduce the backlog of cataract and trichiasis, to improve early detection and management of lagophthalmos, and to provide refractive services are urgently required.


Internalisation of membrane progesterone receptor-α after treatment with progesterone: Potential involvement of a clathrin-dependent pathway.
Internalisation and recycling of seven trans-membrane domain receptors is a critical regulatory event for their signalling. The mechanism(s) by which membrane progesterone receptor-α (mPRα) number is regulated on the cell surface is unclear. In this study, we investigated the cellular distribution of mPRα and mechanisms of mPRα trafficking using a cell line derived from a primary culture of human myometrial cells (M11) as an experimental model. RT-PCR and immunofluorescent analysis demonstrated expression of mPRα in M11 cells with mPRα primarily distributed on the cell surface under basal conditions. For the first time, plasma membrane localisation of mPRα was confirmed using immuno-gold transmission electron microscopy. Stimulation of M11 cells with progesterone (P4, 100 nM) resulted in internalisation of mPRα from the plasma membrane to the cytoplasm (10 min) and subsequent partial translocation back to the cell surface (20 min). We investigated potential endocytotic pathways involved in trafficking of mPRα after its internalisation. Partial co-localisation of clathrin with mPRα was obvious after 10 min of P4 treatment. Of note, chlorpromazine (inhibitor of clathrin-mediated pathway) inhibited the endocytosis of mPRα, whereas treatment with nystatin (inhibitor of caveolae-mediated pathway) did not affect internalisation. Collectively, these data suggest that mPRα is expressed on the cell surface of M11 cells and undergoes endocytosis after P4 stimulation primarily via a clathrin-mediated pathway.


Human clones with natural killer function can activate B cells and secrete B cell differentiation factors.
Large granular lymphocyte clones were prepared from normal human mononuclear cells. Seven clones were studied in detail. All had high cytotoxic activity against the natural killer (NK) cell target K562 and all were T11- and DR-positive but T4- and T8-negative: none released migration inhibitory factor, a characteristic of helper T cell clones. When these NK cell clones were co-cultured with autologous B cells in a 1:1 ratio, 4 of the 7 induced both IgM and IgG synthesis. Ig production could not be further enhanced by the addition of B cell differentiation factors. The cells stimulated included antigen-specific memory B cells, as the Ig induced contained specific antibody to an antigen, tetanus toxoid, to which the B cell donors had recently been immunized. Supernatants from the helper/NK clones contained B cell differentiation factors, and were able to induce IgG synthesis from the lymphoblastoid cell line CESS and from co-cultured T and B cells. However, NK clone supernatants, unlike the clones themselves, were not effective at inducing Ig synthesis from purified B cells. Instead it appears that NK clones first activate B cells and thus render them responsive to the factors that the clones secrete.


Body fat distribution, insulin resistance, and metabolic diseases.
Obesity has now developed into a world-wide epidemic and is associated with large economic costs and prevalent diseases, particularly with central body fat distribution. Insulin resistance almost invariably occurs, and might be a major trigger for disease-generating mechanisms either directly or via generation of other disease precursors ("risk factors"). The hypothalamo-pituitary-adrenal (HPA) axis seems to be hypersensitive in abdominal obesity, a statement supported by increased responses to challenges from the adrenals to central regulatory centers. Furthermore, the feedback control by central glucocorticoid receptors, probably a secondary, functional consequence of an elevated HPA axis activity, because the receptor gene appears normal. Secretion of sex steroid and growth hormones is diminished, which might be consequence of elevated HPA axis activity. Hyperandrogenicity in women is probably of adrenal origin and another consequence of the sensitivity of the HPA axis. The endocrine abnormalities thus are periodically elevated cortisol and androgen (women) concentrations, as well as low secretions of gender-specific steroid and growth hormones. Since elevated cortisol, and low sex-steroid and growth hormone secretions, probably direct storage fat to visceral depots, the multiple endocrine abnormalities probably cause enlargement of these depots. Furthermore, these hormonal abnormalities most likely at least contribute to the creation of insulin resistance with additional effects of elevated fatty acids from central fat depots, which are sensitive to lipid mobilization agents. This chain of events indicates the central role of the hypersensitive HPA axis. Known causes of sensitization of this axis have been identified in subjects with abdominal obesity, including depression, anxiety, alcohol, and smoking. A common cause of HPA axis activation is perceived stress, with a depressive, defeatist, or "helplessness" reaction. In subjects with abdominal preponderance of body fat stores a number of psychosocial and socioeconomics handicaps have been identified, hypothetically predisposing to such reactions. In a primate model (monkeys), mild psychosocial stress is followed by identical psychological, endocrine, anthropometric, and metabolic abnormalities as in humans with abdominal preponderance of body fat stores, including early signs of diabetes and cardiovascular disease. These findings strongly support the interpretation that a stress reaction activating the HPA axis is involved also in the human syndrome. Interventions with normalization of the endocrine perturbations are followed by clear improvements of the multiple abnormalities in both clinical, experimental, cellular and molecular studies, suggesting that the pathogenesis of abdominal preponderance of body fat and its endocrine, anthropometric and metabolic abnormalities are indeed consequences of the endocrine abnormalities identified.


Experimental study to assess the impact of vasopressors administered during maintenance of the brain-dead donation in the quality of the intestinal graft.
The hemodynamic maintenance of brain-dead donors will influence the quality of the organs procured for transplantation, including the intestine. Although norepinephrine (NE) and dopamine (DA) are commonly used to sustain mean arterial pressure in humans, there are no standardized protocols for their use during maintenance of brain-dead donors. Our aim was to compare the effects of each drug, in the intestinal graft quality using a rat brain-dead donation model. Wistar rats (N = 17) underwent brain death (BD) for 2 hours with NE (NE group) or with DA (DA group) administration; the control group was mechanically ventilated for 2 hours without BD. Jejunum biopsies were obtained at the end of the maintenance period. Histological damage was evaluated using Park-Chiu scale. Villi/crypt ratio, mucosal thickness, Goblet cell count, and villi density were evaluated using ImageJ software (US National Institutes of Health, Bethesda, MD). Barrier damage was assessed by bacterial translocation culture counting on liver samples. The inflammatory status of the intestine was evaluated by CD3+ counting by immunohistochemistry and gene expression analysis of interleukin (IL)-6, IL-22, and CXCL10. Norepinephrine-treated donors had higher focal ischemic injury in the intestinal mucosa without a substantial modification of morphometrical parameters compared with DA-treated donors. CD3+ mucosal infiltration was greater in intestines procured from brain-dead donors, being highest in NE (p ˂ 0.001). Local inflammatory mediators were affected in BD: DA and NE groups showed a trend to lower expression of IL-22, whereas CXCL10 expression was higher in NE versus control group. Brain death promoted intestinal bacterial translocation, but the use of NE resulted in the highest bacterial counting in the liver (p ˂ 0.01). Our results favor the use of DA instead of NE as main vasoactive drug to manage BD-associated hemodynamic instability. Dopamine may contribute to improve the quality of the intestinal graft, by better preserving barrier function and lowering immune cell infiltration.


Inpatient treatment of diabetic patients in Asia: evidence from India, China, Thailand and Malaysia.
The prevalence of Type 2 diabetes mellitus (DM) has grown rapidly, but little is known about the drivers of inpatient spending in low- and middle-income countries. This study aims to compare the clinical presentation and expenditure on hospital admission for inpatients with a primary diagnosis of Type 2 DM in India, China, Thailand and Malaysia. We analysed data on adult, Type 2 DM patients admitted between 2005 and 2008 to five tertiary hospitals in the four countries, reporting expenditures relative to income per capita in 2007. Hospital admission spending for diabetic inpatients with no complications ranged from 11 to 75% of per-capita income. Spending for patients with complications ranged from 6% to over 300% more than spending for patients without complications treated at the same hospital. Glycated haemoglobin was significantly higher for the uninsured patients, compared with insured patients, in India (8.6 vs. 8.1%), Hangzhou, China (9.0 vs. 8.1%), and Shandong, China (10.9 vs. 9.9%). When the hospital admission expenditures of the insured and uninsured patients were statistically different in India and China, the uninsured always spent less than the insured patients. With the rising prevalence of DM, households and health systems in these countries will face greater economic burdens. The returns to investment in preventing diabetic complications appear substantial. Countries with large out-of-pocket financing burdens such as India and China are associated with the widest gaps in resource use between insured and uninsured patients. This probably reflects both overuse by the insured and underuse by the uninsured.


EZH2-Targeted Therapies in Cancer: Hype or a Reality.
Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as ARID1A, KDM6, and BAP1 are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.


Magnetic resonance imaging assessment of the velopharyngeal mechanism at rest and during speech in Chinese adults and children.
Recent applications of the magnetic resonance imaging (MRI) technique introduced accurate 3-dimensional measurements of the velopharyngeal mechanism. Further standardization of the data acquisition and analysis protocol was successfully applied to imaging adults at rest and during phonation. This study was designed to test and modify a noninvasive protocol for evaluating young children without using general anesthesia. In addition, the velopharyngeal structures and their maximal motion were compared between adults and children. MRI data were acquired in 12 young adults and 9 children at rest and during speech production. Multiple measurements were made on the velopharyngeal and craniofacial structures as well as on the levator veli palatini muscle. Most of the ratio measurements of structural shape and maximal motion in the velopharyngeal and craniofacial regions were not significantly different between the adults and the children, despite the fact that the children had much smaller structures than the adults. The proportion of the velopharyngeal mechanism remains stable in young children and adults so that the motions of the velum and pharyngeal walls are adequate to close the velopharyngeal port completely.


Rates of breastfeeding in Australia by state and socioeconomic status: evidence from the 1995 National Health Survey.
To estimate rates of breastfeeding in the first year of life in Australia, according to state and socioeconomic status. Analysis of data from the 1995 Australian National Health Survey. Estimated breastfeeding rates are 81.8% on discharge from hospital, 57.1% fully breastfed at three months and 62.6% fully or partially breastfed at three months. At six months, it is estimated that 18.6% of babies are fully breastfed and 46.2% fully or partially breastfed. At one year, 21.2% of infants are receiving some breastmilk. Comparison between states demonstrates that there is considerable variation in breastfeeding practice within Australia. Rates of breastfeeding also vary according to the socioeconomic status of the geographic area in which the child is living, with a strong inverse relationship between rates of breastfeeding and socioeconomic status. Australia's target for breastfeeding in the year 2000 is to have 80% of babies at least partially breastfed for the first six months of life. Although Australia has good rates of initiation of breastfeeding these levels are not maintained over time, and it seems unlikely that we will reach the year 2000 targets.


Light-induced translocation of Drosophila visual Arrestin2 depends on Rac2.
Photoreceptor cells are remarkable in their ability to adjust their sensitivity to light over a wide range of intensities. Rapid termination of the photoresponse is achieved in part by shuttling proteins in and out of the light-transducing compartment of the photoreceptor cells. One protein that undergoes light-dependent translocation is the rhodopsin regulatory protein arrestin. However, the mechanisms coupling rhodopsin to arrestin movement are poorly understood. Here we show that light-dependent shuttling of the major arrestin in Drosophila photoreceptor cells, Arrestin2 (Arr2), occurs independently of known elements of the phototransduction cascade. Disruptions of the trimeric G protein, phospholipase Cbeta, the TRP channel, or the Na(+)/Ca(2+) exchanger did not influence Arr2 localization. Rather, we found that loss of the small GTPase Rac2 severely impaired Arr2 movement and prolonged the termination of the photoresponse. Our findings demonstrate that light-induced translocation of Arr2 occurs through a noncanonical rhodopsin/Rac2 pathway, which is distinct from the classical phototransduction cascade.


Lewy body pathology in normal elderly subjects.
Lewy bodies and Lewy neurites are the hallmark neuropathologic findings in Parkinson disease, Parkinson disease with dementia, dementia with Lewy bodies, and other alpha-synucleinopathies. They have also been described in the brains of normal older individuals and referred to as incidental Lewy body disease. The purpose of this study was to determine the prevalence of Lewy bodies and Lewy neurites (Lewy body pathology [LBP]) in 139 autopsies from our normal volunteer control group of the University of Kentucky Alzheimer's Disease Center. All subjects were followed longitudinally and were cognitively normal and without any type of movement disorder, neuropsychiatric features, or other CNS findings. The brains of 33 of 139 normal subjects contained LBP in various regions. The most common regions involved were the medulla (26%), amygdala (24%), pons (20%), and midbrain (20%). No mean statistical differences were found between those with and without LBP on any demographic or cognitive variable, Braak stage, or neurofibrillary tangle and neuritic plaque quantitation. An explanation for the high prevalence of LBP in our elderly, well-educated study group is not clear, although it does not seem to be related to aging or the presence of Alzheimer disease pathology. Overall, our findings support the concept that incidental Lewy body disease most likely represents preclinical or presymptomatic Parkinson disease, Parkinson disease with dementia, or dementia with Lewy bodies.


[Extramembranous glomerulonephritis induced by lithium].
We report the case of a patient who developed a nephrotic syndrome after lithium carbonate therapy. The nephrotic syndrome disappeared after withdrawal of therapy and recurred when the patient was rechallenged with the same drug. This seems a convincing argument to believe that lithium was the causal agent. Renal biopsy specimens showed membranous nephropathy, suggesting that immune-complex formation was involved in the reaction to the drug. Membranous nephropathy is an exceptional and benign hazard during lithium therapy, and underlines the need for periodic urinalysis in patients treated with the drug.


How morphological development can guide evolution.
Organisms result from adaptive processes interacting across different time scales. One such interaction is that between development and evolution. Models have shown that development sweeps over several traits in a single agent, sometimes exposing promising static traits. Subsequent evolution can then canalize these rare traits. Thus, development can, under the right conditions, increase evolvability. Here, we report on a previously unknown phenomenon when embodied agents are allowed to develop and evolve: Evolution discovers body plans robust to control changes, these body plans become genetically assimilated, yet controllers for these agents are not assimilated. This allows evolution to continue climbing fitness gradients by tinkering with the developmental programs for controllers within these permissive body plans. This exposes a previously unknown detail about the Baldwin effect: instead of all useful traits becoming genetically assimilated, only traits that render the agent robust to changes in other traits become assimilated. We refer to this as differential canalization. This finding also has implications for the evolutionary design of artificial and embodied agents such as robots: robots robust to internal changes in their controllers may also be robust to external changes in their environment, such as transferal from simulation to reality or deployment in novel environments.


Polymorphism and transcription of Mhc class I genes in a passerine bird, the great reed warbler.
The class I genes of the major histocompatibility complex (Mhc) are here investigated for the first time in a passerine bird. The great reed warbler is a rare species in Sweden with a few semi-isolated populations. Yet, we found extensive Mhc class I variation in the study population. The variable exon 3, corresponding to the alpha2 domain, was amplified from genomic DNA with degenerated primers. Seven different genomic class I sequences were detected in a single individual. One of the sequences had a deletion leading to a shift in the reading frame, indicating that it was not a functional gene. A randomly selected clone was used as a probe for restriction fragment length polymorphism (RFLP) studies in combination with the restriction enzyme Pvu II. The RFLP pattern was complex with 21-25 RFLP fragments per individual and extensive variation. Forty-nine RFLP genotypes were detected in 55 tested individuals. To study the number of transcribed genes, we isolated 14 Mhc class I clones from a cDNA library from a single individual. We found eight different sequences of four different lengths (1.3-2.2 kilobases), suggesting there are at least four transcribed loci. The number of nonsynonymous substitutions (dN) in the peptide binding region of exon 3 were higher than the number of synonymous substitutions (dS), indicating balancing selection in this region. The number of transcribed genes and the numerous RFLP fragments found so far suggest that the great reed warbler does not have a "minimal essential Mhc" as has been suggested for the chicken.


Impact of follow ups, time interval and study duration in diffusion & myelin MRI clinical study in MS.
It is currently unknown how quantitative diffusion and myelin MRI designs affect the results of a longitudinal study. We used two independent datasets containing 6 monthly MRI measurements from 20 healthy controls and 20 relapsing-remitting multiple sclerosis (RR-MS) patients. Six designs were tested, including 3 MRI acquisitions, either over 6 months or over a shorter study duration, with balanced (same interval) or unbalanced (different interval) time intervals between MRI acquisitions. First, we show that in RR-MS patients, the brain changes over time obtained with 3 MRI acquisitions were similar to those observed with 5 MRI acquisitions and that designs with an unbalanced time interval showed the highest similarity, regardless of study duration. No significant brain changes were found in the healthy controls over the same periods. Second, the study duration affects the sample size in the RR-MS dataset; a longer study requires more subjects and vice versa. Third, the number of follow-up acquisitions and study duration affect the sensitivity and specificity of the associations with clinical parameters, and these depend on the white matter bundle and MRI measure considered. Together, this suggests that the optimal design depends on the assumption of the dynamics of change in the target population and the accuracy required to capture these dynamics. Thus, this work provides a better understanding of key factors to consider in a longitudinal study and provides clues for better strategies in clinical trial design.


Mitochondrial adaptations in skeletal muscle to hindlimb unloading.
To gain insight into the regulation of mitochondrial adaptations to hindlimb unloading (HU), the activity of mitochondrial enzymes and the expression of nuclear-encoded genes which control mitochondrial properties in mouse gastrocnemius muscle were investigated. Biochemical and enzyme histochemical analysis showed that subsarcolemmal mitochondria were lost largely than intermyofibrillar mitochondria after HU. Gene expression analysis revealed disturbed or diminished gene expression patterns. The three main results of this analysis are as follows. First, in contrast to peroxisome proliferator-activated receptor γ coactivator 1 β (PGC-1β) and PGC-1-related coactivator, which were down-regulated by HU, PGC-1α was up-regulated concomitant with decreased expression of its DNA binding transcription factors, PPARα, and estrogen-related receptor α (ERRα). Moreover, there was no alteration in expression of nuclear respiratory factor 1, but its downstream target gene, mitochondrial transcription factor A, was down-regulated. Second, both mitofusin 2 and fission 1, which control mitochondrial morphology, were down-regulated. Third, ATP-dependent Lon protease, which participates in mitochondrial-protein degradation, was also down-regulated. These findings suggest that HU may induce uncoordinated expression of PGC-1 family coactivators and DNA binding transcription factors, resulting in reducing ability of mitochondrial biogenesis. Furthermore, down-regulation of mitochondrial morphology-related genes associated with HU may be also involved in alterations in intracellular mitochondrial distribution.


ABO-mismatched renal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and the Midwest Organ Bank (MOB).
Successful ABO-mismatched renal transplantation (RT) (blood group A2 donor to blood group B or O recipient) has occurred in adults in the setting of a low titer (< or =4) natural isoagglutinin (anti-A) level in the recipient of the mismatched organ. Similar experiences have rarely occurred in children. Between 1986-1996, 11 pediatric patients (6 male and 5 female) received 11 ABO-mismatched kidneys [7 cadaveric (CAD) and 4 living related donor (LRD)]. There were 8 O recipients/A2 donor pairs, 2 B recipients/A2 donor pairs and 1 B recipient/A2B donor pair. Recipient age at the time of RT was 14.7+/-3.0 yr (mean +/- SD). Prior to RT, 2 recipients underwent splenectomy and none received donor-specific transfusions. Induction and early maintenance immunosuppression consisted of corticosteroids (11 pts), ALG/ATG (6 pts), OKT3 (3 pts), azathioprine (11 pts) and cyclosporine (8 pts). The mean 30-d cyclosporine dosage was 10.6+/-4.0 mg/kg/d. Eight patients suffered > or =1 acute rejection episodes, the initial episode occurring within the first 31 d post-transplant in 7 of them. Five grafts (45.4%) failed secondary to vascular thrombosis (1), acute rejection (2) and chronic rejection (2). The remaining grafts (54.5%) all functioned for >1000 d (range: 1023-3746 d). The pre-transplant anti-A titer was determined in 6 pts; in 4 it was low (2) and in 2 it was high (8). Graft survival in all but one of these patients (whose titer was 8 and who suffered a non-rejection-related vascular thrombosis) was > or =2 yr. In summary, ABO-mismatched RT in pediatric patients is an uncommon practice. However, the adult experience and our preliminary pediatric experience suggests that evaluation of recipient isoagglutinin levels in this setting may be helpful in the selection of donor/recipient pairs in whom mismatched transplantation can be successful.


End-to-End Notifications and Interactivity in Standard Based EHR Networks.
One of the main challenges of EHR system is providing information in an adequate and timely manner to its user which can be as well professionals as patients. In both usage scenarios the acceptance and usage of such system benefits from alerting and notification functionality on events. Since this aspect is hardly covered in interoperability and EHR standards the goal of this paper is to identify workflows and extensions to standard based EHR system to provide this functionality. Using requirements engineering technics and a three-tire analysis phase a list of requirements and an architecture based on IHE standards could be identified. In this concept patients, professional and administrators have been identified as main user groups of such systems. Notification events for the user groups could be categorized to the core attribute families Type and Transport Channel. The notifications itself are triggered by events that could be defined. Outlining the workflows that trigger events in the IHE based infrastructure we identified the challenge of differentiating system generated or based events which are also caused by the notification system's operation. This might lead to invalid event triggers and therefore must be discussed in future work.