Invasion of Host Cells by Microsporidia.
Microsporidia are found worldwide and both vertebrates and invertebrates can serve as hosts for these organisms. While microsporidiosis in humans can occur in both immune competent and immune compromised hosts, it has most often been seen in the immune suppressed population, e.g., patients with advanced HIV infection, patients who have had organ transplantation, those undergoing chemotherapy, or patients using other immune suppressive agents. Infection can be associated with either focal infection in a specific organ (e.g., keratoconjunctivitis, cerebritis, or hepatitis) or with disseminated disease. The most common presentation of microsporidiosis being gastrointestinal infection with chronic diarrhea and wasting syndrome. In the setting of advanced HIV infection or other cases of profound immune deficiency microsporidiosis can be extremely debilitating and carries a significant mortality risk. Microsporidia are transmitted as spores which invade host cells by a specialized invasion apparatus the polar tube (PT). This review summarizes recent studies that have provided information on the composition of the spore wall and PT, as well as insights into the mechanism of invasion and interaction of the PT and spore wall with host cells during infection.


Restaurant menu labelling: Is it worth adding sodium to the label?
Several provincial and federal bills have recommended various forms of menu labelling that would require information beyond just calories; however, the additional benefit of including sodium information is unknown. The objective of this study was to determine whether sodium information on menus helps consumers make lower-sodium choices and to understand what other factors influence the effect of menu labelling on consumers' meal choices. A total of 3,080 Canadian consumers completed an online survey that included a repeated measures experiment in which consumers were asked to select what they would typically order from four mock-restaurant menus. Subsequently, consumers were randomly allocated to see one of three menu-labelling treatments (calories; calories and sodium; or calories, sodium and serving size) and were given the option to change their order. There was a significant difference in the proportion of consumers who changed their order, varying from 17% to 30%, depending on the restaurant type. After participants had seen menu labelling, sodium levels decreased in all treatments (p<0.0001). However, in three of the four restaurant types, consumers who saw calorie and sodium information ordered meals with significantly less sodium than consumers who saw only calorie information (p<0.01). Consumers who saw sodium labelling decreased the sodium level of their meal by an average of 171-384 mg, depending on the restaurant. In the subset of consumers who saw sodium information and chose to change their order, sodium levels decreased by an average of 681-1,360 mg, depending on the restaurant. Sex, intent to lose weight and the amount of calories ordered at baseline were the most important predictors of who used menu labelling. Eighty percent of survey panelists wanted to see nutrition information when dining out. Including sodium information alongside calorie information may result in a larger decrease in the amount of sodium ordered by restaurant-goers.


Impact of community participation on treatment outcomes and compliance of DOTS patients in Iraq.
We assessed the effect of community participation on treatment outcomes for tuberculosis patients undergoing directly-observed therapy, short course (DOTS). From February to December 2001 172 newly diagnosed patients in Baghdad were allocated into 2 treatment groups. The intervention group were visited daily at home for the 2-month initial phase by trained members of the Iraqi Women's Federation while the control group attended the local health centre for treatment. Cure rates for patients treated at home were significantly better than controls (83.7% versus 68.6%), so too was compliance (100.0% versus 14.0%). Smear conversion rates were significantly better in intervention cases compared with controls at all stages. Default rates were similar in both groups (11.6% versus 10.5%), as was mortality (1 patient each).


Fluorescent proteins for live-cell imaging with super-resolution.
Fluorescent proteins (FPs) from the GFP family have become indispensable as marker tools for imaging live cells, tissues and entire organisms. A wide variety of these proteins have been isolated from natural sources and engineered to optimize their properties as genetically encoded markers. Here we review recent developments in this field. A special focus is placed on photoactivatable FPs, for which the fluorescence emission can be controlled by light irradiation at specific wavelengths. They enable regional optical marking in pulse-chase experiments on live cells and tissues, and they are essential marker tools for live-cell optical imaging with super-resolution. Photoconvertible FPs, which can be activated irreversibly via a photo-induced chemical reaction that either turns on their emission or changes their emission wavelength, are excellent markers for localization-based super-resolution microscopy (e.g., PALM). Patterned illumination microscopy (e.g., RESOLFT), however, requires markers that can be reversibly photoactivated many times. Photoswitchable FPs can be toggled repeatedly between a fluorescent and a non-fluorescent state by means of a light-induced chromophore isomerization coupled to a protonation reaction. We discuss the mechanistic origins of the effect and illustrate how photoswitchable FPs are employed in RESOLFT imaging. For this purpose, special FP variants with low switching fatigue have been introduced in recent years. Despite nearly two decades of FP engineering by many laboratories, there is still room for further improvement of these important markers for live cell imaging.


A National Audit of Pancreatic Enzyme Prescribing in Pancreatic Cancer from 2015 to 2023 in England Using OpenSAFELY-TPP.
Cancer treatments were variably disrupted during the coronavirus disease 2019 (COVID-19) pandemic. UK guidelines recommend pancreatic enzyme replacement therapy (PERT) to all people with unresectable pancreatic cancer. The aim was to investigate the impact of the COVID-19 pandemic on PERT prescribing to people with unresectable pancreatic cancer and to investigate the national and regional rates from January 2015 to January 2023. With the approval of NHS England, we conducted this study using 24 million electronic health records of people within the OpenSAFELY-TPP research platform. There were 22,860 people diagnosed with pancreatic cancer in the study cohort. We visualized the trends over time and modeled the effect of the COVID-19 pandemic with the interrupted time-series analysis. In contrast to many other treatments, prescribing of PERT was not affected during the pandemic. Overall, since 2015, the rates increased steadily over time by 1% every year. The national rates ranged from 41% in 2015 to 48% in early 2023. There was substantial regional variation, with the highest rates of 50% to 60% in West Midlands. In pancreatic cancer, if PERT is prescribed, it is usually initiated in hospitals by clinical nurse specialists and continued after discharge by primary care practitioners. At just under 50% in early 2023, the rates were still below the recommended 100% standard. More research is needed to understand barriers to prescribing of PERT and geographic variation to improve quality of care. Prior work relied on manual audits. With OpenSAFELY, we developed an automated audit that allows for regular updates (https://doi.org/10.53764/rpt.a0b1b51c7a).


Methyl isobutyl ketone exposure-related increases in specific measures of α2u-globulin (α2u) nephropathy in male rats along with in vitro evidence of reversible protein binding.
Chronic exposure to methyl isobutyl ketone (MIBK) resulted in an increase in the incidence of renal tubule adenomas and occurrence of renal tubule carcinomas in male, but not female Fischer 344 rats. Since a number of chemicals have been shown to cause male rat renal tumors through the α2u nephropathy-mediated mode of action, the objective of this study is to evaluate the ability of MIBK to induce measures of α2u nephropathy including renal cell proliferation in male and female F344 rats following exposure to the same inhalation concentrations used in the National Toxicology Program (NTP) cancer bioassay (0, 450, 900, or 1800ppm). Rats were exposed 6h/day for 1 or 4 weeks and kidneys excised approximately 18h post exposure to evaluate hyaline droplet accumulation (HDA), α2u staining of hyaline droplets, renal cell proliferation, and to quantitate renal α2u concentration. There was an exposure-related increase in all measures of α2u nephropathy in male, but not female rat kidneys. The hyaline droplets present in male rat kidney stained positively for α2u. The changes in HDA and α2u concentration were comparable to d-limonene, an acknowledged inducer of α2u nephropathy. In a separate in vitro study using a two-compartment vial equilibration model to assess the interaction between MIBK and α2u, the dissociation constant (Kd) was estimated to be 1.27×10(-5)M. This Kd is within the range of other chemicals known to bind to α2u and cause nephropathy. Together, the exposure-related increase in measures of α2u nephropathy, sustained increase in renal cell proliferation along with an indication of reversible binding of MIBK to α2u, support the inclusion of MIBK in the category of chemicals exerting renal effects through a protein droplet α2u nephropathy-mediated mode of action (MoA).


Tidying up international nucleotide sequence databases: ecological, geographical and sequence quality annotation of its sequences of mycorrhizal fungi.
Sequence analysis of the ribosomal RNA operon, particularly the internal transcribed spacer (ITS) region, provides a powerful tool for identification of mycorrhizal fungi. The sequence data deposited in the International Nucleotide Sequence Databases (INSD) are, however, unfiltered for quality and are often poorly annotated with metadata. To detect chimeric and low-quality sequences and assign the ectomycorrhizal fungi to phylogenetic lineages, fungal ITS sequences were downloaded from INSD, aligned within family-level groups, and examined through phylogenetic analyses and BLAST searches. By combining the fungal sequence database UNITE and the annotation and search tool PlutoF, we also added metadata from the literature to these accessions. Altogether 35,632 sequences belonged to mycorrhizal fungi or originated from ericoid and orchid mycorrhizal roots. Of these sequences, 677 were considered chimeric and 2,174 of low read quality. Information detailing country of collection, geographical coordinates, interacting taxon and isolation source were supplemented to cover 78.0%, 33.0%, 41.7% and 96.4% of the sequences, respectively. These annotated sequences are publicly available via UNITE (http://unite.ut.ee/) for downstream biogeographic, ecological and taxonomic analyses. In European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena/), the annotated sequences have a special link-out to UNITE. We intend to expand the data annotation to additional genes and all taxonomic groups and functional guilds of fungi.


Provider Perceptions of Parent Health Literacy and Effect on Asthma Treatment Recommendations and Instructions.
Little is known about how pediatric providers assess parental health literacy, how concordant they are with validated measures of health literacy, and how these perceptions may influence treatment recommendations, how instructions are given or how reliable they perceive parents to be in carrying out instructions. Two hundred and eighty-one parents of 6-12-year-old asthma patients attending a pediatric clinic visit were recruited to a cross-sectional study of health literacy and asthma outcomes. Fourteen pediatric healthcare providers participated. Parents completed surveys that included 2 measures of health literacy: the Test of Function Health Literacy in Adults (TOFHLA) and the Rapid Estimate of Adult Literacy in Medicine (REALM). Immediately postvisit, pediatric providers completed a brief survey asking their assessment of the parent's health literacy and how it impacted treatment instructions and recommendations. Kappa statistics tested concordance; chi square and logistic regression tested associations among provider ratings, rating concordance, and demographic factors. Six providers were interviewed regarding the bases for their ratings. Providers' perceptions influenced asthma treatment recommendations (p=0.001) and how treatment instructions were given (p=0.001). Providers indicated that their perceptions were shaped by parent's verbal communication skills and patterns of past behavior related to children's asthma management. Data from 277 parents indicated that most had adequate health literacy with a lower percentage scored as adequate by the REALM versus the TOFHLA. Pediatric provider estimates of parental health literacy had low concordance with the validated measures. Providers were more likely to designate whites as adequately health literate. Pediatric asthma providers' perceptions of parents' health literacy can influence treatment recommendations and instructional practices.


Laser beams and resonators.
This paper is a review of the theory-of laser beams and resonators. It is meant to be tutorial in nature and useful in scope. No attempt is made to be exhaustive in the treatment. Rather, emphasis is placed on formulations and derivations which lead to basic understanding and on results which bear practical significance.


Population delimitation across contrasting evolutionary clines in deer mice (Peromyscus maniculatus).
Despite current interest in population genetics, a concrete definition of a "population" remains elusive. Multiple ecologically and evolutionarily based definitions of population are in current use, which focus, respectively, on demographic and genetic interactions. Accurate population delimitation is crucial for not only evolutionary and ecological population biology, but also for conservation of threatened populations. Along the Pacific Coast of North America, two contrasting patterns of geographic variation in deer mice (Peromyscus maniculatus) converge within the state of Oregon. Populations of these mice diverge morphologically across an east-west axis, and they diverge in mitochondrial DNA haplotypes across a north-south axis. In this study, we investigate these geographically contrasting patterns of differentiation in the context of ecological and evolutionary definitions (paradigms) of populations. We investigate these patterns using a new and geographically expansive sample that integrates data on morphology, mitochondrial DNA, and nuclear DNA. We found no evidence of nuclear genetic differentiation between the morphologically and mitochondrially distinct populations, thus indicating the occurrence of gene flow across Oregon. Under the evolutionary paradigm, Oregon populations can be considered a single population, whereas morphological and mitochondrial differentiations do not indicate distinct populations. In contrast, under the ecological paradigm morphological differentiation indicates distinct populations based on the low likelihood of demographic interactions between geographically distant individuals. The two sympatric but mitochondrially distinct haplogroups form a single population under the ecological paradigm. Hence, we find that the difference between evolutionary and ecological paradigms is the time-scale of interest, and we believe that the more chronologically inclusive evolutionary paradigm may be preferable except in cases where only a single generation is of interest.


MAF1 is a chronic repressor of RNA polymerase III transcription in the mouse.
Maf1-/- mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fasted versus refed wild-type mice are largely confined to low and intermediate occupancy genes; high occupancy genes are unchanged. However, in Maf1-/- mice, pol III occupancy of the vast majority of active loci in liver and the levels of specific precursor tRNAs in this tissue and other organs are higher than wild-type in both fasted and refed conditions. Thus, MAF1 functions as a chronic repressor of active pol III loci and can modulate transcription under different conditions. Our findings support the futile RNA cycle hypothesis, elaborate the mechanism of pol III repression by MAF1 and demonstrate a modest effect of MAF1 on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins.


Mouse models of neurodegenerative diseases: criteria and general methodology.
The major symptom of Alzheimer's disease is rapidly progressing dementia, coinciding with the formation of amyloid and tau deposits in the central nervous system, and neuronal death. At present familial cases of dementias provide the most promising foundation for modelling neurodegeneration. We describe the mnemonic and other major behavioral symptoms of tauopathies, briefly outline the genetics underlying familiar cases and discuss the arising implications for modelling the disease in mostly transgenic mouse lines. We then depict to what degree the most recent mouse models replicate pathological and cognitive characteristics observed in patients.There is no universally valid behavioral test battery to evaluate mouse models. The selection of individual tests depends on the behavioral and/or memory system in focus, the type of a model and how well it replicates the pathology of a disease and the amount of control over the genetic background of the mouse model. However it is possible to provide guidelines and criteria for modelling the neurodegeneration, setting up the experiments and choosing relevant tests. One should not adopt a "one (trans)gene, one disease" interpretation, but should try to understand how the mouse genome copes with the protein expression of the transgene in question. Further, it is not possible to recommend some mouse models over others since each model is valuable within its own constraints, and the way experiments are performed often reflects the idiosyncratic reality of specific laboratories. Our purpose is to improve bridging molecular and behavioural approaches in translational research.


A novel option for reducing free light chains in myeloma kidney: supra-hemodiafiltration with endogenous reinfusion (HFR).
In myeloma cast nephropathy, fast reduction of serum free light chain (FLC) levels correlates with renal recovery. Recently, extracorporeal treatments using filters with a high-molecular weight cut-off have been successfully used for FLC removal. However, using these new filters, high cost and elevated albumin leakage are common drawbacks. We studied a new and cheaper therapeutic approach with adsorbent resins to evaluate its efficacy. We treated four patients, affected by dialysis-dependent acute kidney injury (AKI) due to biopsy proven de novo FLC myeloma cast nephropathy. Each patient underwent bortezomib chemotherapy and extracorporeal treatment with the supra-hemodiafiltration with endogenous reinfusion (HFR) technique (Supra-HFR, Bellco Mirandola, Modena, Italy). Supra-HFR is a kind of hemodiafiltration that utilizes separated convection, diffusion and adsorption. The sorbent cartridge has a high affinity for FLC (both κ and λ) but is able to re-infuse albumin, avoiding the need for albumin perfusions. Supra HFR treatments (4 h each) were carried out for eight consecutive days and then every other day. All patients showed a significant reduction of serum FLC, whereas serum albumin concentration remained unchanged. Renal function recovered in three out of four patients. FLC removal with adsorbent resins represents an effective therapeutic strategy that does not require replacement with albumin .


New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies.
Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 ± 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90-110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of -35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with (14)C, with a final activity of 0.097 nCi mg(-1) of NPs. In chronic studies, the biodistribution profile is tracked using low level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical functionality as their non-radiolabeled counterparts. Identical chemical functionality of the radiolabeled probes to the non-radiolabeled probes was an important consideration to generate statistically similar biodistribution data sets using multiple imaging and detection techniques. The radiolabeling approach described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.


Aging and cardioprotection.
Advanced age is a strong independent predictor for death, disability, and morbidity in patients with structural heart disease. With the projected increase in the elderly population and the prevalence of age-related cardiovascular disabilities worldwide, the need to understand the biology of the aging heart, the mechanisms for age-mediated cardiac vulnerability, and the development of strategies to limit myocardial dysfunction in the elderly have never been more urgent. Experimental evidence in animal models indicate attenuation in cardioprotective pathways with aging, yet limited information is available regarding age-related changes in the human heart. Human cardiac aging generates a complex phenotype, only partially replicated in animal models. Here, we summarize current understanding of the aging heart stemming from clinical and experimental studies, and we highlight targets for protection of the vulnerable senescent myocardium. Further progress mandates assessment of human tissue to dissect specific aging-associated genomic and proteomic dynamics, and their functional consequences leading to increased susceptibility of the heart to injury, a critical step toward designing novel therapeutic interventions to limit age-related myocardial dysfunction and promote healthy aging.


The Influence of Caregiver Preparedness on Caregiver Contributions to Self-care in Heart Failure and the Mediating Role of Caregiver Confidence.
Caregiver contributions (CC) to heart failure (HF) self-care maintenance (ie, CC to maintaining HF stability) and management (ie, CC to dealing with HF signs and symptoms) improve patient outcomes, but it is unknown whether caregiver preparedness influences CC to self-care and whether caregiver confidence mediates this process. We evaluated the influence of caregiver preparedness on CC to HF self-care maintenance and management and the mediating role of caregiver confidence. This is a secondary analysis of the MOTIVATE-HF study. Patients were 18 years or older, with a diagnosis of HF in New York Heart Association classes II to IV, who had insufficient self-care and did not have severe cognitive impairment. Patients' informal caregivers were those people inside or outside the family who gave most of the informal care to the patients. We used the Caregiver Preparedness Scale and the Caregiver Contribution to Self-Care of HF Index. We tested a path analysis model and the indirect effects. Caregivers (n = 323) were 55 (SD, 15) years old on average and predominantly female (77%). The path analysis showed that higher scores in caregiver preparedness were associated with higher scores in caregiver confidence. In turn, higher caregiver confidence was associated with higher CC to self-care maintenance and management. Caregiver confidence mediated the association between caregiver preparedness and CC to self-care maintenance and management. Caregiver confidence may play a role in CC to self-care. Interventions to improve CC to HF self-care should not only be focused on improving caregiver preparedness but also should consider the role of caregiver confidence.


Feedforward object-vision models only tolerate small image variations compared to human.
Invariant object recognition is a remarkable ability of primates' visual system that its underlying mechanism has constantly been under intense investigations. Computational modeling is a valuable tool toward understanding the processes involved in invariant object recognition. Although recent computational models have shown outstanding performances on challenging image databases, they fail to perform well in image categorization under more complex image variations. Studies have shown that making sparse representation of objects by extracting more informative visual features through a feedforward sweep can lead to higher recognition performances. Here, however, we show that when the complexity of image variations is high, even this approach results in poor performance compared to humans. To assess the performance of models and humans in invariant object recognition tasks, we built a parametrically controlled image database consisting of several object categories varied in different dimensions and levels, rendered from 3D planes. Comparing the performance of several object recognition models with human observers shows that only in low-level image variations the models perform similar to humans in categorization tasks. Furthermore, the results of our behavioral experiments demonstrate that, even under difficult experimental conditions (i.e., briefly presented masked stimuli with complex image variations), human observers performed outstandingly well, suggesting that the models are still far from resembling humans in invariant object recognition. Taken together, we suggest that learning sparse informative visual features, although desirable, is not a complete solution for future progresses in object-vision modeling. We show that this approach is not of significant help in solving the computational crux of object recognition (i.e., invariant object recognition) when the identity-preserving image variations become more complex.


A simple method for 3D analysis of immunolabeled axonal tracts in a transparent nervous system.
Clearing techniques have been developed to transparentize mouse brains, thereby preserving 3D structure, but their complexity has limited their use. Here, we show that immunolabeling of axonal tracts followed by optical clearing with solvents (3DISCO) and light-sheet microscopy reveals brain connectivity in mouse embryos and postnatal brains. We show that the Robo3 receptor is selectively expressed by medial habenula axons forming the fasciculus retroflexus (FR) and analyzed the development of this commissural tract in mutants of the Slit/Robo and DCC/Netrin pathways. Netrin-1 and DCC are required to attract FR axons to the midline, but the two mutants exhibit specific and heterogeneous axon guidance defects. Moreover, floor-plate-specific deletion of Slit ligands with a conditional Slit2 allele perturbs not only midline crossing by FR axons but also their anteroposterior distribution. In conclusion, this method represents a unique and powerful imaging tool to study axonal connectivity in mutant mice.


Clinical colour vision tests.
The structure and function of the available and significant clinical colour vision tests are reviewed in the light of the needs in the clinical examination of congenital and acquired colour vision deficiencies. The tests are grouped and described as pseudo-isochromatic plates, arrangement tests, matching tests and vocational tests. The colorimetric constructions of the test types are described and the efficiency of their performance and usefulness discussed. Recommendations are made for basic and extended test batteries, when examining of congenital and acquired colour vision deficiencies in the consulting room.


The beta secretase BACE1 regulates the expression of insulin receptor in the liver.
Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.


Coping and resilience in farming families affected by drought.
The present study was a qualitative investigation of the impact of drought on rural families of southern New South Wales, Australia, with particular emphasis on the concept of resilience in times of stress. The aim was to provide insight, from a psychological perspective, into the experiences of rural farmers in a time of adversity, and to identify the coping resources utilized by these farming families. Participants were 11 members of five families from Blighty, a small farming town in the Riverina district, experiencing drought and decreased water allocation to their local area. Family members were interviewed on two separate occasions at their farms. Analysis of interview transcripts revealed that a wide range of coping strategies were being utilized by these families from problem-focussed coping, optimism and positive appraisal to less adaptive strategies such as cognitive dissonance, denial and avoidance of negative social influences. A significant finding was the discovery of a range of collective coping strategies used by the families in this study and the reliance on social capital as an adaptive resource. There were signs, however, that social cohesion of this community had become compromised due to competition for resources. The adaptive coping mechanisms traditionally employed by these farming families are starting to weaken and urgent work to enhance the individual coping strategies of farmers is needed. Furthermore, Government needs to recognise the importance of social capital as a coping resource that will enable farming families to adapt and survive drought conditions into the future. Providing financial assistance to support current community initiatives and collective coping strategies may prove more beneficial to farmers than allocating inadequate amounts of funding to individual farming families.


Phylogeny of Cas9 determines functional exchangeability of dual-RNA and Cas9 among orthologous type II CRISPR-Cas systems.
The CRISPR-Cas-derived RNA-guided Cas9 endonuclease is the key element of an emerging promising technology for genome engineering in a broad range of cells and organisms. The DNA-targeting mechanism of the type II CRISPR-Cas system involves maturation of tracrRNA:crRNA duplex (dual-RNA), which directs Cas9 to cleave invading DNA in a sequence-specific manner, dependent on the presence of a Protospacer Adjacent Motif (PAM) on the target. We show that evolution of dual-RNA and Cas9 in bacteria produced remarkable sequence diversity. We selected eight representatives of phylogenetically defined type II CRISPR-Cas groups to analyze possible coevolution of Cas9 and dual-RNA. We demonstrate that these two components are interchangeable only between closely related type II systems when the PAM sequence is adjusted to the investigated Cas9 protein. Comparison of the taxonomy of bacterial species that harbor type II CRISPR-Cas systems with the Cas9 phylogeny corroborates horizontal transfer of the CRISPR-Cas loci. The reported collection of dual-RNA:Cas9 with associated PAMs expands the possibilities for multiplex genome editing and could provide means to improve the specificity of the RNA-programmable Cas9 tool.


High incidence of antimicrobial resistant organisms including extended spectrum beta-lactamase producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus in nasopharyngeal and blood isolates of HIV-infected children from Cape Town, South Africa.
There is little information on nasopharyngeal (NP) flora or bacteremia in HIV-infected children. Our aim was to describe the organisms and antimicrobial resistance patterns in children enrolled in a prospective study comparing daily and three times weekly trimethoprim-sulfamethoxazole (TMP-SMX) and isoniazid (INH) or placebo prophylaxis. NP swabs were taken at baseline from HIV-infected children enrolled in the study. Standard microbiological techniques were used. Children were grouped according to previous or current exposure to TMP-SMX and whether enrolled to the study during a period of hospitalization. Blood culture results were also recorded within 12 months of baseline. Two hundred and three children, median age 1.8 (Interquartile [IQ]: 0.7-4) years had NP swabs submitted for culture. One hundred and eighty-four (90.7%) had either stage B or C HIV disease. One hundred and forty-one (69.8%) were receiving TMP-SMX and 19 (9.4%) were on antiretroviral therapy. The majority, 168 (82%) had a history of hospitalization and 91 (44.8%) were enrolled during a period of hospitalization. Thirty-two subjects (16.2%) died within 12 months of study entry. One hundred and eighty-one potential pathogens were found in 167 children. The most commonly isolated organisms were Streptococcus pneumoniae (48: 22.2%), Gram-negative respiratory organisms (Haemophilus influenzae and Moraxella catarrhalis) (47: 21.8%), Staphylococcus aureus (44: 20.4%), Enterobacteriaceae 32 (14.8%) and Pseudomonas 5 (2.3%). Resistance to TMP-SMX occurred in > 80% of pathogens except for M. catarrhalis (2: 18.2% of tested organisms). TMP-SMX resistance tended to be higher in those receiving it at baseline (p = 0.065). Carriage of Methicillin resistant S. aureus (MRSA) was significantly associated with being on TMP-SMX at baseline (p = 0.002). Minimal inhibitory concentrations (MIC) to penicillin were determined for 18 S. pneumoniae isolates: 7 (38.9%) were fully sensitive (MIC <or= 0.06 microg/ml), 9 (50%) had intermediate resistance (MIC 0.12 - 1 microg/ml) and 2 (11.1%) had high level resistance (MIC >or=2 microg/ml). Fifty percent of Enterobacteriaceae produced extended spectrum beta-lactamases (ESBL) (resistant to third generation cephalosporins) and 56% were resistant to gentamicin. Seventy-seven percent of S. aureus were MRSA. Carriage of resistant organisms was not associated with hospitalization.On multivariate logistic regression, risk factors for colonization with Enterobacteriaceae were age <or= one year (Odds ratio 4.4; 95% Confidence Interval 1.9-10.9; p = 0.0008) and CDC stage C disease (Odds ratio 3.6; 95% Confidence Interval 1.5-8.6; p = 0.005)Nineteen (9.4%) subjects had 23 episodes of bacteremia. Enterobacteriaceae were most commonly isolated (13 of 25 isolates), of which 6 (46%) produced ESBL and were resistant to gentamicin. HIV-infected children are colonized with potential pathogens, most of which are resistant to commonly used antibiotics. TMP-SMX resistance is extremely common. Antibiotic resistance is widespread in colonizing organisms and those causing invasive disease. Antibiotic recommendations should take cognizance of resistance patterns. Antibiotics appropriate for ESBL-producing Enterobacteriaceae and MRSA should be used for severely ill HIV-infected children in our region. Further study of antibiotic resistance patterns in HIV-infected children from other areas is needed.


Socialization and individual antecedents of adolescents' and young adults' moral motivation.
Socialization and individual differences were examined as antecedents of moral motivation in representative samples of 15-year-old adolescents (N = 1,258; 54% female) and 21-year-old young adults (N = 584; 53% female). The adolescents' primary caregivers (N = 1,056) also participated. The strength of moral motivation was rated by participants' responses to two hypothetical moral dilemmas in terms of action decisions, emotion attributions, and justifications. Socialization was measured by the perceived quality of friendship, parent-child relationships, and educational background. The importance attached to social justice and various personality traits were also assessed. Adolescents' moral motivation was positively associated with the quality of their parent-child relationship and the importance of social justice. Young adults' moral motivation was predicted by the perceived quality of friendships, the importance of social justice, and agreeableness. For both groups, moral motivation was greater in females. The theoretical implications of the findings for the development of moral motivation are discussed.


Refractive-index-sensing optical comb based on photonic radio-frequency conversion with intracavity multi-mode interference fiber sensor.
Optical frequency combs (OFCs) have attracted attention as optical frequency rulers due to their tooth-like discrete spectra together with their inherent mode-locking nature and phase-locking control to a frequency standard. Based on this concept, their applications until now have been demonstrated in the fields of optical frequency metrology. However, if the utility of OFCs can be further expanded beyond their application by exploiting new aspects of OFCs, this will lead to new developments in optical metrology and instrumentation. Here, we report a fiber sensing application of OFCs based on a coherent link between the optical and radio frequencies, enabling high-precision refractive index measurement based on frequency measurement in radio-frequency (RF) region. Our technique encodes a refractive index change of a liquid sample into a repetition frequency of OFC by a combination of an intracavity multi-mode-interference fiber sensor and wavelength dispersion of a cavity fiber. Then, the change in refractive index is read out by measuring the repetition frequency in RF region based on a frequency standard. Use of an OFC as a photonic RF converter will lead to the development of new applications in high-precision fiber sensing with the help of functional fiber sensors and precise RF measurement.


Prospective SARS-CoV-2 cohort study among primary health care providers during the second COVID-19 wave in Flanders, Belgium.
Primary health care providers (PHCPs) are assumed to be at high risk of a COVID-19 infection, as they are exposed to patients with usually less personal protective equipment (PPE) than other frontline health care workers (HCWs). Nevertheless, current research efforts focussed on the assessment of COVID-19 seroprevalence rates in the general population or hospital HCWs. We aimed to determine the seroprevalence in PHCPs during the second SARS-CoV-2 wave in Flanders (Belgium) and compared it to the seroprevalence in the general population. We also assessed risk factors, availability of PPE and attitudes towards the government guidelines over time. A prospective cohort of PHCPs (n = 698), mainly general practitioners, was asked to complete a questionnaire and self-sample capillary blood by finger-pricking at five distinct points in time (June-December 2020). We analysed the dried blood spots for IgG antibodies using a Luminex multiplex immunoassay. The seroprevalence of PHCPs remained stable between June and September (4.6-5.0%), increased significantly from October to December (8.1-13.4%) and was significantly higher than the seroprevalence of the general population. The majority of PHCPs were concerned about becoming infected, had adequate PPE and showed increasing confidence in government guidelines. The marked increase in seroprevalence during the second COVID-19 wave shows that PHCPs were more at risk during the second wave compared to the first wave in Flanders. This increase was only slightly higher in PHCPs than in the general population suggesting that the occupational health measures implemented provided sufficient protection when managing patients.


Cytomegalovirus infection: an Indian perspective.
Human cytomegalovirus (CMV) poses an important public health problem as it may cause serious morbidity and mortality in congenitally infected newborns and immunocompromised patients, most notably transplant recipients and HIV-infected persons. It is probably one of the most common infections known to humans and is characterized by a self-limiting infection in healthy individuals. CMV infection is the single most frequent cause of infectious complications in the early period following kidney transplantation Post-transfusion cytomegalovirus infection is of concern in the immunocompetent as well as in certain categories of immunocompromised individuals such as neonates, pregnant women, recipients of bone marrow and other organ transplants and individuals with immunodeficiency disorders. The emergence of AIDS in India has necessitated the establishment of reliable tests for diagnosis of cytomegalovirus infection as a damaged immune system permits cytomegalovirus reactivation. The magnitude of this problem in India and the various diagnostic modalities used have not been adequately investigated and, hence, CMV infection is still a major health problem warranting strong preventive measures. The ultimate goal of the prevention program is to develop a vaccine that can be administered to seronegative women of childbearing age to prevent primary infection during pregnancy.


Support for Fathers of Children With Heart Defects.
The purpose of the study was to illuminate the meanings of the lived experiences of support as disclosed by fathers of children with congenital heart defect (CHD). Narrative interviews were conducted individually with five fathers of children diagnosed with CHD. A phenomenological-hermeneutic method was used to interpret the verbatim transcribed narrative interviews. The meanings of the lived experiences of support for the fathers were identified in two themes and illustrate the fathers' feelings of being supported when being in a mutual relationship with others. A third theme illustrates the situation when support is absent. Our findings indicate that support for fathers of children with CHD might be best promoted by the philosophy of family-centered care.


Extreme-longevity mutations orchestrate silencing of multiple signaling pathways.
Long-lived mutants provide unique insights into the genetic factors that limit lifespan in wild-type animals. Most mutants and RNA interference targets found to extend life, typically by 1.5- to 2.5-fold, were discovered in C. elegans. Several longevity-assurance pathways are conserved across widely divergent taxa, indicating that mechanisms of lifespan regulation evolved several hundred million years ago. Strong mutations to the C. elegans gene encoding AGE-1/PI3KCS achieve unprecedented longevity by orchestrating the modulation (predominantly silencing) of multiple signaling pathways. This is evident in a profound attenuation of total kinase activity, leading to reduced phosphoprotein content. Mutations to the gene encoding the catalytic subunit of PI3K (phosphatidylinositol 3-kinase) have the potential to modulate all enzymes that depend on its product, PIP3, for membrane tethering or activation by other kinases. Remarkably, strong mutants inactivating PI3K also silence multiple signaling pathways at the transcript level, partially but not entirely mediated by the DAF-16/FOXO transcription factor. Mammals have a relatively large proportion of somatic cells, and survival depends on their replication, whereas somatic cell divisions in nematodes are limited to development and reproductive tissues. Thus, translation of longevity gains from nematodes to mammals requires disentangling the downstream consequences of signaling mutations, to avoid their deleterious consequences.


Three-dimensional structures of the free and antigen-bound Fab from monoclonal antilysozyme antibody HyHEL-63(,).
Antigen-antibody complexes provide useful models for studying the structure and energetics of protein-protein interactions. We report the cloning, bacterial expression, and crystallization of the antigen-binding fragment (Fab) of the anti-hen egg white lysozyme (HEL) antibody HyHEL-63 in both free and antigen-bound forms. The three-dimensional structure of Fab HyHEL-63 complexed with HEL was determined to 2.0 A resolution, while the structure of the unbound antibody was determined in two crystal forms, to 1.8 and 2.1 A resolution. In the complex, 19 HyHEL-63 residues from all six complementarity-determining regions (CDRs) of the antibody contact 21 HEL residues from three discontinuous polypeptide segments of the antigen. The interface also includes 11 bound water molecules, 3 of which are completely buried in the complex. Comparison of the structures of free and bound Fab HyHEL-63 reveals that several of the ordered water molecules in the free antibody-combining site are retained and that additional waters are added upon complex formation. The interface waters serve to increase shape and chemical complementarity by filling cavities between the interacting surfaces and by contributing to the hydrogen bonding network linking the antigen and antibody. Complementarity is further enhanced by small (<3 A) movements in the polypeptide backbones of certain antibody CDR loops, by rearrangements of side chains in the interface, and by a slight shift in the relative orientation of the V(L) and V(H) domains. The combining site residues of complexed Fab HyHEL-63 exhibit reduced temperature factors compared with those of the free Fab, suggesting a loss in conformational entropy upon binding. To probe the relative contribution of individual antigen residues to complex stabilization, single alanine substitutions were introduced in the epitope of HEL recognized by HyHEL-63, and their effects on antibody affinity were measured using surface plasmon resonance. In agreement with the crystal structure, HEL residues at the center of the interface that are buried in the complex contribute most to the binding energetics (DeltaG(mutant) - DeltaG(wild type) > 3.0 kcal/mol), whereas the apparent contributions of solvent-accessible residues at the periphery are much less pronounced (<1.5 kcal/mol). In the latter case, the mutations may be partially compensated by local rearrangements in solvent structure that help preserve shape complementarity and the interface hydrogen bonding network.


Neurotoxicity of ethyl methacrylate in rats.
Ethyl methacrylate (ethyl 2-methyl-2-propenoate, EMA) has been implicated in the development of neurologic impairment following occupational exposure. The potential of EMA to produce neurotoxicity was investigated in adult male Sprague-Dawley rats in two experiments. In the first experiment, animals were administered 100, 200, 400, or 800 mg/kg by daily intraperitoneal (i.p.) injections for 60 d. Control rats received daily i.p. injections of 1 ml saline/kg. Clinical observations, spontaneous motor activity, and performance in the Morris water maze were assessed. Alterations in clinical parameters in the higher dose groups included lethargy, impaired breathing, decreased weight gain, and increased mortality. Alterations in motor activity were observed at 100 mg/kg, a dose that did not cause alterations in clinical parameters, body weight gain, or mortality. There was also a dose-dependent impairment in performance in the Morris water maze. In the second experiment, animals were administered EMA in drinking water at concentrations of 0.1, 0.2, or 0.5% for 60 d. Control rats were administered tap water. Animals were perfused at the termination of exposure and samples of brain, spinal cord, and sciatic nerve were prepared for histological examination. Spongiform alterations were observed in fiber tracts of the forebrain, brainstem, and spinal cord. Clusters of axonal swellings were scattered throughout the dorsal, ventral, and lateral columns of the spinal cord, and typically involved internodal segments of two or three neighboring axons. Shrunken axons with separated myelin lamellae and large axons with thinner than normal myelin sheaths were apparent in the sciatic nerve. The patterns of alterations in the white matter of the spinal cord and the sciatic nerve are consistent with myelinopathy, but additional experiments are necessary to confirm whether oligodendroglia and Schwann cells are the primary sites of injury. In addition to the alterations associated with myelin, there was a decrease in the density of neurons in the ventral horn of the spinal cord. While the observed effects of EMA on the nervous system of rats are consistent with neurologic symptoms of workers exposed to EMA, additional experiments are necessary to determine if the level and route of exposures associated with occupational use produce these impairments in experimental animals.


The effects of topical anesthesia on oral burning in burning mouth syndrome.
Burning mouth syndrome (BMS) is an oral pain disorder of uncertain origin. Central or peripheral pain mechanisms may play a role in the oral burning of BMS. We tested the effect of a topical anesthetic (dyclonine HCl) on patients' intensity ratings for oral burning, taste dysgeusia and the taste of two chemical stimuli (1.0 M NaCl and 1.0 M sucrose). A total of 33 patients (9 male and 24 female, average age: 60 yr) are included in this analysis. The anesthetic reduced the perceptual intensity of both chemicals in these patients on four out of five postanesthesia trials (p < 0.01). The BMS cohort included 12 patients whose burning increased (p < 0.001), 14 patients whose burning did not change, and 7 patients whose burning decreased (p < 0.001) after anesthesia. Baseline dysgeusias (n = 13) decreased in intensity (p < 0.001) after anesthesia, suggesting BMS dysgeusia is related to the activation of peripheral taste mechanisms. The results also suggest that BMS oral burning may be a disorder of peripheral pain pathways in some patients.


Long-term outcomes of acute myeloid leukemia in adults in Pakistan.
To describe the long-term outcomes of Acute Myeloid Leukemia (AML) and to study clinicopathological features at presentation, morphological subtypes and remission rates. Demographic information, response to therapy and survival of patients (>14 years of age) admitted between January 1988 to August 1996 with acute myeloid leukaemia was retrieved and analysed. Seventy-four patients were admitted with a diagnosis of AML during the study period. There were 43 males and 31 females. Age ranged between 15 and 70 years with a mean age of 38 years. The most common presenting feature was fever (67.5%) and the morphological subtype according to French-American-British Group (FAB) criteria was M4. Fifty-five patients received treatment and were evaluable for response and outcomes. Thirty-six (65.4%) patients had complete remission. Sixteen (29.1%) died during the first 28 days after starting induction chemotherapy. The median survival was 11 months. Six (11%) patients (4 females, 2 males) are surviving beyond 4 years (long-term survivors). Our study suggests that the long-term outcomes of adults with AML are comparable to what has been reported in the literature for patients who do not receive bone marrow transplants.


Targeting Germ Cell Tumors with the Newly Synthesized Flavanone-Derived Compound MLo1302 Efficiently Reduces Tumor Cell Viability and Induces Apoptosis and Cell Cycle Arrest.
Less toxic treatment strategies for testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic flavonoid compound (MLo1302) from the 3-nitroflavanone family of DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of cisplatin resistant cell line NCCIT-R), with IC50s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT protein expression, similar to decitabine, and showed a partial effect in cell differentiation, reducing protein expression of pluripotency markers. RT2 profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased protein expression of cleaved caspase 8 and activated caspase 2, and reduced proliferation (BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore, synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients.


A quantitative view on multivalent nanomedicine targeting.
Although the concept of selective delivery has been postulated over 100 years ago, no targeted nanomedicine has been clinically approved so far. Nanoparticles modified with targeting ligands to promote the selective delivery of therapeutics towards a specific cell population have been extensively reported. However, the rational design of selective particles is still challenging. One of the main reasons for this is the lack of quantitative theoretical and experimental understanding of the interactions involved in cell targeting. In this review, we discuss new theoretical models and experimental methods that provide a quantitative view of targeting. We show the new advancements in multivalency theory enabling the rational design of super-selective nanoparticles. Furthermore, we present the innovative approaches to obtain key targeting parameters at the single-cell and single molecule level and their role in the design of targeting nanoparticles. We believe that the combination of new theoretical multivalent design and experimental methods to quantify receptors and ligands aids in the rational design and clinical translation of targeted nanomedicines.


Mechanical traction for mechanical neck disorders: a systematic review.
To assess whether mechanical traction, either alone or in combination with other treatments, improves pain, function/disability, patient satisfaction and global perceived effect in adults with mechanical neck disorders. We conducted a systematic review up to September 2004 of randomized controlled trials and used pre-defined levels of evidence for qualitative analysis. Two independent reviewers conducted study selection, data abstraction and methodological quality assessment. Using a random effects model, relative risk and standardized mean differences were calculated. The reasonableness of combining studies was assessed on clinical and statistical grounds. In the absence of heterogeneity, pooled effect measures were calculated. Of the 10 selected trials, one study was of high quality. Our review revealed low-quality trials for mechanical neck disorders, showing evidence of benefit favouring intermittent traction for pain reduction. Continuous traction showed no significant difference for defined outcomes. Inconclusive evidence for continuous and intermittent traction exists due to trial methodological quality. Two clinical conclusions may be drawn, one favouring the use of intermittent traction and the other not supporting the use of continuous traction. Attention to research design flaws and description of traction characteristics is needed.


Principles and applications of steric exclusion chromatography.
We introduce a chromatography method for purification of large proteins and viruses that works by capturing them at a non-reactive hydrophilic surface by their mutual steric exclusion of polyethylene glycol (PEG). No direct chemical interaction between the surface and the target species is required. We refer to the technique as steric exclusion chromatography. Hydroxyl-substituted polymethacrylate monoliths provide a hydrophilic surface and support convective mass transport that is unaffected by the viscosity of the PEG. Elution is achieved by reducing PEG concentration. Selectivity correlates with molecular size, with larger species retained more strongly than smaller species. Retention increases with PEG size and concentration. Salts weaken retention in proportion to their concentration and Hofmeister ranking. Retention is enhanced near the isoelectric point of the target species. Virus binding capacity was measured at 9.9×10(12) plaque forming units per mL of monolith. 99.8% of host cell proteins and 93% of DNA were eliminated. Mass recovery exceeded 90%. IgM capacity was greater than 60 mg/mL. 95% of host cell proteins were eliminated from IgM produced in protein-free media, and mass recovery was up to 90%. Bioactivity was fully conserved by both viruses and antibodies. Process time ranged from less than 30 min to 2 h depending on the product concentration in the feed stream.


Damage-induced phosphorylation of Sld3 is important to block late origin firing.
Origins of replication are activated throughout the S phase of the cell cycle such that some origins fire early and others fire late to ensure that each chromosome is completely replicated in a timely fashion. However, in response to DNA damage or replication fork stalling, eukaryotic cells block activation of unfired origins. Human cells derived from patients with ataxia telangiectasia are deficient in this process due to the lack of a functional ataxia telangiectasia mutated (ATM) kinase and elicit radioresistant DNA synthesis after γ-irradiation(2). This effect is conserved in budding yeast, as yeast cells lacking the related kinase Mec1 (ATM and Rad3-related (ATR in humans)) also fail to inhibit DNA synthesis in the presence of DNA damage. This intra-S-phase checkpoint actively regulates DNA synthesis by inhibiting the firing of late replicating origins, and this inhibition requires both Mec1 and the downstream checkpoint kinase Rad53 (Chk2 in humans). However, the Rad53 substrate(s) whose phosphorylation is required to mediate this function has remained unknown. Here we show that the replication initiation protein Sld3 is phosphorylated by Rad53, and that this phosphorylation, along with phosphorylation of the Cdc7 kinase regulatory subunit Dbf4, blocks late origin firing in Saccharomyces cerevisiae. Upon exposure to DNA-damaging agents, cells expressing non-phosphorylatable alleles of SLD3 and DBF4 (SLD3-m25 and dbf4-m25, respectively) proceed through the S phase faster than wild-type cells by inappropriately firing late origins of replication. SLD3-m25 dbf4-m25 cells grow poorly in the presence of the replication inhibitor hydroxyurea and accumulate multiple Rad52 foci. Moreover, SLD3-m25 dbf4-m25 cells are delayed in recovering from transient blocks to replication and subsequently arrest at the DNA damage checkpoint. These data indicate that the intra-S-phase checkpoint functions to block late origin firing in adverse conditions to prevent genomic instability and maximize cell survival.


In vitro dissolution of Synthos ceramics in an acellular physiological environment.
"Synthos" (beta-tricalcium phosphate) implants in bone are resorbed and replaced with endogenous bone. This investigation was conducted to study by continuous flow and static system techniques, whether or not resorption of synthos occurs by passive dissolution at 37 degrees C. Calcium and phosphates were released in a time dependent manner from synthos in calcium and phosphate free Tris-Hcl buffer (pH 7.4). Scanning electron micrographs (SEM) of buffer exposed ceramics indicated breakdown of grain structure. In contrast, levels of human plasma calcium and phosphate were not altered by ceramics. Significant amounts of 32p were absorbed by the ceramics in the first hour and 45Ca in the second hour of exposure to plasma containing the radioactive isotopes. Exposure of ceramics to plasma did not alter the levels of plasm isotopes significantly for the remaining duration of the experiment. However, breakdown of grain structure was evident in SEM's of ceramics exposed to plasma. It appears that in an acellular physiological environment, dissolution of synthos is diffusion dependent and is limited to a localized surface exchange phenonmenon.


Growth-related signaling in vascular smooth muscle cells is deregulated by TCDD during the G0/G1 transition.
Experiments have been conducted to examine the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on growth-related signaling in vascular smooth muscle cells (SMCs). A 40% reduction of peak DNA synthesis was observed in SMCs only when TCDD was added during the G0/G1 transition of the cell cycle. Enhanced phosphorylation of several endogenous proteins during this period was coincident with increased tyrosine kinase activity as early as 15 min following TCDD challenge. No changes in protein phosphorylation status occurred in cells treated with TCDD during the G1/S transition or during S phase. Cotreatment of quiescent SMCs with 10 nM TCDD and serum for 3 h reduced serum-inducible binding activity to a 12-O-tetradecanoyl phorbol 13-acetate responsive element (TRE) by approximately 40%. No alterations of constitutive TRE binding were observed in quiescent SMCs treated with TCDD for up to 5 h. These data show that mitogen-related signaling in vascular SMCs is modulated by TCDD selectively during the G0/G1 transition, and these effects influence the growth behavior of these cells.


Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations.
Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.


Jacalin domain in wheat jasmonate-regulated protein Ta-JA1 confers agglutinating activity and pathogen resistance.
Ta-JA1 is a jacalin-like lectin from wheat (Triticum aestivum) plants. To date, its homologs are only observed in the Gramineae family. Our previous experiments have demonstrated that Ta-JA1 contains a modular structure consisting of an N-terminal dirigent domain and a C-terminal jacalin-related lectin domain (JRL) and this protein exhibits a mannose-specific lectin activity. The over-expression of Ta-JA1 gene provides transgenic plants a broad-spectrum resistance to diseases. Here, we report the differential activities of the dirigent and JRL domains of Ta-JA1. In vitro assay showed that the recombinant JRL domain could effectively agglutinate rabbit erythrocytes and pathogen bacteria Pseudomonas syringe pv tabaci. These hemagglutination activities could be inhibited by mannose but not by galactose. In contrast, the recombinant dirigent domain did not show agglutination activity. Corresponding to these differentiations of activities, similar to full-length of Ta-JA1, the over-expression of JRL domain in transgenic plants also increased resistance to the infection of P. syringe. Unlike JRL, the over-expression of dirigent domain in transgenic plants led to alteration of the seedling sensitivity to salts. In addition, a d(N)/d(S) ratio analysis of Ta-JA1 and its related proteins showed that this protein family functionally limited to a few crop plants, such as maize, rice and wheat.


alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome.
alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations in familial cases of the disease and its presence in Lewy bodies. Here we show that over-expression of wild-type human alpha-synuclein is sufficient to induce inclusion formation in SH-SY5Y cells. In this cellular model, proteasome inhibition leads to an increase of alpha-synuclein accumulation in vivo without ubiquitylation. In accordance, we find that in vitro, unmodified alpha-synuclein can be directly degraded by the 20S proteasome. These findings suggest an ubiquitin-independent mechanism of proteasomal degradation for alpha-synuclein and other natively unfolded proteins.


Continuing education: a comprehensive approach to improving cancer pain management and patient satisfaction.
To report on the development and outcomes of a comprehensive program to improve cancer pain management and patient satisfaction. Published research and guidelines, review articles, and patients' personal experiences. A comprehensive cancer pain management program includes performance improvement, patient satisfaction, nursing education, and pain management rounds. This approach to pain can result in effective pain management, patients' reports of acceptable levels of pain, and an increase in patient satisfaction. Semiweekly pain management rounds provided the opportunity for nurses to practice equianalgesic dosing and make recommendations for changes in pain management. Effective pain management plans can lead to an increase in scores that measure patient satisfaction. Nursing pain management education and subsequent use of pain management principles during and between pain management rounds can lead to effective pain management and satisfaction for patients with cancer. Research is needed to assess whether comprehensive programs can change pain management practices in other patient populations.


Effects of CXCR4 siRNA/dextran-spermine nanoparticles on CXCR4 expression and serum LDH levels in a mouse model of colorectal cancer metastasis to the liver.
Liver metastasis is the main cause of mortality related to colorectal cancer. CXCR4 is necessary for the outgrowth of colon cancer micrometastases. In oncology, it has been demonstrated that several human tumors release lactate dehydrogenase (LDH) into the circulation. CXCR4 gene expression and serum LDH levels are often increased in patients with colorectal cancer. Despite technological advances in cancer therapy, five-year overall survival is still around 50%. Therefore, better treatment needs to be developed. RNA interference (RNAi) is a modern and powerful tool for inhibition of gene expression. However, the rate-limiting step in this technology is effective delivery of RNAi agents. We have investigated a novel strategy of CXCR4 siRNA therapy and its effect on serum LDH levels in a BALB/C mouse model of colorectal cancer metastasis to the liver. Hepatic metastasis was established by injecting a CT26.WT mouse colon carcinoma cell line via the tail vein. Our results demonstrated that CXCR4 siRNA/ dextran-spermine nanoparticles achieved high silencing efficiency with low toxicity. Favorable localization of the nanoparticles was confirmed with CXCR4 gene expression in the liver, that was correlated with serum LDH levels. More research will be needed to determine the effect of CXCR4 silencing on serum LDH levels, which may be a useful marker for predicting liver metastasis in colorectal cancer.


Immunological properties of surface proteins of Clostridium difficile.
Sera from patients with Clostridium difficile-associated disease (CDAD) and sera from a control group were analysed by an ELISA to detect antibodies directed against four surface proteins and toxins A and B of C. difficile. The surface proteins were the flagellar cap protein FliD, the flagellin FliC, the adhesin Cwp66 divided into two domains, Cwp66-Nterminal and Cwp66-Cterminal, and the fibronectin-binding protein Fbp68. For each antigen, antibody levels in the CDAD patient group and in the control group were compared. In the CDAD patient group, the mean of the antibody levels decreased from Cwp66-Cterminal to Fbp68, FliD, toxins B and A, Cwp66-Nterminal and finally FliC, suggesting different immunogenic properties among these adhesins. For Cwp66-Nterminal, FliC, FliD and Fbp68, the antibody level observed in the control group was higher than in the CDAD group with a statistically significant difference whereas the antibody level for toxins A and B was not statistically different. In conclusion, this study suggests that during the clinical course of disease, C. difficile adhesins are able to induce an immune response which could play a role in the defence mechanism of the host.


DNA damage responses in cells exposed to sulphur mustard.
Sulphur mustard (SM) is a blistering agent that causes debilitating damage to the skin, eyes and respiratory system. In cases of severe exposure, immunodepletion can occur as well as death, due to secondary infections. The toxicity of SM is thought to be mediated in part by the alkylation of nucleic acids and proteins, although the exact mechanisms are not clear. In addition, although the first known use of SM was in military conflict nearly 100 years ago, there are still no effective treatments or preventative measures. In order to develop treatments it is necessary to have a detailed understanding of the cellular biochemical changes induced by SM as well as information on the mechanisms that cells employ to protect against SM toxicity. We have previously demonstrated that the homologous recombination (HR) DNA repair pathway promotes cell survival after SM. This study investigated the role of other DNA repair pathways in the cellular response to SM, specifically base excision repair (BER), nucleotide excision repair (NER) and non-homologous end joining (NHEJ) as well as studying the activation and regulation of DNA damage signalling pathways. Our data confirmed that HR is the major repair pathway protecting against acute SM toxicity, with NER and NHEJ also contributing to cell survival. In addition, this study demonstrated the dose- and time-dependent activation of DNA damage signalling pathways after SM in human TK6 lymphoblastoid cells, in particular the phosphorylation of CHK1, CHK2 and p53. These phosphorylation events were orchestrated by a combination of the ATM and ATR protein kinases.


Ocean acidification slows nitrogen fixation and growth in the dominant diazotroph Trichodesmium under low-iron conditions.
Dissolution of anthropogenic CO(2) increases the partial pressure of CO(2) (pCO(2)) and decreases the pH of seawater. The rate of Fe uptake by the dominant N(2)-fixing cyanobacterium Trichodesmium declines as pH decreases in metal-buffered medium. The slower Fe-uptake rate at low pH results from changes in Fe chemistry and not from a physiological response of the organism. Contrary to previous observations in nutrient-replete media, increasing pCO(2)/decreasing pH causes a decrease in the rates of N(2) fixation and growth in Trichodesmium under low-Fe conditions. This result was obtained even though the bioavailability of Fe was maintained at a constant level by increasing the total Fe concentration at low pH. Short-term experiments in which pCO(2) and pH were varied independently showed that the decrease in N(2) fixation is caused by decreasing pH rather than by increasing pCO(2) and corresponds to a lower efficiency of the nitrogenase enzyme. To compensate partially for the loss of N(2) fixation efficiency at low pH, Trichodesmium synthesizes additional nitrogenase. This increase comes partly at the cost of down-regulation of Fe-containing photosynthetic proteins. Our results show that although increasing pCO(2) often is beneficial to photosynthetic marine organisms, the concurrent decreasing pH can affect primary producers negatively. Such negative effects can occur both through chemical mechanisms, such as the bioavailability of key nutrients like Fe, and through biological mechanisms, as shown by the decrease in N(2) fixation in Fe-limited Trichodesmium.


The effect of fear of falling on prefrontal cortex activation and efficiency during walking in older adults.
Neural inefficiency is inferred when higher brain activations are associated with similar or worse performance. Improved neural efficiency is achieved when task-related brain activations are reduced after practice. No information is available on the effect of fear-of-falling (FOF) on brain activation during walking. We hypothesized that the presence of FOF would be associated with neural inefficiency and with a delay in improving neural efficiency during dual-task walking. Task conditions included single-task walk (STW), Alpha (cognitive interference), and dual-task walk (DTW). Functional near-infrared spectroscopy (fNIRS)-derived HbO2 in the prefrontal cortex (PFC) was used to quantify task-related changes in brain activation. Practice included three repeated counterbalanced trials for each task. Participants with FOF (n = 19; mean age = 79.84 ± 6.01 years; %female = 68.42) and without FOF (n = 56; mean age = 76.73 ± 6.39 years; %female = 44.64) were included. The presence of FOF was associated with slower stride velocity (estimate = - 12.354; p = 0.0154) and with greater increases in PFC HbO2 from STW to DTW (estimate = 0.303, p = 0.0009) and from Alpha to DTW (estimate = 0.387, p < 0.0001). Compared to controls, participants reporting FOF demonstrated an attenuated decline in PFC HbO2 from the first to the second DTW trials (estimate = 0.264; p = 0.0173). In contrast, compared to controls, participants with FOF demonstrated greater decline in Alpha PFC HbO2 from trial 1 to trial 2 (estimate = - 0.419, p < 0.0001) and from trial 1 to 3 (estimate = - 0.281, p = 0.0006). The change in PFC HbO2 over repeated STW trials was not significant and was not moderated by FOF status. The presence of FOF was associated with higher and inefficient PFC activation during DTW in older adults.


Effect of postpartum administration of ketoprofen on proinflammatory cytokine concentration and their correlation with lipogenesis and ketogenesis in Holstein dairy cows.
Early lactation period in dairy cows could be harmful to their health since it is challenging and demanding. Proinflammatory cytokine concentrations are increased in the early phase of the inflammatory response and during the early lactation period in cows. The aim of this study was to determine if ketoprofen treatment in the first days following parturition would decrease proinflammatory cytokine concentration and their correlation between lipid mobilization, ketogenesis and metabolic parameters in cows. The study was conducted on 30 cows divided into two groups of 15 cows each. The experimental group was treated with 3 mg × kg.bw.-1 ketoprofen for three consecutive days after parturition. The blood samples were collected on the first day of treatment and in the first and second week postpartum and they were analyzed for biochemical parameters such as non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), glucose, cholesterol and total bilirubine and inflammatory parameters such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interferon-γ (IFN-γ). The results suggested that ketoprofen- treated cows had a significantly lower concentration of TNF-α, IL-1α, IFN-γ, NEFA and BHBA in the first and second postpartum week compared to the control group. Ketoprofen administration increased glucose levels (the first week, p⟨0.05), increased cholesterol levels (the second week, p⟨0.01) and decreased serum total bilirubin levels (second week, p⟨0.01) compared to the control group of cows. A positive correlation was found between TNF-α and NEFA and total bilirubin, significantly more expressed in the control than in experimental group of cows (p⟨0.01) and it was also found between IL-1α and NEFA (p⟨0.01). A negative correlation was found between TNF-α and glucose and cholesterol, significantly more expressed in the control than in experimental group of cows (p⟨0.01). A positive correlation was also found between IL-1α and glucose (p⟨0.01). Ketoprofen given parenterally to Holstein cows immediately after calving could reduce inflammation and decrease the relation between inflammatory response and lipogenesis and ketogenesis in postpartum cows.


Quantum fluctuations beyond the Gutzwiller approximation.
We present a simple scheme to evaluate linear response functions including quantum fluctuation corrections on top of the Gutzwiller approximation. The method is derived for a generic multiband lattice Hamiltonian without any assumption about the dynamics of the variational correlation parameters that define the Gutzwiller wavefunction, and which thus behave as genuine dynamical degrees of freedom that add on those of the variational uncorrelated Slater determinant. We apply the method to the standard half-filled single-band Hubbard model. We are able to recover known results, but, as by-product, we also obtain few novel ones. In particular, we show that quantum fluctuations can reproduce almost quantitatively the behaviour of the uniform magnetic susceptibility uncovered by dynamical mean field theory, which, though enhanced by correlations, is found to be smooth across the paramagnetic Mott transition. By contrast, the simple Gutzwiller approximation predicts that susceptibility to diverge at the transition.


Blood volume and the carotid baroreceptor reflex in conscious rabbits.
1. The effects of acute blood volume change in conscious rabbits on a.c. gain of the carotid baroreceptor reflex with respect to heart rate, blood pressure, cardiac output and systemic vascular resistance were studied. 2. With acute, isohaemic increase in blood volume by 20% and 40% the only consistent trend was a decrease in gain for systemic vascular resistance. 3. With acute reduction in blood volume there was a consistent tendency for gain for heart rate to fall. With 20% reduction in blood volume, gain for cardiac output fell but gain for systemic vascular resistance rose and its phage-lag became shorter, so that gain for blood pressure was unaltered. The enhanced gain for systemic vascular resistance was not sustained with 35% reduction in blood volume, so that gain for blood pressure fell. 4. Thus control of blood pressure by the carotid sinus reflex is remarkably unaffected by acute change in blood volume, and is impaired only when there is depression of gain for cardiac output without a concomitant rise in gain for systemic vascular resistance.


Increasing rates of gastroenteritis hospital discharges in US adults and the contribution of norovirus, 1996-2007.
Diarrhea remains an important cause of morbidity, but until the mid 1990s, hospital admissions for diarrhea in the US adult population were declining. We aimed to describe recent trends in gastroenteritis hospitalizations and to determine the contribution of norovirus. We analyzed all gastroenteritis-associated hospital discharges during 1996-2007 from a nationally representative data set of hospital inpatient stays. Annual rates of discharges by age were calculated. Time-series regression models were fitted using cause-specified discharges as explanatory variables; model residuals were analyzed to estimate norovirus- and rotavirus-associated discharges. We then calculated the annual hospital charges for norovirus-associated discharges. Sixty-nine percent of all gastroenteritis discharges were cause-unspecified and rates increased by ≥ 50% in all adult and elderly age groups (≥ 18 years of age) from 1996 through 2007. We estimate an annual mean of 71,000 norovirus-associated hospitalizations, costing $493 million per year, with surges to nearly 110,000 hospitalizations per year in epidemic seasons. We also estimate 24,000 rotavirus hospitalizations annually among individuals aged ≥ 5 years. Gastroenteritis hospitalizations are increasing, and we estimate that norovirus is the cause of 10% of cause-unspecified and 7% of all-cause gastroenteritis discharges. Norovirus should be routinely considered as a cause of gastroenteritis hospitalization.


Effect of temperature on the development and survival of immature stages of the carambola fruit fly, Bactrocera carambolae, and the Asian papaya fruit fly, Bactrocera papayae, reared on guava diet.
Members of the Bactrocera dorsalis Hendel (Diptera: Tephritidae) complex constitute well-recognized destructive pests of fruits in peninsular Thailand. The development and survival of immature stages of the carambola fruit fly, Bactrocera carambolae Drew & Hancock, and the Asian papaya fruit fly, Bactrocera papayae Drew & Hancock, were compared at six constant temperatures of 15, 20, 25, 27, 30, and 35°C, 70 ± 5% relative humidity, and a photoperiod of 12:12 (L:D). The objectives were to determine the effect of temperature on the developmental stages for optimizing rearing and to understand the geographical pattern of occurrence of these fruit fly species. A strong and positive linear relationship was observed between temperature and developmental rate of immature stages of B. carambolae. Similarly, a strong and positive linear relationship was observed between temperature and developmental rate of B. papayae. A temperature summation model was used to estimate the lower threshold temperature and the thermal constant. Bactrocera papayae was significantly faster in development and higher in survival and appeared to be better adapted to low temperatures than B. carambolae, as it exhibited the lowest threshold temperatures at all immature stages. The observed differences in response to various temperatures revealed to some extent the impact of temperature on these species' distribution in peninsular Thailand and other parts of the world.


Development of a loop-mediated isothermal amplification method for rapid mass-screening of sand flies for Leishmania infection.
Entomological monitoring of Leishmania infection in leishmaniasis endemic areas offers epidemiologic advantages for predicting the risk and expansion of the disease, as well as evaluation of the effectiveness of control programs. In this study, we developed a highly sensitive loop-mediated isothermal amplification (LAMP) method for the mass screening of sand flies for Leishmania infection based on the 18S rRNA gene. The LAMP technique could detect 0.01 parasites, which was more sensitive than classical PCR. The method was robust and could amplify the target DNA within 1h from a crude sand fly template without DNA purification. Amplicon detection could be accomplished by the newly developed colorimetric malachite green (MG)--mediated naked eye visualization. Pre-addition of MG to the LAMP reaction solution did not inhibit amplification efficiency. The field applicability of the colorimetric MG-based LAMP assay was demonstrated with 397 field-caught samples from the endemic areas of Ecuador and eight positive sand flies were detected. The robustness, superior sensitivity, and ability to produce better visual discriminatory reaction products than existing LAMP fluorescence and turbidity assays indicated the field potential usefulness of this new method for surveillance and epidemiological studies of leishmaniasis in developing countries.


Adolescents who take overdoses: outcome in terms of changes in psychopathology and the adolescents' attitudes to care and to their overdose.
Adolescent self-poisoners were followed up 3 months after taking an overdose. High levels of psychopathology were found, with 72% (18/25) of the adolescents having a diagnosable psychiatric disorder and 48% (12/25) major depression. All the adolescents were offered follow-up treatment from health or social services. Compliance with treatment was very high. Seventy-two per cent of the adolescents found treatment useful to them. The adolscents received a generally sympathetic response from their significant others. Fifty-four per cent of the adolescents thought that their overdose had resulted overall in improvements to their lives but 44% would consider taking an overdose again in similar circumstances.


Nuclear cataract and myopia during hyperbaric oxygen therapy.
The effect on the human lens of prolonged hyperbaric oxygen therapy is reported. Eye examinations were given to 25 patients before, during, and after a series of 150 or more exposures to hyperbaric oxygen. All patients changed refraction in the direction of myopia during treatment. Fifteen of the patients had clear lens nuclei before treatment. Seven of these developed a nuclear cataract with reduced visual acuity during treatment. Reversible lens myopia has previously been noticed as a side effect of exposure to hyperbaric oxygen, but the cataractogenic effect in man has not been reported by other workers. This report strongly supports the theory of an oxidative damage to the lens proteins as a cause of nuclear cataract.


Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury.
Using a large, international cohort, we sought to determine the effect of initial technique of renal replacement therapy (RRT) on the outcome of acute renal failure (ARF) in the intensive care unit (ICU). We enrolled 1218 patients treated with continuous RRT (CRRT) or intermittent RRT (IRRT) for ARF in 54 ICUs in 23 countries. We obtained demographic, biochemical and clinical data and followed patients to either death or hospital discharge. Information was analyzed to assess the independent impact of treatment choice on survival and renal recovery. Patients treated first with CRRT (N=1006, 82.6%) required vasopressor drugs and mechanical ventilation more frequently compared to those receiving IRRT (N=212, 17.4%), (p<0.0001). Unadjusted hospital survival was lower (35.8% vs. 51.9%, p<0.0001). However, unadjusted dialysis-independence at hospital discharge was higher after CRRT (85.5% vs. 66.2%, p<0.0001). Multivariable logistic regression showed that choice of CRRT was not an independent predictor of hospital survival or dialysis-free hospital survival. However, the choice of CRRT was a predictor of dialysis independence at hospital discharge among survivors (OR: 3.333, 95% CI: 1.845 - 6.024, p<0.0001). Further adjustment using a propensity score did not significantly change these results. We conclude that worldwide, the choice of CRRT as initial therapy is not a predictor of hospital survival or dialysis-free hospital survival but is an independent predictor of renal recovery among survivors.


MEDLEY: Intent-based Recommendations to Support Dashboard Composition.
Despite the ever-growing popularity of dashboards across a wide range of domains, their authoring still remains a tedious and complex process. Current tools offer considerable support for creating individual visualizations but provide limited support for discovering groups of visualizations that can be collectively useful for composing analytic dashboards. To address this problem, we present MEDLEY, a mixed-initiative interface that assists in dashboard composition by recommending dashboard collections (i.e., a logically grouped set of views and filtering widgets) that map to specific analytical intents. Users can specify dashboard intents (namely, measure analysis, change analysis, category analysis, or distribution analysis) explicitly through an input panel in the interface or implicitly by selecting data attributes and views of interest. The system recommends collections based on these analytic intents, and views and widgets can be selected to compose a variety of dashboards. MEDLEY also provides a lightweight direct manipulation interface to configure interactions between views in a dashboard. Based on a study with 13 participants performing both targeted and open-ended tasks, we discuss how MEDLEY's recommendations guide dashboard composition and facilitate different user workflows. Observations from the study identify potential directions for future work, including combining manual view specification with dashboard recommendations and designing natural language interfaces for dashboard authoring.


MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies.
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.


Pneumococcal septic arthritis: review of 190 cases.
This article reports 13 cases of pneumococcal septic arthritis and reviews another 177 cases reported since 1965. Of 2407 cases of septic arthritis from large series, 156 (6%) were caused by Streptococcus pneumoniae. Mortality was 19% among adults and 0% among children. Pneumococcal bacteremia was the strongest predictor of mortality. At least 1 knee was involved in 56% of adults. Polyarticular disease (36%) and bacteremia (72%) were more common among adults with septic arthritis caused by S. pneumoniae than among adults with other causative organisms. Only 50% of adults with pneumococcal septic arthritis had another focus of pneumococcal infection, such as pneumonia. Functional outcomes were good in 95% of patients. Uncomplicated pneumococcal septic arthritis can be managed with arthrocentesis and 4 weeks of antibiotic therapy; most cases of pneumococcal prosthetic joint infection can be managed without prosthesis removal. A fatal case of septic arthritis caused by a beta-lactam-resistant strain of S. pneumoniae is also presented.


Probing the dynamics of an optically trapped particle by phase sensitive back focal plane interferometry.
The dynamics of an optically trapped particle are often determined by measuring intensity shifts of the back-scattered light from the particle using position sensitive detectors. We present a technique which measures the phase of the back-scattered light using balanced detection in an external Mach-Zehnder interferometer scheme where we separate out and beat the scattered light from the particle and that from the top surface of our trapping chamber. The technique has improved axial motion resolution over intensity-based detection, and can also be used to measure lateral motion of the trapped particle. In addition, we are able to track the Brownian motion of trapped 1.1 and 3 μm diameter particles from the phase jitter and show that, similar to intensity-based measurements, phase measurements can also be used to simultaneously determine displacements of the trapped particle as well as the spring constant of the trap. For lateral displacements, we have matched our experimental results with a simulation of the overall phase contour of the back-scattered light by using plane wave decomposition in conjunction with Mie scattering theory. The position resolution is limited by path drifts of the interferometer which we have presently reduced to demonstrate the capability of sub-nm displacement resolution in the axial direction for 1.1 μm diameter particles by locking the interferometer to a frequency stabilized diode laser.


UK Renal Registry 16th annual report: chapter 3 demographic and biochemistry profile of kidney transplant recipients in the UK in 2012: national and centre-specific analyses.
National transplant registries routinely focus on centre-specific patient and graft survival rates following renal transplantation. However other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important quality of care indicators. Renal transplant activity, incident graft survival data and donor information were obtained from NHS Blood and Transplant. Laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients. The main increase in transplant activity in 2012 was the use of donors after circulatory death. The death-censored graft failure rate was similar to previous years at 2.2% and the transplant patient death rates remained stable at 2.3 per 100 patient years. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year posttransplant patients. Analysis of prevalent transplants by chronic kidney disease stage showed 13.7% with an eGFR <30 ml/min/1.73 m(2) and 1.7% with an eGFR <15 ml/min/1.73 m(2). Of those with CKD stage 5T, 33% had haemoglobin concentrations <100 g/L, 27.6% phosphate concentrations 1.7 mmol/L and 20.5% adjusted calcium concentrations 2.5 mmol/L. Infection (23%) and malignancy (20%) remained amongst the commonest causes of death in patients with a functioning renal transplant. Significant variations in clinical outcomes (unadjusted for patient specific variables) amongst kidney transplant recipients continued to exist in the UK and may reflect differences in healthcare delivery between renal centres.


Rearrangement of the T-cell-receptor beta-chain gene in the diagnosis of lymphoproliferative disorders.
The arrangement of the T-cell-receptor and immunoglobulin genes has been analysed in 77 cases of lymphoproliferative disorder. All 6 T-cell leukaemias and 16 of 19 T-cell lymphomas showed rearrangement of the gene coding for the beta chain of the T-cell receptor, associated in all cases with a germline arrangement of the immunoglobulin genes. All 36 B-cell leukaemias and all 16 B-cell lymphomas showed rearrangement of immunoglobulin genes; the T-cell-receptor gene was in the germline configuration in most of these cases but showed a rearranged pattern in 3 cases (2 chronic lymphatic leukaemias and 1 immunoblastic lymphoma). The combined use of T-cell-receptor and immunoglobulin gene probes promises to be a valuable means of identifying and classifying T-cell neoplasms.