Leveraging shared connectivity to aggregate heterogeneous datasets into a common response space.
Connectivity hyperalignment can be used to estimate a single shared response space across disjoint datasets. We develop a connectivity-based shared response model that factorizes aggregated fMRI datasets into a single reduced-dimension shared connectivity space and subject-specific topographic transformations. These transformations resolve idiosyncratic functional topographies and can be used to project response time series into shared space. We evaluate this algorithm on a large collection of heterogeneous, naturalistic fMRI datasets acquired while subjects listened to spoken stories. Projecting subject data into shared space dramatically improves between-subject story time-segment classification and increases the dimensionality of shared information across subjects. This improvement generalizes to subjects and stories excluded when estimating the shared space. We demonstrate that estimating a simple semantic encoding model in shared space improves between-subject forward encoding and inverted encoding model performance. The shared space estimated across all datasets is distinct from the shared space derived from any particular constituent dataset; the algorithm leverages shared connectivity to yield a consensus shared space conjoining diverse story stimuli.


Revisiting de Beer's textbook example of heterochrony and jaw elongation in fish: calmodulin expression reflects heterochronic growth, and underlies morphological innovation in the jaws of belonoid fishes.
Heterochronic shifts during ontogeny can result in adaptively important innovations and might be initiated by simple developmental switches. Understanding the nature of these developmental events can provide insights into fundamental molecular mechanisms of evolutionary change. Fishes from the Suborder Belonoidei display a vast array of extreme craniofacial morphologies that appear to have arisen through a series of heterochronic shifts. We performed a molecular heterochrony study, comparing postembryonic jaw development in representatives of the Suborder Belonoidei, the halfbeak Dermogenys pusilla (where the lower jaw is considerably elongated compared to the upper jaw) and the needlefish Belone belone (where both jaws are elongated), to a representative of their sister group the Suborder Adrianichthyoidei, the medaka Oryzias latipes, which has retained the ancestral morphology. Early in development, the lower jaw displays accelerated growth both in needlefish and halfbeak compared to medaka, and secondary acceleration of the upper jaw is seen in needlefish later in their development, representing a case of mosaic heterochrony. We identified toothless extensions of the dentaries as innovations of Belonoid fishes and the source of heterochronic growth. The molecular basis of growth heterochronies in the Belonoidei was examined through comparing expression of skeletogenic genes during development of halfbeak and medaka. The calmodulin paralogue calm1 was identified as a potential regulator of jaw length in halfbeak as its expression gradually increases in the lower jaw, but not the upper jaw, in a pattern that matches its outgrowth. Moreover, medaka displays equal expression of calm1 in the upper and lower jaws, consistent with the lack of jaw outgrowth in this species. Heterochronic shifts in jaw growth have occurred repeatedly during the evolution of Belonoid fishes and we identify toothless extensions of the dentaries as an important innovation of this group. Our results suggest that calm1 contributes to jaw heterochrony in halfbeak, potentially driving further heterochronic shifts in jaw growth across the Suborder Belonoidei, such as the upper jaw acceleration observed in needlefish.


Systematic Pan-Cancer Analysis Reveals Immune Cell Interactions in the Tumor Microenvironment.
With the recent advent of immunotherapy, there is a critical need to understand immune cell interactions in the tumor microenvironment in both pan-cancer and tissue-specific contexts. Multidimensional datasets have enabled systematic approaches to dissect these interactions in large numbers of patients, furthering our understanding of the patient immune response to solid tumors. Using an integrated approach, we inferred the infiltration levels of distinct immune cell subsets in 23 tumor types from The Cancer Genome Atlas. From these quantities, we constructed a coinfiltration network, revealing interactions between cytolytic cells and myeloid cells in the tumor microenvironment. By integrating patient mutation data, we found that while mutation burden was associated with immune infiltration differences between distinct tumor types, additional factors likely explained differences between tumors originating from the same tissue. We concluded this analysis by examining the prognostic value of individual immune cell subsets as well as how coinfiltration of functionally discordant cell types associated with patient survival. In multiple tumor types, we found that the protective effect of CD8+ T cell infiltration was heavily modulated by coinfiltration of macrophages and other myeloid cell types, suggesting the involvement of myeloid-derived suppressor cells in tumor development. Our findings illustrate complex interactions between different immune cell types in the tumor microenvironment and indicate these interactions play meaningful roles in patient survival. These results demonstrate the importance of personalized immune response profiles when studying the factors underlying tumor immunogenicity and immunotherapy response. Cancer Res; 77(6); 1271-82. ©2017 AACR.


Low-Loss Transmission Lines for High-Power Terahertz Radiation.
Applications of high-power Terahertz (THz) sources require low-loss transmission lines to minimize loss, prevent overheating and preserve the purity of the transmission mode. Concepts for THz transmission lines are reviewed with special emphasis on overmoded, metallic, corrugated transmission lines. Using the fundamental HE(11) mode, these transmission lines have been successfully implemented with very low-loss at high average power levels on plasma heating experiments and THz dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiments. Loss in these lines occurs directly, due to ohmic loss in the fundamental mode, and indirectly, due to mode conversion into high order modes whose ohmic loss increases as the square of the mode index. An analytic expression is derived for ohmic loss in the modes of a corrugated, metallic waveguide, including loss on both the waveguide inner surfaces and grooves. Simulations of loss with the numerical code HFSS are in good agreement with the analytic expression. Experimental tests were conducted to determine the loss of the HE(11) mode in a 19 mm diameter, helically-tapped, three meter long brass waveguide with a design frequency of 330 GHz. The measured loss at 250 GHz was 0.029 ± 0.009 dB/m using a vector network analyzer approach and 0.047 ± 0.01 dB/m using a radiometer. The experimental results are in reasonable agreement with theory. These values of loss, amounting to about 1% or less per meter, are acceptable for the DNP NMR application. Loss in a practical transmission line may be much higher than the loss calculated for the HE(11) mode due to mode conversion to higher order modes caused by waveguide imperfections or miter bends.


Rosmarinic acid suppresses colonic inflammation in dextran sulphate sodium (DSS)-induced mice via dual inhibition of NF-κB and STAT3 activation.
Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Although UC is generally treated with anti-inflammatory drugs or immunosuppressants, most of these treatments often prove to be inadequate. Rosmarinic acid (RA) is a phenolic ester included in various medicinal herbs such as Salvia miltiorrhiz and Perilla frutescens. Although RA has many biological and pharmacological activities, the anti-inflammatory effect of RA in colonic tissue remains unclear. In this study, we investigated the anti-inflammatory effects and underlying molecular mechanism of RA in mice with dextran sulphate sodium (DSS)-induced colitis. In the DSS-induced colitis model, RA significantly reduced the severity of colitis, as assessed by disease activity index (DAI) scores, colonic damage, and colon length. In addition, RA resulted in the reduction of the inflammatory-related cytokines, such as IL-6, IL-1β, and IL-22, and protein levels of COX-2 and iNOS in mice with DSS-induced colitis. Furthermore, RA effectively and pleiotropically inhibited nuclear factor-kappa B and signal transducer and activator of transcription 3 activation, and subsequently reduced the activity of pro-survival genes that depend on these transcription factors. These results demonstrate that RA has an ameliorative effect on colonic inflammation and thus a potential therapeutic role in colitis.


Hypothermic Oxygenated Perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation.
To evaluate the impact of a novel oxygenated perfusion approach on rejection after orthotopic liver transplantation (OLT). Hypothermic oxygenated perfusion (HOPE) was designed to prevent graft failure after OLT. One of the mechanisms is downregulation of Kupffer cells (in situ macrophages). We, therefore, designed experiments to test the effects of HOPE on the immune response in an allogeneic rodent model of nonarterialized OLT. Livers from Lewis rats were transplanted into Brown Norway rats to induce liver rejection in untreated recipients within 4 weeks. Next, Brown Norway recipients were treated with tacrolimus (1 mg/kg), whereas in a third group, liver grafts from Lewis rats underwent HOPE or deoxygenated machine perfusion for 1 hour before implantation, but recipients received no immunosuppression. In a last step, low-dose tacrolimus treatment (0.3 mg/kg) was assessed with and without HOPE. Allogeneic OLT without immunosuppression led to death within 3 weeks after nonarterialized OLT due to severe acute rejection. Full-dose tacrolimus prevented rejection, whereas low-dose tacrolimus led to graft fibrosis within 4 weeks. HOPE treatment without immunosuppression also protected from lethal rejection. The combination of low-dose tacrolimus and 1-hour HOPE resulted in 100% survival within 4 weeks without any signs of rejection. We demonstrate that allograft treatment by HOPE not only protects against preservation injury but also impressively downregulates the immune system, blunting the alloimmune response. Therefore, HOPE may offer many beneficial effects, not only to rescue marginal grafts but also by preventing rejection and the need for immunosuppression.


Effects on perceptual development of visual deprivation during infancy.
We measured three aspects of vision in children treated for unilateral congenital cataract: visual resolution, the symmetry of optokinetic nystagmus (OKN), and peripheral vision. Good visual resolution was achieved by children who had had the earliest treatment and who had had the normal eye patched close to 50% of the waking time throughout early childhood. All children treated for unilateral congenital cataract showed a marked asymmetry of OKN regardless of the age of treatment. One child with early treatment who could be tested with the Goldmann perimeter also showed especially poor sensitivity in the nasal visual field of her aphakic eye. We found no such deficits in the vision of children who had had normal visual experience during early infancy and then later developed cataracts in one or both eyes. The limitations observed in children treated for congenital cataract are similar to those reported in normal human infants, in normal kittens, and in cats which were visually deprived early in life.


Uncertainty and invariance in the human visual cortex.
The way in which input noise perturbs the behavior of a system depends on the internal processing structure of the system. In visual psychophysics, there is a long tradition of using external noise methods (i.e., adding noise to visual stimuli) as tools for system identification. Here, we demonstrate that external noise affects processing of visual scenes at different cortical areas along the human ventral visual pathway, from retinotopic regions to higher occipitotemporal areas implicated in visual shape processing. We found that when the contrast of the stimulus was held constant, the further away from the retinal input a cortical area was the more its activity, as measured with functional magnetic resonance imaging (fMRI), depended on the signal-to-noise ratio (SNR) of the visual stimulus. A similar pattern of results was observed when trials with correct and incorrect responses were analyzed separately. We interpret these findings by extending signal detection theory to fMRI data analysis. This approach reveals the sequential ordering of decision stages in the cortex by exploiting the relation between fMRI response and stimulus SNR. In particular, our findings provide novel evidence that occipitotemporal areas in the ventral visual pathway form a cascade of decision stages with increasing degree of signal uncertainty and feature invariance.


Around the Fungal Clock: Recent Advances in the Molecular Study of Circadian Clocks in Neurospora and Other Fungi.
Night follows day and as a consequence, organisms have evolved molecular machineries that allow them to anticipate and respond to the many changes that accompany these transitions. Circadian clocks are precise yet plastic pacemakers that allow the temporal organization of a plethora of biological process. Circadian clocks are widespread across the tree of life and while their exact molecular components differ among phyla, they tend to share common design principles. In this review, we discuss the circadian system of the filamentous fungus Neurospora crassa. Historically, this fungus has served a key role in the genetic and molecular dissection of circadian clocks, aiding in their detailed mechanistic understanding. Recent studies have provided new insights into the daily molecular dynamics that constitute the Neurospora circadian oscillator, some of which have questioned traditional paradigms describing timekeeping mechanisms in eukaryotes. In addition, recent reports support the idea of a dynamic network of transcription factors underlying the rhythmicity of thousands of genes in Neurospora, many of which oscillate only under specific conditions. Besides Neurospora, which harbors the best characterized circadian system among filamentous fungi, the recent characterization of the circadian system of the plant-pathogenic fungus Botrytis cinerea has provided additional insights into the physiological impact of the clock and potential additional functions of clock proteins in fungi. Finally, we speculate on the presence of FRQ or FRQ-like proteins in diverse fungal lineages.


A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.
Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP4M1 mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI. We identified a novel homozygous AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease. This study shows an AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability.


Use of once-daily netilmicin to treat infants with suspected sepsis in a neonatal intensive care unit.
Once-daily administration of aminoglycoside antibiotics has become the most acceptable dosing schedule for the majority of patients. There are few published data on the impact of post-natal age on aminoglycoside concentrations in preterm infants receiving once-daily dosage regimens. Netilmicin was administered as a once-daily dose of 4 mg/kg. In 141 episodes of suspected sepsis in 123 babies, trough netilmicin concentrations ranged from undetectable to 4.0 mg/l. Netilmicin concentrations were above a level of 2 mg/l in 10.6% of episodes. Netilmicin concentrations decreased with increasing post-natal age and weight. Levels were higher in males compared to females. Increased creatinine concentrations were associated with higher netilmicin concentrations. This study emphasises the importance of post-natal age as a determinant of aminoglycoside concentrations with a once-daily dosing regimen in a neonatal intensive care population. Trough levels should be carefully monitored and consideration given to extending dosage intervals particularly when netilmicin is administered once daily to preterm infants in the first week of life.


No association of serotonin transporter gene variation with sudden infant death syndrome (SIDS) in Caucasians.
Genetic studies on SIDS have been motivated by clinical, epidemiological, and/or neuropathological observations made of SIDS victims. One of the candidate genes is the serotonin transporter (5-HTT) gene, based on decreased serotonergic receptor binding observed in the brain-stems of SIDS victims. Two polymorphisms in the regulatory region of the 5-HTT gene differentially modulate gene expression (promoter, intron 2). The promoter allelic variants long (L) and extra long (XL) and the intron 2 12-repeat allele seem to be associated with SIDS; however, the 5-HTT promoter allele distribution varies widely by ethnicity. We investigated the DNA of 145 Caucasian SIDS cases and 58 controls and could find no significant association between our Caucasian SIDS cases and controls either for the promoter L allele and the intron 2 12-repeat allele, or for the combined L-12 haplotype as well as the L- or 12-containing genotypes.


[meso-5,10,15,20-Tetra-kis(3-methyl-thio-phen-2-yl)porphyrinato-κ(4) N,N',N'',N''']nickel(II) benzene hemisolvate.
In the title compound, [Ni(C40H28N4S4)]·0.5C6H6, the Ni(II) atom is in a square-planar geometry defined by four pyrrole N atoms. There is considerable buckling in the porphyrin ring with the dihedral angles between the N4 donor set and the pyrrole rings being in the range 16.24 (5)-22.47 (5)°. Each of the six-membered chelate rings is twisted about an Ni-N bond and the dihedral angles between diagonally opposite chelate rings are 21.36 (4) and 23.87 (4)°; each pair of rings is oriented in opposite directions. The methyl-thienyl rings are twisted out of the plane of the central N4 core with dihedral angles in the range 75.98 (2)-88.70 (5)°. All four methyl-thienyl groups are disordered over two sets of sites, as is commonly found with such groups, with occupancies of 0.553 (8):0.447 (8), 0.579 (7):0.421 (7), 0.796 (6):0.204 (6) and 0.956 (7):0.044 (7). The benzene solvent mol-ecule was found to be present in half-occupancy.


Percutaneous transluminal angioplasty adjunct to thrombolysis for acute middle cerebral artery rethrombosis.
To report three patients, each of whom had acute rethrombosis of a reopened middle cerebral artery after urokinase treatment for proximal stenosis (percutaneous transluminal angioplasty of the stenosis was performed adjunctive to the thrombolytic treatment to preserve the success of the thrombolysis), and a fourth patient who had percutaneous transluminal angioplasty right after the completion of thrombolysis and had no rethrombosis despite a partial dilatation of the severe stenosis. Thrombolytic treatment was carried out by a coaxial technique with a Tracker 18 catheter through a 5-F angiographic catheter; 80,000 U in 5 mL of urokinase were intermittently injected every 15 minutes after an initial dose of 250,000 U. All patients were given 3000 U of heparin with a booster dose of 1000 U every hour. Angioplasty was performed with a Stealth catheter balloon, 2 to 3 mm x 1.5 cm. Three patients recovered without hemorrhage after percutaneous transluminal angioplasty and thrombolytic treatment. Percutaneous transluminal angioplasty was unsuccessful in one patient because of the inability to pass a 2-mm Stealth balloon catheter, and the result was a second rethrombosis. This patient had a poor recovery. Acute thrombosis of the middle cerebral artery may be associated with severe proximal stenosis. Rethrombosis may occur even after complete thrombolysis. Percutaneous transluminal angioplasty may be safely performed to prevent rethrombosis.


RNA-sequencing analysis of umbilical cord plasma microRNAs from healthy newborns.
MicroRNAs are a class of small non-coding RNA that regulate gene expression at a post-transcriptional level. MicroRNAs have been identified in various body fluids under normal conditions and their stability as well as their dysregulation in disease has led to ongoing interest in their diagnostic and prognostic potential. Circulating microRNAs may be valuable predictors of early-life complications such as birth asphyxia or neonatal seizures but there are relatively few data on microRNA content in plasma from healthy babies. Here we performed small RNA-sequencing analysis of plasma processed from umbilical cord blood in a set of healthy newborns. MicroRNA levels in umbilical cord plasma of four male and four female healthy babies, from two different centres were profiled. A total of 1,004 individual microRNAs were identified, which ranged from 426 to 659 per sample, of which 269 microRNAs were common to all eight samples. Many of these microRNAs are highly expressed and consistent with previous studies using other high throughput platforms. While overall microRNA expression did not differ between male and female cord blood plasma, we did detect differentially edited microRNAs in female plasma compared to male. Of note, and consistent with other studies of this type, adenylation and uridylation were the two most prominent forms of editing. Six microRNAs, miR-128-3p, miR-29a-3p, miR-9-5p, miR-218-5p, 204-5p and miR-132-3p were consistently both uridylated and adenylated in female cord blood plasma. These results provide a benchmark for microRNA profiling and biomarker discovery using umbilical cord plasma and can be used as comparative data for future biomarker profiles from complicated births or those with early-life developmental disorders.


Cell cycle-regulated transcription of the CLB2 gene is dependent on Mcm1 and a ternary complex factor.
Clb2 is the major B-type mitotic cyclin required for entry into mitosis in the budding yeast Saccharomyces cerevisiae. We showed that accumulation of CLB2 transcripts in G2 cells is controlled at the transcriptional level and identified a 55-bp upstream activating sequence (UAS) containing an Mcm1 binding site as being necessary and sufficient for cell cycle regulation. Sequences within the cell cycle-regulated UAS were shown to bind Mcm1 in vitro, and mutation which abolished Mcm1-dependent DNA binding activity eliminated cell cycle-regulated transcription in vivo. A second protein with no autonomous DNA binding activity was also recruited into Mcm1-UAS complexes, generating a ternary complex. A point mutation in the CLB2 UAS which blocked ternary complex formation, but still allowed Mcm1 to bind, resulted in loss of cell cycle regulation in vivo, suggesting that the ternary complex factor is also important in control of CLB2 transcription. We discuss the possibility that the CLB2 gene is coregulated with other genes known to be regulated with the same periodicity and suggest that Mcm1 and the ternary complex factor may coordinately regulate several other G2-regulated transcripts.


Flow-parametric regulation of shear-driven phase separation in two and three dimensions.
The Cahn-Hilliard equation with an externally prescribed chaotic shear flow is studied in two and three dimensions. The main goal is to compare and contrast the phase separation in two and three dimensions, using high-resolution numerical simulation as the basis for the study. The model flow is parametrized by its amplitudes (thereby admitting the possibility of anisotropy), length scales, and multiple time scales, and the outcome of the phase separation is investigated as a function of these parameters as well as the dimensionality. In this way, a parameter regime is identified wherein the phase separation and the associated coarsening phenomenon are not only arrested but in fact the concentration variance decays, thereby opening up the possibility of describing the dynamics of the concentration field using the theories of advection diffusion. This parameter regime corresponds to long flow correlation times, large flow amplitudes and small diffusivities. The onset of this hyperdiffusive regime is interpreted by introducing Batchelor length scales. A key result is that in the hyperdiffusive regime, the distribution of concentration (in particular, the frequency of extreme values of concentration) depends strongly on the dimensionality. Anisotropic scenarios are also investigated: for scenarios wherein the variance saturates (corresponding to coarsening arrest), the direction in which the domains align depends on the flow correlation time. Thus, for correlation times comparable to the inverse of the mean shear rate, the domains align in the direction of maximum flow amplitude, while for short correlation times, the domains initially align in the opposite direction. However, at very late times (after the passage of thousands of correlation times), the fate of the domains is the same regardless of correlation time, namely alignment in the direction of maximum flow amplitude. A theoretical model to explain these features is proposed. These features and the theoretical model carry over to the three-dimensional case, albeit that an extra degree of freedom pertains, such that the dynamics of the domain alignment in three dimensions warrant a more detailed consideration, also presented herein.


Measuring nepotism through shared last names: the case of Italian Academia.
Nepotistic practices are detrimental for academia. Here I show how disciplines with a high likelihood of nepotism can be detected using standard statistical techniques based on shared last names among professors. As an example, I analyze the set of all 61,340 Italian academics. I find that nepotism is prominent in Italy, with particular disciplinary sectors being detected as especially problematic. Out of 28 disciplines, 9 - accounting for more than half of Italian professors - display a significant paucity of last names. Moreover, in most disciplines a clear north-south trend emerges, with likelihood of nepotism increasing with latitude. Even accounting for the geographic clustering of last names, I find that for many disciplines the probability of name-sharing is boosted when professors work in the same institution or sub-discipline. Using these techniques policy makers can target cuts and funding in order to promote fair practices.


Validity of particle size analysis techniques for measurement of the attrition that occurs during vacuum agitated powder drying of needle-shaped particles.
Analysis of needle-shaped particles of cellobiose octaacetate (COA) obtained from vacuum agitated drying experiments was performed using three particle size analysis techniques: laser diffraction (LD), focused beam reflectance measurements (FBRM) and dynamic image analysis. Comparative measurements were also made for various size fractions of granular particles of microcrystalline cellulose. The study demonstrated that the light scattering particle size methods (LD and FBRM) can be used qualitatively to study the attrition that occurs during drying of needle-shaped particles, however, for full quantitative analysis, image analysis is required. The algorithm used in analysis of LD data assumes the scattering particles are spherical regardless of the actual shape of the particles under evaluation. FBRM measures a chord length distribution (CLD) rather than the particle size distribution (PSD), which in the case of needles is weighted towards the needle width rather than their length. Dynamic image analysis allowed evaluation of the particles based on attributes of the needles such as length (e.g. the maximum Feret diameter) or width (e.g. the minimum Feret diameter) and as such, was the most informative of the techniques for the analysis of attrition that occurred during drying.


Knee Pain from Osteoarthritis: Pathogenesis, Risk Factors, and Recent Evidence on Physical Therapy Interventions.
For patients presenting knee pain coming from osteoarthritis (OA), non-pharmacological conservative treatments (e.g., physical therapy interventions) are among the first methods in orthopedics and rehabilitation to prevent OA progression and avoid knee surgery. However, the best strategy for each patient is difficult to establish, because knee OA's exact causes of progression are not entirely understood. This narrative review presents (i) the most recent update on the pathogenesis of knee OA with the risk factors for developing OA and (ii) the most recent evidence for reducing knee pain with physical therapy intervention such as Diathermy, Exercise therapy, Ultrasounds, Knee Brace, and Electrical stimulation. In addition, we calculated the relative risk reduction in pain perception for each intervention. Our results show that only Brace interventions always reached the minimum for clinical efficiency, making the intervention significant and valuable for the patients regarding their Quality of Life. In addition, more than half of the Exercise and Diathermy interventions reached the minimum for clinical efficiency regarding pain level. This literature review helps clinicians to make evidence-based decisions for reducing knee pain and treating people living with knee OA to prevent knee replacement.


Reversal of late septic shock with supraphysiologic doses of hydrocortisone.
Preliminary studies have suggested that low doses of corticosteroids might rapidly improve hemodynamics in late septic shock treated with catecholamines. We examined the effect of hydrocortisone on shock reversal, hemodynamics, and survival in this particular setting. Prospective, randomized, double-blind, placebo-controlled study. Two intensive care units of a University hospital. Forty-one patients with septic shock requiring catecholamine for >48 hrs. Patients were randomly assigned either hydrocortisone (100 mg i.v. three times daily for 5 days) or matching placebo. Reversal of shock was defined by a stable systolic arterial pressure (>90 mm Hg) for > or =24 hrs without catecholamine or fluid infusion. Of the 22 hydrocortisone-treated patients and 19 placebo-treated patients, 15 (68%) and 4 (21%) achieved 7-day shock reversal, respectively, a difference of 47% (95% confidence interval 17% to 77%; p = .007). Serial invasive hemodynamic measurements for 5 days did not show significant differences between both groups. At 28-day follow-up, reversal of shock was higher in the hydrocortisone group (p = .005). Crude 28-day mortality was 7 (32%) of 22 treated patients and 12 (63%) of 19 placebo patients, a difference of 31% (95% confidence interval 1% to 61%; p = .091). Shock reversal within 7 days after the onset of corticosteroid therapy was a very strong predictor of survival. There were no significant differences in outcome in responders and nonresponders to a short corticotropin test. The respective rates of gastrointestinal bleeding and secondary infections did not differ between both groups. Administration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock for a mean of >96 hrs resulted in a significant improvement in hemodynamics and a beneficial effect on survival. These beneficial effects do not appear related to adrenocortical insufficiency.


Synthesis, antifungal activity, and QSAR studies of 1,6-dihydropyrimidine derivatives.
A practical synthesis of pyrimidinone would be very helpful for chemists because pyrimidinone is found in many bioactive natural products and exhibits a wide range of biological properties. The biological significance of pyrimidine derivatives has led us to the synthesis of substituted pyrimidine. With the aim of developing potential antimicrobials, new series of 5-cyano-6-oxo-1,6-dihydro-pyrimidine derivatives namely 2-(5-cyano-6-oxo-4-substituted (aryl)-1,6-dihydropyrimidin-2-ylthio)-N-substituted (phenyl) acetamide (C1-C41) were synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), mass analysis, and proton nuclear magnetic resonance ((1)H NMR). All the compounds were screened for their antifungal activity against Candida albicans (MTCC, 227). Quantitative structure activity relationship (QSAR) studies of a series of 1,6-dihydro-pyrimidine were carried out to study various structural requirements for fungal inhibition. Various lipophilic, electronic, geometric, and spatial descriptors were correlated with antifungal activity using genetic function approximation. Developed models were found predictive as indicated by their square of predictive regression values (r(2pred)) and their internal and external cross-validation. Study reveals that CHI_3_C, Molecular_SurfaceArea, and Jurs_DPSA_1 contributed significantly to the activity along with some electronic, geometric, and quantum mechanical descriptors. A careful analysis of the antifungal activity data of synthesized compounds revealed that electron withdrawing substitution on N-phenyl acetamide ring of 1,6-dihydropyrimidine moiety possess good activity.


Transducing properties of a pre-structured α-helical DPT-peptide containing a short canine adenovirus type 2 E4orf4 PP2A1-binding sequence.
Induction of the death pathway resulting from the specific interaction of the PP2A1 phosphatase with adenoviral E4orf4 protein is a promising approach for cancer therapy. With the aim of deregulating tumor pathways, and mimicking E4orf4 anti-cancer signal, we have previously proposed the DPT technology concept, based on design of specific PP1/PP2A interacting penetrating peptides. Using biochemical, structural and cell survival experiments, we have characterized new DPT-peptides containing short PP2A binding sequences. We identified overlapping sequences, located within the N-terminal domain E4orf423-46 of canine adenoviral E4orf4 protein, that interact with the PP2A-Bα subunit of PP2A1 holoenzyme. We characterized DPT-E4orf44 and TAT-E4orf44, two bi-partite cell penetrating peptides containing the 12 PP2A1 binding residues of the canine type 2 E4orf427-38 sequence, respectively fused to the DPT-sh1 and TAT shuttle sequences. Surprisingly DPT-E4orf44, in contrast to inactive TAT-E4orf44, adopted a well defined α-helical structure and co-precipitated PP2A1 from HeLa cell extracts. DPT-E4orf44 also internalized streptavidin-HRP and inhibited survival of HeLa cells more efficiently than TAT, TAT-E4orf44 or the previously published anti-tumor TAT-derived peptide shepherdin. DPT-E4orf44 also efficiently inhibited the survival of human adherent transformed cells, including wild type and p53 mutated colonic HCT116 cells, without affecting survival of human non-transformed fibroblasts. We characterized the transducing properties of a new α-helical DPT-E4orf44 peptide containing a short PP2A-interacting sequence from canine Adenoviral E4orf4 protein. Our results suggest that α-helical structured DPT peptides specifically interacting with PP2A could be a valuable anti-cancer drug design scaffold.


Bilateral thoracic endometriosis affecting the lung and diaphragm.
Endometriosis of the lung and the diaphragm is rare. Patients may present with symptoms such as shortness of breath, chest pain, and shoulder pain or they may be asymptomatic. Of note, there have been few reports of bilateral catamenial disease, and no reports, to our knowledge, of bilateral pathology proven pulmonary parenchymal endometriosis. A 43-year-old with stage IV endometriosis and large leiomyoma underwent a laparoscopic hysterectomy and treatment of endometrial lesions in 2005. In March and April of 2011, she presented with bilateral pneumothoraces. She subsequently underwent video-assisted thoracoscopy as well as resection and fulguration of bilateral lung and diaphragmatic endometriosis. Pathology confirmed endometrial implants in the lung parenchyma bilaterally. Catamenial pneumothorax is the most common presentation of thoracic endometriosis. However, bilateral catamenial pneumothoraces are rare. To the best of our knowledge, this case reflects the first report of pathology proven bilateral lung and diaphragm endometriosis.


Improving the use of research evidence in guideline development: 16. Evaluation.
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the last of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. We reviewed the literature on evaluating guidelines and recommendations, including their quality, whether they are likely to be up-to-date, and their implementation. We also considered the role of guideline developers in undertaking evaluations that are needed to inform recommendations. We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. Our answers to these questions were informed by a review of instruments for evaluating guidelines, several studies of the need for updating guidelines, discussions of the pros and cons of different research designs for evaluating the implementation of guidelines, and consideration of the use of uncertainties identified in systematic reviews to set research priorities. How should the quality of guidelines or recommendations be appraised? WHO should put into place processes to ensure that both internal and external review of guidelines is undertaken routinely. A checklist, such as the AGREE instrument, should be used. The checklist should be adapted and tested to ensure that it is suitable to the broad range of recommendations that WHO produces, including public health and health policy recommendations, and that it includes questions about equity and other items that are particularly important for WHO guidelines. When should guidelines or recommendations be updated? Processes should be put into place to ensure that guidelines are monitored routinely to determine if they are in need of updating. People who are familiar with the topic, such as Cochrane review groups, should do focused, routine searches for new research that would require revision of the guideline. Periodic review of guidelines by experts not involved in developing the guidelines should also be considered. Consideration should be given to establishing guideline panels that are ongoing, to facilitate routine updating, with members serving fixed periods with a rotating membership. How should the impact of guidelines or recommendations be evaluated? WHO headquarters and regional offices should support member states and those responsible for policy decisions and implementation to evaluate the impact of their decisions and actions by providing advice regarding impact assessment, practical support and coordination of efforts. Before-after evaluations should be used cautiously and when there are important uncertainties regarding the effects of a policy or its implementation, randomised evaluations should be used when possible. What responsibility should WHO take for ensuring that important uncertainties are addressed by future research when the evidence needed to inform recommendations is lacking? Guideline panels should routinely identify important uncertainties and research priorities. This source of potential priorities for research should be used systematically to inform priority-setting processes for global research.


Acute hyperalgesia and delayed dry eye after corneal abrasion injury.
Corneal nerves mediate pain from the ocular surface, lacrimation, and blinking, all of which protect corneal surface homeostasis and help preserve vision. Because pain, lacrimation and blinking are rarely assessed at the same time, it is not known whether these responses and their underlying mechanisms have similar temporal dynamics after acute corneal injury. We examined changes in corneal nerve density, evoked and spontaneous pain, and ocular homeostasis in Sprague-Dawley male rats after a superficial epithelial injury with heptanol. We also measured changes in calcitonin gene-related peptide (CGRP), which has been implicated in both pain and epithelial repair. Hyperalgesia was seen 24 hours after abrasion injury, while basal tear production was normal. One week after abrasion injury, pain responses had returned to baseline levels and dry eye symptoms emerged. There was no correlation between epithelial nerve density and pain responses. Expression of both ATF3 (a nerve injury marker) and CGRP increased in trigeminal ganglia 24 hours after injury when hyperalgesia was seen, and returned to normal one week later when pain behavior was normal. These molecular changes were absent in the contralateral ganglion, despite reductions in corneal epithelial nerve density in the uninjured eye. By contrast, CGRP was upregulated in peripheral corneal endings 1 week after injury, when dry eye symptoms emerged. Our results demonstrate dynamic trafficking of CGRP within trigeminal sensory nerves following corneal injury, with elevations in the ganglion correlated with pain behaviors and elevations in peripheral endings correlated with dry eye symptoms.


Social behavior profile in young males with fragile X syndrome: characteristics and specificity.
The present study characterizes distinctive and specific features of social behavior impairment, termed social behavior profile (SBP), in young males with fragile X syndrome (FraX). Fourteen males with FraX and autism (FraX+Aut), ages 3-8 years, were compared with either 41 FraX boys without autism (Aut), 7 age-matched males with developmental language delay and autism (DLD+Aut), or with 11 boys with non-selected (for language delay) idiopathic autism (IA), on several standardized instruments assessing social behavior and autistic features (i.e., autism diagnostic interview-revised, ADI-R). We found that FraX+Aut subjects displayed more impairment in overall cognition, problem/aberrant behavior, and adaptive behavior than the rest of the FraX cohort, even when individuals with pervasive developmental disorder (PDD) were included in the latter. Compared to both DLD+Aut and IA, FraX+Aut males were less impaired in ADI-R reciprocal social interaction (RECS) domain. However, boys with FraX+Aut were in general comparable to DLD+Aut subjects in problem/aberrant and adaptive behaviors. Based on the contrast between FraX+Aut and non-autistic FraX and DLD+Aut, we were able to identify measures (e.g., child behavior checklist (CBCL) withdrawn subscale) that better define social interaction impairment in FraX. Comparisons with DLD+Aut and IA led to the conclusion that communication impairment (COMM) and stereotypic behavior contribute relatively more to the diagnosis of autism in FraX+Aut. In agreement with recent studies, our data suggest that FraX+Aut, and more generally SBP, is a distinctive subphenotype among boys with FraX, which may share some pathophysiological mechanisms with IA.


DPI Selectively Inhibits Intracellular NADPH Oxidase Activity in Human Neutrophils.
Neutrophils are capable of producing significant amounts of reactive oxygen species (ROS) by the phagocyte NADPH oxidase, which consists of membrane-bound and cytoplasmic subunits that assemble during activation. Neutrophils harbor two distinct pools of the membrane-localized oxidase components, one expressed in the plasma membrane and one in the membranes of intracellular granules. Assembly of active oxidase at either type of membrane leads to release of extracellular ROS or to the production of ROS inside intracellular compartments, respectively. The cytoplasmic NADPH oxidase subunit p40phox seems selectively critical for the ability to generate intracellular ROS, and the recent characterization of patients with p40phox deficiency implies that selective loss of intracellular neutrophil ROS leads to disease with pronounced hyperinflammatory features, suggesting that these ROS are critical for regulation of inflammation. This study aimed at characterizing two pharmacological NADPH oxidase inhibitors, the newly described GSK2795039 and the widely used diphenyleneiodonium (DPI), focusing on their abilities to inhibit human neutrophil ROS production extra- and intracellularly. Whereas GSK2795039 blocked extra- and intracellular NADPH oxidase activity equally, DPI was found to selectively interfere with intracellular ROS production. Selectivity for the intracellular NADPH oxidase was evident as a lower IC50 value, faster onset, and irreversibility of inhibition. We found no evidence of direct interactions between DPI and p40phox, but the selectivity of DPI confirms that regulation of NADPH oxidase activity in neutrophils differs depending on the subcellular localization of the enzyme. This information may be used to pharmacologically mimic p40phox deficiency and to further our understanding of how intracellular ROS contribute to health and disease.


[Effect of a new bradycardic substance on the isolated rabbit heart].
Beside wall tension and contractility, heart rate is a major determinant of myocardial oxygen consumption. Therefore, a decrease in heart rate could prevent ischemia or reduce its consequences. We examined the effect of a new bradycardic agent of the benzazepinone-type (DK-AH 269) on eight isolated, saline-perfused rabbit hearts, bradycardia resulted from a specific blockade of i(f)-channels in sinus node cells. After control measurements (C), the substance was added in three increasing concentrations (D1: 10(-8) M, D2: 10(-7) M, D3: 10(-6) M). We observed a dose-dependent reduction in heart rate (C: 206 +/- 25, D1: 195 +/- 30, D2: 77 +/- 41, D3: 154 +/- 48/min). In the highest dosage, the duration of diastole was increased by 100%. To characterize systolic function, we measured stroke volume (SV), peak left ventricular pressure (LVPmax) and its first derivative (dP/dtmax). Aortic flow was slightly decreased whereas SV increased to 108% of control after initial reduction at the two lower dosages. LVPmax remained unchanged, and dP/dtmax was dose-dependently reduced to 91, 81, and 70% of control (C: 1885 +/- 376, D1: 1721 +/- 525, D2: 1526 +/- 504, D3: 1327 +/- 337 mm Hg/s); dP/dtmin as a measure of early relaxation was also reduced. The coronary flow per beat did not change compared with control in the presence of the two lower doses of DK-AH 269, but was significantly increased with the highest dose (C: 0.29 +/- 0.06, D1: 0.28 +/- 0.07, D2: 0.29 +/- 0.09, D3: 0.34 +/- 0.11 ml). The myocardial oxygen demand was dose-dependently decreased (C: 10.4 +/- 2.5, D1: 9.6 +/- 2.5, D2: 8.8 +/- 2.6, D3: 7.9 +/- 2.4 ml/min/100 g). The relation between subendocardial and subepicardial flow, assessed with colored microspheres, exhibited no changes in the presence of the highest dose of DK-AH 269 (C: 1.28 +/- 0.09, D3: 1.27 +/- 0.08). DK-AH 269 reduced heart rate in isolated rabbit hearts and increased the duration of diastole. Whereas systolic function was primarily left unchanged, coronary flow per beat and oxygen consumption were decreased. According to our results, this new bradycardic agent could be useful in treating coronary heart disease.


High levels of anti-tuberculin (IgG) antibodies correlate with the blocking of T-cell proliferation in individuals with high exposure to Mycobacterium tuberculosis.
To determine the effect of anti-tuberculin antibodies in the T-cell proliferation in response to tuberculin and Candida antigens in individuals with different levels of tuberculosis (TB) risk. Sixteen high-risk TB individuals, 30 with an intermediate TB risk (group A), and 45 with a low TB risk (group B), as well as 49 control individuals, were studied. Tuberculin skin test (TST) results were analyzed and serum levels of antibodies (IgG and IgM) against purified protein derivative (PPD) were measured by ELISA. Tuberculin and Candida antigens were used to stimulate T-cell proliferation in the presence of human AB serum or autologous serum. High levels of anti-tuberculin IgG antibodies were found to be significantly associated with the blocking of T-cell proliferation responses in cultures stimulated with tuberculin but not with Candida antigens in the presence of autologous serum. This phenomenon was particularly frequent in high-risk individuals with high levels of anti-tuberculin IgG antibodies in the autologous serum when compared to the other risk groups, which exhibited lower levels of anti-tuberculin antibodies. Although cellular immunity plays a central role in the protection against TB, humoral immunity is critical in the control of Mycobacterium tuberculosis infection in high-risk individuals with latent TB infection.


Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.
Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10(-8). UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50,008 unique samples: 10,002 individuals with low FEV1, 10,000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 × 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 × 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Medical Research Council.


T lymphocytes in genital lymph nodes protect mice from intravaginal infection with herpes simplex virus type 2.
Herpes simplex virus type 2 (HSV-2) is a human venereal pathogen that causes lethal neurological illness after intravaginal inoculation into BALB/cJ mice. Intravaginal vaccination of mice with an attenuated strain of HSV-2 rapidly induces immunity to a lethal intravaginal challenge with wild-type HSV-2. This resistance is transferrable to syngeneic mice with genital lymph node (GLN) cells but not with cells from other lymphoid sources. Here we demonstrate that minimal numbers of HSV-2-stimulated GLN T lymphocytes are required for resistance to genital infection by HSV-2 and that such cells migrate preferentially into HSV-2-infected genital tissue. Furthermore, the results suggest that HSV-2-specific cytotoxic T lymphocytes from the GLN may be one effector cell population participating locally in genital immunity to the virus. These findings indicate that mucosal immunity to genital HSV-2 infection requires the antigen stimulation of migratory T cells in the GLN.


Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series.
Melorheostosis (MEL) is an uncommon, sclerosing disease, characterised by hyperostosis of long bones, resembling the flowing of candle wax. The disease is sporadic and the pathogenesis is still poorly understood. Occasionally, the same family can include individuals with MEL and Osteopoikilosis (OPK), a disease characterised by multiple round foci of increased bone density. LEMD3 gene mutations are related to OPK and Buschke-Ollendorff Syndrome, a genetic condition in which an association between MEL, OPK and skin lesions is observed. In rare cases, LEMD3 mutations and recently mosaic MAP2K1 gene mutations have been correlated to MEL suggesting that somatic mosaicism could be causative of the disease. In this study, we described the clinical, radiological and molecular findings of 19 individuals with MEL and 8 with OPK and compared the results to the medical literature. The molecular analyses of this case series corroborate the available data in the medical literature, indicating that LEMD3 germline mutations are not a major cause of isolated MEL and reporting five further cases of OPK caused by LEMD3 germline mutations.


Variables Related to Communication About Prognosis Between Nurses and Patients at Heart Failure Clinics in Sweden and the Netherlands.
In contrast to recommendations in recent guidelines, prognosis is not optimally discussed with patients with heart failure (HF). Reasons for not doing so can be related to both patient and provider characteristics. The purpose of the study was to explore which patient- and nurse-related variables influence discussing prognosis with patients at an HF clinic. Data from a previous survey on attitudes and clinical practice of HF nurses on discussing prognosis that was conducted in Sweden and the Netherlands were combined with data from a registration on topics that nurses discussed with their patients during a prespecified week at the HF clinic. Multivariable logistic regression analysis was performed to assess which variables are related to discussing prognosis. A total of 275 HF nurses (mean age, 49 years) and data of 1633 patients with HF (mean age, 71 years) were included in the study. Prognosis was discussed with 42% of all patients during the visit at the HF clinic. Patients with whom prognosis was discussed were more often in New York Heart Association classes III to IV (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.44-2.26). Nurses discussing prognosis reported more knowledge on the topic (OR, 1.71; 95% CI, 1.36-2.16) and discussed more topics with the patient (OR, 1.27; 95% CI, 1.21-1.32). Dutch HF nurses were more likely to discuss prognosis compared with their Swedish colleagues (OR, 1.83; 95% CI, 1.43-2.33). Discussing prognosis with patients with HF by nurses at the HF clinic is related to the characteristics of patients and HF nurses. Future interventions to improve communications about prognosis therefore should have a broad approach.


Monoclonal antibodies against human pancreatic adenocarcinoma: distribution of DU-PAN-2 antigen on glandular epithelia and adenocarcinomas.
This report describes the distribution of antigen DU-PAN-2, defined by a monoclonal antibody raised against human pancreatic carcinoma cells, on a variety of tumors and nonneoplastic tissues. With the use of an immunoperoxidase technique, the antigen was detected on 16 of 16 pancreatic carcinomas, on 5 of 5 gallbladder or bile duct carcinomas, on the great majority of stomach adenocarcinomas, and, less commonly, on adenocarcinomas of other primary sites. Substantial intratumor heterogeneity of antigen expression was noted. DU-PAN-2 antigen was present on many types of normal glandular epithelial cells but often was more weakly expressed than on the corresponding tumors. The immunomorphology of staining, coupled with biochemical information known about the antigen, supports the notion that the DU-PAN-2 antigen is a mucin-like substance. Its relative restriction of expression on different types of glandular epithelium suggests that DU-PAN-2 antibody might be a useful reagent for helping to determine the site of origin of adenocarcinomas.


Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement.
Many diabetic patients continue to have hyperglycaemia on maximal sulphonylurea therapy. Five different therapeutic options, with the prime aim of achieving normal fasting plasma glucose concentrations, have been compared in 15 asymptomatic, sulphonylurea-treated type 2 diabetic patients in a randomized crossover study of 8-week periods. In 24 h metabolic profiles the overnight mean (+/- 1SD) basal plasma glucose level on sulphonylurea therapy was 8.9 +/- 4.2 mmol/l. This was slightly improved with added metformin therapy (7.3 +/- 4.3 mmol/l, p = 0.013), but reduced to normal by added ultralente insulin (5.2 +/- 3.2 mmol/l, p less than 0.001), ultralente insulin alone (5.1 +/- 1.6 mmol/l, p = 0.005) or by ultralente and soluble insulin (4.7 +/- 1.4 mmol/l, p = 0.003). The mean glycosylated haemoglobin concentration was reduced significantly only by the treatments which included insulin. None of the patients had severe or incapacitating hypoglycaemia and only when on additional soluble insulin did patients show a significant gain in weight. Combining sulphonylurea therapy with ultralente insulin did not significantly improve overall glucose control over treatment with ultralente alone, although the insulin dose required to restore fasting normoglycaemia was significantly lower (median (interquartile range), 25 (12-41) versus 40 (27-80) U/day, p = 0.001). In type 2 diabetic patients who continue to have fasting hyperglycaemia on maximal sulphonylurea therapy, fasting normoglycaemia can be achieved easily, without minimal changes in diet or lifestyle, by means of a basal insulin supplement.


Adenovirus disease in six small bowel, kidney and heart transplant recipients; pathology and clinical outcome.
Adenoviruses are emerging as important viral pathogens in hematopoietic stem cell and solid organ transplant recipients, impacting morbidity, graft survival, and even mortality. The risk seems to be highest in allogeneic hematopoietic stem cell transplant recipients as well as heart, lung, and small bowel transplant recipients. Most of the adenovirus diseases develop in the first 6 months after transplantation, particularly in pediatric patients. Among abdominal organ recipients, small bowel grafts are most frequently affected, presumably due to the presence of a virus reservoir in the mucosa-associated lymphoid tissue. Management of these infections may be difficult and includes the reduction of immunosuppression, whenever possible, combined with antiviral therapy, if necessary. Therefore, an awareness of the pathology associated with such infections is important in order to allow early detection and specific treatment. We reviewed six transplant recipients (small bowel, kidney, and heart) with adenovirus graft involvement from two institutions. We sought to compare the diagnostic morphology and the clinical and laboratory findings. The histopathologic features of an adenovirus infection of the renal graft and one native kidney in a heart transplant recipient included a vaguely granulomatous mixed inflammatory infiltrate associated with rare cells showing a cytopathic effect (smudgy nuclei). A lymphocytic infiltrate, simulating T cell rejection, with admixture of eosinophils was also seen. In the small bowel grafts, there was a focal mixed inflammatory infiltrate with associated necrosis in addition to cytopathic effects. In the heart, allograft adenovirus infection was silent with no evidence of inflammatory changes. Immunohistochemical stain for adenovirus was positive in all grafts and in one native kidney. All patients were subsequently cleared of adenovirus infection, as evidenced by follow-up biopsies, with no loss of the grafts. Adenovirus infection can involve allografts as well as native organs in solid organ transplant recipients. Infection is associated with variable necrosis and acute inflammation, in addition to a rejection-like infiltrate. Hematuria in non-renal solid organ transplant recipients may be associated with adenovirus nephritis and clinically silent graft involvement. Prompt diagnosis (aided by immunohistochemistry (IHC) and serology), with specific treatment, can prevent graft loss.


Laryngeal cleft and eosinophilic gastroenteritis: report of 2 cases.
Although laryngotracheoesophageal clefts are often found in association with other well-described anomalies, we know of no previous reported association with eosinophilic gastroenteritis, a disorder of unknown etiology characterized by eosinophilic infiltration of the gastrointestinal tract. We treated 2 children who had laryngeal clefts and eosinophilic gastroenteritis. Since the esophageal inflammatory changes found in eosinophilic gastroenteritis may persist despite aggressive therapy, management of the laryngotracheoesophageal clefts is more complicated. The diagnosis of eosinophilic gastroenteritis should not be overlooked in patients with laryngotracheoesophageal clefts and warrants prompt referral to a pediatric gastroenterologist.


Evaluation of Hydration Free Energy by Level-Set Variational Implicit-Solvent Model with Coulomb-Field Approximation.
In this article, we systematically apply a novel implicit-solvent model, the variational implicit-solvent model (VISM) together with the Coulomb-Field Approximation (CFA), to calculate the hydration free energy of a large set of small organic molecules. Because these molecules have been studied in detail by molecular dynamics simulations and other implicit-solvent models, they provide a good benchmark for evaluating the performance of VISM-CFA. With all-atom Amber force field parameters, VISM-CFA is able to reproduce well not only the experimental and MD simulated total hydration free energy but also the polar and nonpolar contributions individually. The correlation between VISM-CFA and experiments is R2 = 0.763 for the total hydration free energy, with a root-mean-square deviation (RMSD) of 1.83 kcal/mol, and the correlation to results from TIP3P explicit water MD simulations is R2 = 0.839 with a RMSD = 1.36 kcal/mol. In addition, we demonstrate that VISM captures dewetting phenomena in the p53/MDM2 complex and hydrophobic characteristics in the system. This work demonstrates that the level-set VISM-CFA can be used to study the energetic behavior of realistic molecular systems with complicated geometries in solvation, protein-ligand binding, protein-protein association, and protein folding processes.


Prognostic significance of c-erbB-2/HER2 expression in advanced uterine cervical carcinoma with para-aortic lymph node metastasis treated with radiation therapy.
This paper looks at whether c-erbB-2/HER2 expression in uterine cervical carcinoma before treatment is a predictive parameter of prognosis in patients with para-aortic lymph node metastasis (PALN) in advanced disease after treatment with radiation therapy (RT). Twenty-one patients with PALN at the first visit and/or during follow-up and treated with RT for PALN lesions were studied. Their clinical stages were IIIB or greater and they were referred to the National Institute of Radiological Sciences Hospital for RT between 1987 and 1995. They consisted of 12 patients with PALN detected at the first visit and nine with PALN detected during the follow-up period. All patients had no distant metastasis except PALN. They were treated with a combination of external whole pelvis and intracavitary irradiation to the primary pelvic lesions. The PALN was treated with external irradiation alone with anterior-posterior parallel opposed fields and anterior oblique fields or anterior-posterior parallel opposed oblique fields. The average total dose to PALN was 53.3 Gy (40-61Gy). Tissue samples were obtained from cervical tumors (primary lesions) before RT. Immunohistochemical staining was performed using anti-c-erbB-2/HER2 monoclonal antibody for conventional paraffin sections. c-erbB-2/HER2 positive staining was observed in cancer membrane and cytoplasm. Nine specimens were positive for c-erb-B2/HER2 and the total positive rate was 43%. The 5-year survival rate was 38% for all patients. The 5-year survival rate of the c-erbB-2/HER2 positive patients was 28%, representing a trend toward poorer prognosis than the 52% of negative patients (P = 0.10). Multivariate analysis using Cox proportional hazards model showed that c-erbB-2/HER2 was an independent prognostic factor (P = 0.024). The present study suggests that c-erbB-2/HER2 expression of cervical tumors might be a predictive parameter of prognosis after radiation therapy for PALN of very advanced uterine cervical carcinoma patients.


Evaluation of an ethnopharmacologically selected Bhutanese medicinal plants for their major classes of phytochemicals and biological activities.
As many as 229 medicinal plants have been currently used in the Bhutanese Traditional Medicine (BTM) as a chief ingredient of polyherbal formulations and these plants have been individually indicated for treating various types of infections including malaria, tumor, and microbial. We have focused our study only on seven species of these plants. We aim to evaluate the antiplasmodial, antimicrobial, anti-Trypanosoma brucei rhodesiense and cytotoxicity activities of the seven medicinal plants of Bhutan selected using an ethno-directed bio-rational approach. This study creates a scientific basis for their use in the BTM and gives foundation for further phytochemical and biological evaluations which can result in the discovery of new drug lead compounds. A three stage process was conducted which consisted of: (1) an assessment of a pharmacopoeia and a formulary book of the BTM for their mode of plant uses; (2) selecting 25 anti-infective medicinal plants based on the five established criteria, collecting them, and screening for their major classes of phytochemicals using appropriate test protocols; and (3) finally analyzing the crude extracts of the seven medicinal plants, using the standard test protocols, for their antiplasmodial, antimicrobial, anti-Trypanosoma brucei rhodesiense and cytotoxicity activities as directed by the ethnopharmacological uses of each plant. Out of 25 medicinal plants screened for their major classes of phytochemicals, the majority contained tannins, alkaloids and flavonoids. Out of the seven plant species investigated for their biological activities, all seven of them exhibited mild antimicrobial properties, five plants gave significant in vitro antiplasmodial activities, two plants gave moderate anti-Trypanosoma brucei rhodesiense activity, and one plant showed mild cytotoxicity. Meconopsis simplicifolia showed the highest antiplasmodial activity with IC(50) values of 0.40 μg/ml against TM4/8.2 strain (a wild type chloroquine and antifolate sensitive strain) and 6.39 μg/ml against K1CB1 (multidrug resistant strain) strain. Significantly the extracts from this plant did not show any cytotoxicity. These findings provide the scientific basis for the use of seven medicinal plants in the BTM for the treatment of malaria, microbial infections, infectious fevers, and the Trypanosoma brucei rhodesiense infection. The results also form a good preliminary basis for the prioritization of candidate plant species for further in-depth phytochemical and pharmacological investigations toward our quest to unearth lead antiparasitic, anticancer and antimicrobial compounds.


Lethality in a murine model of pulmonary anthrax is reduced by combining nuclear transport modifier with antimicrobial therapy.
In the last ten years, bioterrorism has become a serious threat and challenge to public health worldwide. Pulmonary anthrax caused by airborne Bacillus anthracis spores is a life-threatening disease often refractory to antimicrobial therapy. Inhaled spores germinate into vegetative forms that elaborate an anti-phagocytic capsule along with potent exotoxins which disrupt the signaling pathways governing the innate and adaptive immune responses and cause endothelial cell dysfunction leading to vascular injury in the lung, hypoxia, hemorrhage, and death. Using a murine model of pulmonary anthrax disease, we showed that a nuclear transport modifier restored markers of the innate immune response in spore-infected animals. An 8-day protocol of single-dose ciprofloxacin had no significant effect on mortality (4% survival) of A/J mice lethally infected with B. anthracis Sterne. Strikingly, mice were much more likely to survive infection (52% survival) when treated with ciprofloxacin and a cell-penetrating peptide modifier of host nuclear transport, termed cSN50. In B. anthracis-infected animals treated with antibiotic alone, we detected a muted innate immune response manifested by cytokines, tumor necrosis factor alpha (TNFα), interleukin (IL)-6, and chemokine monocyte chemoattractant protein-1 (MCP-1), while the hypoxia biomarker, erythropoietin (EPO), was greatly elevated. In contrast, cSN50-treated mice receiving ciprofloxacin demonstrated a restored innate immune responsiveness and reduced EPO level. Consistent with this improvement of innate immunity response and suppression of hypoxia biomarker, surviving mice in the combination treatment group displayed minimal histopathologic signs of vascular injury and a marked reduction of anthrax bacilli in the lungs. We demonstrate, for the first time, that regulating nuclear transport with a cell-penetrating modifier provides a cytoprotective effect, which enables the host's immune system to reduce its susceptibility to lethal B. anthracis infection. Thus, by combining a nuclear transport modifier with antimicrobial therapy we offer a novel adjunctive measure to control florid pulmonary anthrax disease.


Molecular radiobiology: the state of the art.
Traditional cytotoxic agents used in cancer therapy were initially discovered based on their ability to kill rapidly dividing cells. The targets of these early-generation agents were typically one or more aspects of DNA synthesis or mitosis. Thus, dose-limiting toxicities commonly associated with these agents include GI dysfunction, immunosuppression, and other consequences of injury to normal tissues in which cells are replicating under normal physiologic conditions. Although many of these agents still play an important role in cancer therapy when given concurrently with radiation therapy, the major thrust of radiobiology research in the last two decades has focused on discovering tumor-specific traits that might be exploited for more selective targeting that would enhance the efficacy of radiotherapy with less normal tissue toxicity. These newer generation molecular targeted therapies interfere with the growth of tumor cells by inhibiting genes and their protein products that are needed specifically by the tumor for survival and expansion. These agents can be complementary to radiotherapy, a spatially targeted agent. Although there have been extraordinary technical advances in radiotherapy in recent years, we are reaching the limits of improvements that radiotherapy delivery technology can bring and need different approaches. This review will highlight promising new tumor biology-based targets and other novel strategies to reduce normal tissue injury, increase tumor control, and expand the use of radiotherapy to treat widespread metastatic disease.


Identifying infants at increased risk for late initiation of immunizations: maternal and provider characteristics.
We identified maternal, provider, and community predictors among infants for late initiation of immunizations. We performed a retrospective cohort study of infants born between January 1, 2002, and December 31, 2004, in Philadelphia, Pennsylvania. Primary outcomes were age in days at first office-based immunization and status as a late starter (i.e., initiating office-based immunizations after 90 days of age). Candidate predictors included sociodemographic and prenatal characteristics, immunization provider practice type and size, and neighborhood factors. We performed hierarchical logistic regression and Cox regression models to identify independent predictors for being a late starter and prolonged time to first immunization. Of the 65,519 infants from this birth cohort in Philadelphia's immunization registry, 54,429 (88.1%) were included in analysis and 12.6% of these were late starters. Infants whose mothers were younger, received less than five prenatal visits, had less than a high school education, had more than two children, and who smoked cigarettes prenatally were significantly more likely to be late starters. Receiving care at hospital/university-based or public health clinics was also significantly associated with likelihood of being a late starter. Neither distance between infant's residence and practice nor neighborhood socioeconomic indicators was independently associated with the outcomes. Common risk factor profiles based on practice type and four maternal characteristics were found to reliably identify infant risk. Maternal receipt of fewer prenatal care visits, younger maternal age, higher birth order, and receiving care at public health clinics were the strongest predictors of being a late starter and time to first immunization. Risk factor profiles based on information already collected at birth can be used to identify higher-risk infants. Early intervention and potentially partnering with prenatal care providers may be key strategies for preventing underimmunization.


Social representations of climate change in Swedish lay focus groups: local or distant, gradual or catastrophic?
This paper explores social representations of climate change, investigating how climate change is discussed by Swedish laypeople interacting in focus group interviews. The analysis focuses on prototypical examples and metaphors, which were key devices for objectifying climate change representations. The paper analyzes how the interaction of focus group participants with other speakers, ideas, arguments, and broader social representations shaped their representations of climate change. Climate change was understood as a global but distant issue with severe consequences. There was a dynamic tension between representations of climate change as a gradual vs. unpredictable process. Implications for climate change communication are discussed.


Resident satisfaction with radiation oncology training.
Residency training environments can differ significantly; therefore, resident satisfaction may vary widely among programs. Here, we sought to examine several variables in program satisfaction through a survey of radiation oncology (RO) trainees in the United States. An anonymous, institutional review board-approved, internet-based survey was developed and distributed to U.S. residents in RO in September 2016. This email-based survey assessed program-specific factors with regard to workload, work-life balance, and education as well as resident-specific factors such as marital status and postgraduate year. Binomial multivariable regression assessed the correlations between these factors and the endpoint of resident-reported likelihood of selecting an alternative RO residency program if given the choice again. A total of 215 residents completed the required survey sections, representing 29.3% of U.S. RO residents. When asked whether residency allowed for an adequate balance between work and personal life, the majority of residents (75.6%) agreed or strongly agreed, but a minority (9.3%) did not feel that residency allowed for sufficient time for personal life. The majority of residents (69.7%) indicated that they would choose the same residency program again, but 12.2% would have made a different choice. Almost three-fourths of residents (73.0%) felt that faculty and staff cared about the educational success of residents, but 9.27% did not. Binomial multivariable regression revealed that senior residents (odds ratio: 6.70; 95% confidence interval, 2.20-22.4) were more likely to desire a different residency program. In contrast, residents who reported constructive feedback use by the residency program (odds ratio:0.22; 95% confidence interval, 0.06-0.91) were more satisfied with their program choice. Most RO residents reported satisfaction with their choice of residency program, but seniors had higher rates of dissatisfaction. Possible interventions to improve professional satisfaction include incorporating constructive resident feedback to enhance the program. The potential impact of job market pressures on seniors should be further explored.


Validation of the Mother-Generated Index in Iran: A Specific Postnatal Quality-of-Life Instrument.
The mother-generated index (MGI) is one of only a few existing specific questionnaires for assessing the postnatal quality of life (QoL). MGI is a single-form questionnaire that asks postnatal mothers to specify up to eight areas of their lives which have been affected by giving birth to a baby. Using this tool, it is possible to score and rank the QoL of mothers. This study aimed to validate the questionnaire for use in Iran. Forward translation was used to translate the questionnaire from English to Farsi (Persian). The questionnaire was then administered to a sample of postnatal women attending two teaching hospitals in Tehran, Iran. Face validity and criterion validity were performed to establish the validity for the Iranian version of the MGI. Face validity was assessed by asking women to indicate whether they understood the wording of the questions, how easy the questionnaire was, and so on. Criterion validity was examined using the Short Form 36-item (SF-36) Health Survey. It was hypothesized that the MGI would significantly correlate with the SF-36. In all, 124 women were approached. Of these, 119 women were eligible and 96 women agreed to take part in the study. Face validity was good and all of the women found the MGI straightforward to complete; as criterion validity, the MGI scores and the subscales of the SF-36 were moderately correlated (for all subscales: Pearson r > 0.4; P < 0.001). The mean MGI primary score was 5.38 (SD = 3.05). Women who had comorbidity had significantly lower MGI scores than women without comorbidity (P = 0.04). Correlation between aggregate of comments and primary score was high (r = 0.68, P < 0.01). In general, the Iranian version of the MGI performed well and our data suggest that it is a valid measure to assess health-related QoL among postnatal women.


Population data on 15 autosomal STRs in a sample from Colombia.
We present population genetic data of 15 STRs (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, PENTA D, PENTA E, TH01, TPOX and VWA) obtained from a sample of 617 unrelated individuals from Colombia. Deviations from Hardy-Weinberg equilibrium were assessed and allele frequencies and parameters of forensic interest for each STR were calculated. The combined power of exclusion (PE) and the combined power of discrimination (PD) for the 15 tested STR loci were 0, 99999895 and more than 0, 9999999, respectively. The combined MP value was 1 in 1, 07888 x 10(-17). Population comparisons between our sample and neighbouring populations from Latin America were carried out. Significant differences in above six markers were observed between our sample and two populations from Rio de Janeiro.


Challenges in the diagnosis of chronic immune-mediated rheumatic diseases.
Diagnosing patients with immune-mediated rheumatic diseases has many facets to be considered, but early and rapid diagnosis is an important prerequisite for correct and straight-forward future management of the patients. For optimal results physicians should not miss any diagnosis (assuring high sensitivity of the diagnostic process), and high specificity is needed in view of future therapeutic interventions. This review focuses on select principal aspects of diagnosis in clinical practice: Challenges of diagnostic approaches in immune-mediated rheumatic diseases include the frequent lack of diagnostic criteria (with subsequent misuse of classification criteria), the urgent need for diagnostic values of history and further examinations to support diagnosis-finding strategies, and differential diagnoses to be excluded (e.g., infections during early disease and follow-up). First, pure application of classification criteria without expert's experience as diagnostic criteria may lead to inappropriate diagnoses in 4-32% of all patients with immune-mediated rheumatic diseases. Second, sensitivity and specificity data for history and clinical examination are necessary not only for routine clinical work, but also for purposes of teaching students and learning physicians. Third, conditions to be excluded before classification of a certain disease are not necessarily excluding a certain diagnosis. Specific interest is given to differentiate infections from early onset or relapse of immune-mediated rheumatic diseases.


Application of a proactive risk analysis to emergency department sickle cell care.
Patients with sickle cell disease (SCD) often seek care in emergency departments (EDs) for severe pain. However, there is evidence that they experience inaccurate assessment, suboptimal care, and inadequate follow-up referrals. The aim of this project was to 1) explore the feasibility of applying a failure modes, effects and criticality analysis (FMECA) in two EDs examining four processes of care (triage, analgesic management, high risk/high users, and referrals made) for patients with SCD, and 2) report the failures of these care processes in each ED. A FMECA was conducted of ED SCD patient care at two hospitals. A multidisciplinary group examined each step of four processes. Providers identified failures in each step, and then characterized the frequency, impact, and safeguards, resulting in risk categorization. Many "high risk" failures existed in both institutions, including a lack of recognition of high-risk or high-user patients and a lack of emphasis on psychosocial referrals. Specific to SCD analgesic management, one setting inconsistently used existing analgesic policies, while the other setting did not have such policies. FMECA facilitated the identification of failures of ED SCD care and has guided quality improvement activities. Interventions can focus on improvements in these specific areas targeting improvements in the delivery and organization of ED SCD care. Improvements should correspond with the forthcoming National Heart, Lung and Blood-sponsored guidelines for treatment of patients with sickle cell disease.


Perception of quality of life amongst end stage renal failure patients undergoing haemodialysis.
The objective of the study was to examine the quality of life amongst the end stage renal disease (ESRD) haemodialysis patients in Malaysia. A cross sectional descriptive study was conducted on 72 ESRD patients at a Dialysis Centre in Malaysia. The modified KDQOL-SF™ subscales, kidney disease-targeted scale and 36 item health survey scale questionnaires were used. The overall health rating was 66.73 ± 11.670 indicating good quality of life. There was no significant difference between quality of life for the different domains according to gender (p >0.05). However, there were significant differences between quality of life in the domain of burden of kidney disease. Physical functioning deteriorated significantly with age (p=0.012) while social functioning was lowest in the 50-65 years age group (p=0.037). Those who had no morbidities had significantly better scores on the effects of kidney (p=0.036), burden of kidney disease (p=0.011) and physical functioning (p=0.025). Patients undergoing haemodialysis have been found to have good quality of life despite having ESRD. It is therefore of paramount importance to constantly monitor the standard of care for these patients to enable them to live their life to the fullest.


Cost-Effectiveness in Hepatic Lobectomy: the Effect of Case Volume on Mortality, Readmission, and Cost of Care.
Higher-volume centers demonstrate better perioperative outcomes for complex surgical interventions, though resource utilization implications of this hospital-level variation are unclear. We hypothesized that for hepatic lobectomy, higher operative volume correlates with better outcomes and lower costs. From 2009 to 2011, 4163 patients undergoing hepatic lobectomy were identified from the University HealthSystems Consortium database. Univariate, multivariate logistic regression, and decision analytic models were constructed to identify differences in hospital utilization and cost. Cost included both index and readmission hospitalizations, when applicable. The annual number of hepatic lobectomies performed by the institutions within the study ranged from 1 to 86. The median age of the 4163 patients was 58 years with a roughly equal gender split (M/F 49 %:51 %) and a racial breakdown which reflected that of the general US population. For all patients, the overall perioperative mortality rate was 2.3 % and the 30-day readmission rate was 13.4 %. Hospitals performing >30 hepatic lobectomies per year had significantly lower mortality and readmission rates than those hospitals performing ≤15 lobectomies annually (both p < 0.05). On multivariate analysis, higher severity of illness (odd ratio (OR) 2.13, 95 % confidence interval (CI) [1.48-3.07], p < 0.001), discharge to rehab (OR 1.84, [1.28-2.64], p < 0.001), home with home health care (OR 1.38, [1.08-1.76], p = 0.01), and surgery at a low-volume hospital (OR 1.49, [1.18-1.88], p < 0.001) were significant predictors of readmission. Conversely, surgical intervention at high-volume centers was associated with decreased risk of readmission (OR 0.67, [0.53-0.85], p < 0.001). When both index and readmission costs were considered, per-patient cost at low-volume centers was 21.9 % higher than at high-volume centers ($19,669 vs. $16,137). Sensitivity analyses adjusting for perioperative mortality and readmission at all centers did not significantly change the analysis. These data, for the first time, demonstrate that hospital volume in hepatic lobectomy is an important, modifiable risk factor for readmission and cost. To optimize resource utilization, patients undergoing complex hepatic surgery should be directed to higher-volume surgical institutions.


Hierarchically porous, ultra-strong reduced graphene oxide-cellulose nanocrystal sponges for exceptional adsorption of water contaminants.
Self-assembly of graphene oxide (GO) nanosheets into porous 3D sponges is a promising approach to exploit their capacity to adsorb contaminants while facilitating the recovery of the nanosheets from treated water. Yet, forming mechanically robust sponges with suitable adsorption properties presents a significant challenge. Ultra-strong and highly porous 3D sponges are formed using GO, vitamin C (VC), and cellulose nanocrystals (CNCs) - natural nanorods isolated from wood pulp. CNCs provide a robust scaffold for the partially reduced GO (rGO) nanosheets resulting in an exceptionally stiff nanohybrid. The concentration of VC as a reducing agent plays a critical role in tailoring the pore architecture of the sponges. By using excess amounts of VC, a unique hierarchical pore structure is achieved, where VC grains act as soft templates for forming millimeter-sized pores, the walls of which are also porous and comprised of micron-sized pores. The unique hierarchical pore structure ensures the interconnectivity of pores even at the core of large sponges as evidenced by micro and nano X-ray computed tomography. The unique pore architecture translates into an exceptional specific surface area for adsorption of a wide range of contaminants, such as dyes, heavy metals, pharmaceuticals and cyanotoxin from water.


Identification of Burkholderia cenocepacia genes required for bacterial survival in vivo.
Burkholderia cenocepacia (formerly Burkholderia cepacia complex genomovar III) causes chronic lung infections in patients with cystic fibrosis. In this work, we used a modified signature-tagged mutagenesis (STM) strategy for the isolation of B. cenocepacia mutants that cannot survive in vivo. Thirty-seven specialized plasposons, each carrying a unique oligonucleotide tag signature, were constructed and used to examine the survival of 2,627 B. cenocepacia transposon mutants, arranged in pools of 37 unique mutants, after a 10-day lung infection in rats by using the agar bead model. The recovered mutants were screened by real-time PCR, resulting in the identification of 260 mutants which presumably did not survive within the lungs. These mutants were repooled into smaller pools, and the infections were repeated. After a second screen, we isolated 102 mutants unable to survive in the rat model. The location of the transposon in each of these mutants was mapped within the B. cenocepacia chromosomes. We identified mutations in genes involved in cellular metabolism, global regulation, DNA replication and repair, and those encoding bacterial surface structures, including transmembrane proteins and cell surface polysaccharides. Also, we found 18 genes of unknown function, which are conserved in other bacteria. A subset of 12 representative mutants that were individually examined using the rat model in competition with the wild-type strain displayed reduced survival, confirming the predictive value of our STM screen. This study provides a blueprint to investigate at the molecular level the basis for survival and persistence of B. cenocepacia within the airways.


Residual moisture determines the level of touch-contact-associated bacterial transfer following hand washing.
We report here a new and critical determinant of the effectiveness of hand hygiene procedures, namely the amount of residual moisture left on the hands after washing and drying. When samples of skin, food and utilities were touched with wet, undried hands, microbial numbers in the order of 68000, 31000 and 1900 respectively translocated to these representative surfaces. Bacterial numbers translocating on touch contact decreased progressively as drying with an air or cloth towel system removed residual moisture from the hands. A 10 s cloth towel-20 s air towel protocol reduced the bacterial numbers translocating to skin, food and utilities on touch contact to 140, 655 and 28 respectively and achieved a 99.8, 94 and 99% reduction in the level of bacterial translocation associated with wet hands. Careful hand drying is a critical factor determining the level of touch-contact-associated bacterial transfer after hand washing and its recognition could make a significant contribution towards improving handcare practices in clinical and public health sectors.


Reactive lysis: the complement-mediated lysis of unsensitized cells. I. The characterization of the indicator factor and its identification as C7.
This paper describes the characteristics of the indicator factor (I) which takes part in reactive hemolysis and its identification as the seventh component of complement. I was shown to be a beta globulin with a sediment coefficient of 5.7S and a molecular weight of about 140,000. Experiments on the depletion of I activity with anti-I antiserum or with activated R euglobulin showed that I was a late acting complement component necessary for the lysis of cells after the EAC142 stage. Complement component analysis of purified I fractions excluded all known components except C7. The physicochemical characteristics of I are compatible with published data on C7. The method of quantitation described represents a convenient method of testing for C7.


Housing costs for adults who are mentally ill and formerly homeless.
The goal of this study was to evaluate the costs, under two different housing conditions, to the state mental health agency of caring for adults who are homeless and mentally ill. One hundred and twelve clients of the Massachusetts Department of Mental Health, living in psychiatric shelters, were randomly assigned to one of two housing types: Evolving Consumer Households or Independent Living apartments. For the next 18 months each client was followed so that the cost of treatment, case management, and housing could be collected and compared. The authors found that treatment and case management costs did not vary by housing type, but housing costs were significantly higher for those assigned to Evolving Consumer Households. Regardless of original housing assignment, treatment costs were lower for clients who remained where they were originally placed. The authors conclude that providing support for clients that increases housing stability reduces their need for treatment and that independent living arrangements may be a more cost-effective policy choice.


A gender-sensitised weight-loss and healthy living program for men with overweight and obesity in Australian Football League settings (Aussie-FIT): A pilot randomised controlled trial.
Recent evidence shows that sport settings can act as a powerful draw to engage men in weight loss. The primary objective of this pilot study was to test the feasibility of delivering and to evaluate preliminary efficacy of Aussie-FIT, a weight-loss program for men with overweight/obesity delivered in Australian Football League (AFL) settings, in preparation for a future definitive trial. This 6-month pilot trial took place in Perth, Australia. Participants were overweight/obese (Body Mass Index [BMI] ≥ 28 kg/m2), middle-aged (35-65 years old) men. Participants were recruited in May 2018, and the intervention took place between June and December 2018. The intervention involved 12 weekly 90-min face-to-face sessions, incorporating physical activity, nutrition, and behaviour change information and practical activities delivered by coaches at 2 clubs. Data were collected at baseline and immediately postintervention. For trial feasibility purposes, 6-month follow-ups were completed. Outcomes were differences in weight loss (primary outcome) and recruitment and retention rates, self-reported measures (for example, psychological well-being), device-measured physical activity, waist size, and blood pressure at 3 months. Within 3 days of advertising at each club, 426 men registered interest; 306 (72%) were eligible. Men were selected on a first-come first-served basis (n = 130; M age = 45.8, SD = 8; M BMI = 34.48 kg/m2, SD = 4.87) and randomised by a blinded researcher. Trial retention was 86% and 63% at 3- and 6-month follow-ups (respectively). No adverse events were reported. At 3 months, mean difference in weight between groups, adjusted for baseline weight and group, was 3.3 kg (95% CI 1.9, 4.8) in favour of the intervention group (p < 0.001). The intervention group's moderate-to-vigorous physical activity (MVPA) was higher than the control group by 8.54 min/day (95% CI 1.37, 15.71, p = 0.02). MVPA among men attracted to Aussie-FIT was high at baseline (intervention arm 35.61 min/day, control arm 38.38 min/day), which may have limited the scope for improvement. Aussie-FIT was feasible to deliver; participants increased physical activity, decreased weight, and reported improvements in other outcomes. Issues with retention were a limitation of this trial. In a future, fully powered randomised controlled trial (RCT), retention could be improved by conducting assessments outside of holiday seasons. Australian New Zealand Clinical Trials Registry: ACTRN12617000515392.