Vasopressin impairs brain, heart and kidney perfusion: an experimental study in pigs after transient myocardial ischemia.
Arginine vasopressin (AVP) is increasingly used to restore mean arterial pressure (MAP) in low-pressure shock states unresponsive to conventional inotropes. This is potentially deleterious since AVP is also known to reduce cardiac output by increasing vascular resistance. The effects of AVP on blood flow to vital organs and cardiac performance in a circulation altered by cardiac ischemia are still not sufficiently clarified. We hypothesised that restoring MAP by low dose, therapeutic level AVP would reduce vital organ blood flow in a setting of experimental acute left ventricular dysfunction. Cardiac output (CO) and arterial blood flow to the brain, heart, kidney and liver were measured in nine pigs using transit-time flow probes. Left ventricular pressure-volume catheter and central arterial and venous catheters were used for haemodynamic recordings and blood sampling. Transient left ventricular ischemia was induced by intermittent left coronary occlusions resulting in a 17% reduction in cardiac output and a drop in MAP from 87 +/- 3 to 67 +/- 4 mmHg (p < 0.001). A low-dose therapeutic level of AVP (0.005 U/kg/min) was used to restore MAP to pre-ischemic values (93 +/- 4 mmHg). AVP further impaired systemic perfusion (CO and brain, heart and kidney blood flow reduced by 29, 18, 23 and 34%, respectively) due to a 2.0-, 2.2-, 1.9- and 2.1-fold increase in systemic, brain, heart and kidney specific vascular resistances. The hypoperfusion induced by AVP was associated with an increased systemic oxygen extraction. Oxygen saturation in blood drawn from the great cardiac vein fell from 29 +/- 1 to 21 +/- 3% (p = 0.01). Finally, these effects were reversed 40 min after AVP was withdrawn. Low dose AVP induced a pronounced reduction in vital organ blood flow in pigs after transient cardiac ischemia. This indicates a potentially deleterious effect of AVP in patients with heart failure or cardiogenic shock due to impaired coronary perfusion.


In Situ Raman Study of Liquid Water at High Pressure.
A pressure shift of Raman band of liquid water (H2O) may be an important tool for measuring residual pressures in mineral inclusions, in situ barometry in high-pressure cells, and as an indicator of pressure-induced structural transitions in H2O. However, there was no consensus as to how the broad and asymmetric water Raman band should be quantitatively described, which has led to fundamental inconsistencies between reported data. In order to overcome this issue, we measured Raman spectra of H2O in situ up to 1.2 GPa using a diamond anvil cell, and use them to test different approaches proposed for the description of the water Raman band. We found that the most physically meaningful description of water Raman band is the decomposition into a linear background and three Gaussian components, associated with differently H-bonded H2O molecules. Two of these components demonstrate a pronounced anomaly in pressure shift near 0.4 GPa, supporting ideas of structural transition in H2O at this pressure. The most convenient approach for pressure calibration is the use of "a linear background + one Gaussian" decomposition (the pressure can be measured using the formula P (GPa) = -0.0317(3)·ΔνG (cm-1), where ΔνG represents the difference between the position of water Raman band, fitted as a single Gaussian, in measured spectrum and spectrum at ambient pressure).


Cloning, sequencing, and expression of Rhodococcus L-phenylalanine dehydrogenase. Sequence comparisons to amino-acid dehydrogenases.
L-Phenylalanine dehydrogenase catalyzes the NAD(+)-dependent, reversible, oxidative deamination of L-phenylalanine to form ammonia, phenyl pyruvate, and NADH. The enzyme has been purified to homogeneity from Rhodococcus sp. M4, and a partial amino acid sequence was obtained. A cosmid library of Rhodococcus sp. M4 genomic DNA was prepared and used to isolate a 2.5-kilobase PstI fragment that contained the pdh gene. The open reading frame of 1068 nucleotides encodes a polypeptide of 356 amino acids, portions of which match the amino acid sequence determined for the purified enzyme. Expression of the Rhodococcus pdh gene in Escherichia coli, which does not contain a phenylalanine dehydrogenase activity, yields a soluble enzyme exhibiting phenylalanine dehydrogenase activity. Both the enzyme purified from Rhodococcus and the enzyme expressed in E. coli are post-translationally modified by removal of the amino-terminal methionine. The overall amino acid sequence is homologous to previously reported sequences of leucine and phenylalanine dehydrogenases as well as several glutamate dehydrogenases. The amino-terminal portion of the enzyme contains residues involved in L-amino acid binding and catalysis, while the carboxyl-terminal portion contains the presumptive dinucleotide-binding domain. A detailed sequence comparison of Rhodococcus phenylalanine dehydrogenase with leucine, phenylalanine, and glutamate dehydrogenases suggests residues involved in general amino acid binding and others that provide for amino acid discrimination.


Thyroid-induced cardiac disorders.
Signs and symptoms of thyroid disease are varied and often vague. ICU patients may have cardiac disorders directly related to altered levels of thyroid hormone rather than inherent cardiac disease. Cardiac manifestations of thyroid disease result from a decrease or an increase in circulating hormone and are usually reversible with treatment. Accurate, ongoing assessment, especially after treatment has begun, is important to help guide safe and effective therapy. Patient education is another priority of nursing care and can be a major factor in helping the patient to achieve and maintain a euthyroid state.


[An experimental study on the prediction of heat stress of workers in a hot environment, with special reference to the relation between wearing suits, work load and environmental temperature].
Hardly any practical approaches have been made on prediction of appearance of heat-stress hazard, although basic studies have extensively been made, including various heat-stress indices. Hence, in the present paper, an applicational prediction equation is presented with regard to the permissible working time without heat-stress hazard on the basis of experimental results. The purpose of this experiment was to examine the significant correlations between elevated rectal temperature, working conditions such as wearing suits, work load, and environmental temperature. The results obtained can be summarized as follows. (1) A critical level of environmental temperature exists. When this level is exceeded, physiological indices such as rectal temperature rapidly increased. According to experimental results, the critical level was about 30 degrees C and the heavier the work load, the lower was the critical level. (2) Moreover, the heavier the wearing suit, the lower became the temperature level. This finding indicated that it was important to choose a suitable apparel under a hot environment in order to keep the workers safe from heat-stress hazard. (3) A general prediction equation of raising the level of rectal temperature compared with that of initial condition was proposed by analysing each experimental condition (suit, work load, and environmental temperature) by use of second order multiple regression method. This equation showed that elevation of rectal temperature was assumed to be proportional to the logarithm of the working periods. (4) The predicted values by this equation corresponded with the experimental values within +/- 0.2-0.3 degrees C, and the correlation coefficient was 0.96. This equation suggests that heavier suits elevated the rectal temperature about 2-3 degrees C when the work load and environmental temperature were moderate. (5) It is possible to predict the permissible working period by this equation. This may be applied to the working plan effectively. Appropriate working conditions can be chosen with regard to apparel, environmental temperature, and work load.


Making sense of perceptions of risk of diseases and vaccinations: a qualitative study combining models of health beliefs, decision-making and risk perception.
Maintaining high levels of childhood vaccinations is important for public health. Success requires better understanding of parents' perceptions of diseases and consequent decisions about vaccinations, however few studies have considered this from the theoretical perspectives of risk perception and decision-making under uncertainty. The aim of this study was to examine the utility of subjective risk perception and decision-making theories to provide a better understanding of the differences between immunisers' and non-immunisers' health beliefs and behaviours. In a qualitative study we conducted semi-structured in-depth interviews with 45 Australian parents exploring their experiences and perceptions of disease severity and susceptibility. Using scenarios about 'a new strain of flu' we explored how risk information was interpreted. We found that concepts of dread, unfamiliarity, and uncontrollability from the subjective perception of risk and ambiguity, optimistic control and omission bias from explanatory theories of decision-making under uncertainty were useful in understanding why immunisers, incomplete immunisers and non-immunisers interpreted severity and susceptibility to diseases and vaccine risk differently. Immunisers dreaded unfamiliar diseases whilst non-immunisers dreaded unknown, long term side effects of vaccines. Participants believed that the risks of diseases and complications from diseases are not equally spread throughout the community, therefore, when listening to reports of epidemics, it is not the number of people who are affected but the familiarity or unfamiliarity of the disease and the characteristics of those who have had the disease that prompts them to take preventive action. Almost all believed they themselves would not be at serious risk of the 'new strain of flu' but were less willing to take risks with their children's health. This study has found that health messages about the risks of disease which are communicated as though there is equality of risk in the population may be unproductive as these messages are perceived as unbelievable or irrelevant. The findings from this study have implications beyond the issue of childhood vaccinations as we grapple with communicating risks of new epidemics, and indeed may usefully contribute to the current debate especially in the UK of how these theories of risk and decision-making can be used to 'nudge' other health behaviours.


Evaluation of Enterococcus mundtii ST4SA and Lactobacillus plantarum 423 as probiotics by using a gastro-intestinal model with infant milk formulations as substrate.
Enterococcus mundtii ST4SA and Lactobacillus plantarum 423 produce bacteriocins with activity against a number of Gram-positive and Gram-negative bacteria. Both strains survived intestinal conditions simulated in a gastro-intestinal model (GIM) with infant milk formulations as substrate and prevented the growth of Listeria monocytogenes ScottA. The strains are inhibited by the antibiotics amoxicillin, cefadroxil, roxithromycin and doxycycline, anti-inflammatory medicaments containing meloxicam, ibuprofen and sodium diklofenak, and analgesics containing paracetamol, codeine phosphate and promethazine. Strain 423 is sensitive to vancomycin and does not contain genes encoding gelatinase, cell aggregation substance (AS), adhesion to collagen (Ace), enterococcus surface protein (Esp), Enterococcus faecalis endocarditis antigen (EfaAfs), cytolysin and non-cytolysin (beta-hemolysin III). Genes encoding AS, cytolysin and non-cytolysin (beta-hemolysin III) were amplified from the genome of strain ST4SA. Survival of strains ST4SA and 423 improved when used as combined cultures in the GIM and compared well with the survival of commercially available probiotics subjected to the same conditions.


Psychological factors in personal and clinical recovery in bipolar disorder.
Research into bipolar disorder (BD) has primarily focused upon clinical recovery (CR), i.e. symptom reduction, and overlooked personally meaningful recovery outcomes emphasized by service users. Personal recovery (PR) has been a major focus in the formulation of mental health policies and guidelines, and yet, research into factors influencing PR in BD is in its infancy. This study compared psychological associates of concurrent PR and CR, and determined psychological factors in PR prospectively at 6 months. 107 participants completed baseline assessments, of whom 84% completed follow-up at 6 months. Controlling for potential confounders, multiple linear and ordinal regression models showed that some psychological factors underpinned both CR and PR at baseline: worse PR and CR outcomes were associated with higher negative self-dispositional appraisals and dysfunctional attitudes. Better PR, but worse CR ([hypo]mania related) were associated with higher adaptive coping. Additionally, better PR (but not CR) was associated with higher concurrent risk taking at baseline and predicted at follow-up by higher levels of baseline rumination. Better CR ([hypo]mania related), but not PR, was associated with lower impulsivity, but higher BAS processes. Psychological and clinical factors were not measured at follow up and may have changed over time. Participants were a convenience sample. Understanding psychological factors driving recovery in BD is essential for refining the conceptual framework of PR, and informing psychological models and related interventions for BD. The identified differences in psychological factors highlight the importance of more individualised, PR focused therapeutic approaches.


Expression pattern of genes encoding farnesyl diphosphate synthase and sesquiterpene cyclase in cotton suspension-cultured cells treated with fungal elicitors.
Cotton plants accumulate sesquiterpene aldehydes in pigment glands. The two enzymes farnesyl diphosphate synthase (FPS) and (+)-delta-cadinene synthase (CAD), a sesquiterpene cyclase, are involved in the biosynthesis of these secondary metabolites. A full-length cDNA (garfps) encoding FPS was isolated from Gossypium arboreum and identified by in vitro enzymatic assay of the garfps protein heterologously expressed in Escherichia coli. Treatment of G. arboreum suspension-cultured cells with an elicitor preparation obtained from the phytopathogenic fungus Verticillium dahliae dramatically induced transcription of both FPS and CAD, paralleling the accumulation of the sesquiterpene aldehydes in these cells. For G. australe, a wild species from Australia, the V. dahliae elicitor preparation also caused an induction of FPS but only a low rate of induction of CAD, apparently because of a constitutive expression of the sesquiterpene cyclase gene in suspension-cultured cells. Two transcripts and proteins of FPS were detected in the elicited G. australe cells; the smaller FPS seemed to be de novo synthesized after elicitation. Furthermore, G. australe-cultured cells accumulated the cadinene, instead of sesquiterpene aldehydes, indicating that the biosynthetic pathway leading to sesquiterpene aldehydes was absent or blocked after FPP cyclization.


Dynamic Whitening Saliency.
General dynamic scenes involve multiple rigid and flexible objects, with relative and common motion, camera induced or not. The complexity of the motion events together with their strong spatio-temporal correlations make the estimation of dynamic visual saliency a big computational challenge. In this work, we propose a computational model of saliency based on the assumption that perceptual relevant information is carried by high-order statistical structures. Through whitening, we completely remove the second-order information (correlations and variances) of the data, gaining access to the relevant information. The proposed approach is an analytically tractable and computationally simple framework which we call Dynamic Adaptive Whitening Saliency (AWS-D). For model assessment, the provided saliency maps were used to predict the fixations of human observers over six public video datasets, and also to reproduce the human behavior under certain psychophysical experiments (dynamic pop-out). The results demonstrate that AWS-D beats state-of-the-art dynamic saliency models, and suggest that the model might contain the basis to understand the key mechanisms of visual saliency. Experimental evaluation was performed using an extension to video of the well-known methodology for static images, together with a bootstrap permutation test (random label hypothesis) which yields additional information about temporal evolution of the metrics statistical significance.


Deciphering lignocellulose deconstruction by the white rot fungus Irpex lacteus based on genomic and transcriptomic analyses.
Irpex lacteus is one of the most potent white rot fungi for biological pretreatment of lignocellulose for second biofuel production. To elucidate the underlying molecular mechanism involved in lignocellulose deconstruction, genomic and transcriptomic analyses were carried out for I. lacteus CD2 grown in submerged fermentation using ball-milled corn stover as the carbon source. Irpex lacteus CD2 efficiently decomposed 74.9% lignin, 86.3% cellulose, and 83.5% hemicellulose in corn stover within 9 days. Manganese peroxidases were rapidly induced, followed by accumulation of cellulase and hemicellulase. Genomic analysis revealed that I. lacteus CD2 possessed a complete set of lignocellulose-degrading enzyme system composed mainly of class II peroxidases, dye-decolorizing peroxidases, auxiliary enzymes, and 182 glycoside hydrolases. Comparative transcriptomic analysis substantiated the notion of a selection mode of degradation. These analyses also suggested that free radicals, derived either from MnP-organic acid interplay or from Fenton reaction involving Fe2+ and H2O2, could play an important role in lignocellulose degradation. The selective strategy employed by I. lacteus CD2, in combination with low extracellular glycosidases cleaving plant cell wall polysaccharides into fermentable sugars, may account for high pretreatment efficiency of I. lacteus. Our study also hints the importance of free radicals for future designing of novel, robust lignocellulose-degrading enzyme cocktails.


An LRR/Malectin Receptor-Like Kinase Mediates Resistance to Non-adapted and Adapted Powdery Mildew Fungi in Barley and Wheat.
Pattern recognition receptors (PRRs) belonging to the multigene family of receptor-like kinases (RLKs) are the sensing devices of plants for microbe- or pathogen-associated molecular patterns released from microbial organisms. Here we describe Rnr8 (for Required for non-host resistance 8) encoding HvLEMK1, a LRR-malectin domain-containing transmembrane RLK that mediates non-host resistance of barley to the non-adapted wheat powdery mildew fungus Blumeria graminis f.sp. tritici. Transgenic barley lines with silenced HvLEMK1 allow entry and colony growth of the non-adapted pathogen, although sporulation was reduced and final colony size did not reach that of the adapted barley powdery mildew fungus B. graminis f.sp. hordei. Transient expression of the barley or wheat LEMK1 genes enhanced resistance in wheat to the adapted wheat powdery mildew fungus while expression of the same genes did not protect barley from attack by the barley powdery mildew fungus. The results suggest that HvLEMK1 is a factor mediating non-host resistance in barley and quantitative host resistance in wheat to the wheat powdery mildew fungus.


Defining the origins of the iliofemoral, ischiofemoral, and pubofemoral ligaments of the hip capsuloligamentous complex utilizing computer navigation.
To use computer navigation software to investigate the specific origins of the hip capsuloligamentous complex. Six fresh frozen cadaver hips were anatomically landmarked utilizing a three-dimensional computer navigation system. The acetabular origins of the iliofemoral, pubofemoral, and ischiofemoral ligaments were statically digitized. Computer software was used to create a 180° (6:00) meridian line positioned over the midpoint of the acetabular notch, and to present the results in a clocklike manner in hours and minutes (00:00) and also degrees relative to the 12 o'clock position. The iliofemoral ligament origin starts at 17° (±31°) from the 12 o'clock position, or 12:35 (±1:02) in hours and minutes, and ends at 69° (±13°) or 2:18 (±0:25), spanning a mean distance of 52° (±19°). The ischiofemoral ligament has the broadest origin, starting at 262° (±12°) or 8:44 (±0:24), and ending at 353° (±17°) or 11:45 (±0:14), spanning a mean distance of 90° (±6°). The pubofemoral ligament origin is the smallest, starting at 121° (±5°) or 4:02 (±0:11), and ending at 163° (±9°) or 5:27 (±0:18), spanning a mean distance of 42° (±5°). The iliofemoral ligament origin demonstrates the greatest anatomic variability with regards to its location and its size (p = 0.002). This study demonstrates that there is significant variability in the size and location of the iliofemoral ligament origin versus the pubofemoral and ischiofemoral ligaments. Level IV anatomic cadaveric study. See the guidelines online for a complete description of level of evidence.


Prevalence of antibodies to Toxoplasma gondii in pigeons (Columba livia) in Taiwan.
Starting from January 2004 to December 2004, 665 blood serum samples from pigeons (Columba livia) were collected from 44 pigeonaries in 11 counties and 20 regions in Taiwan. These samples were examined by latex agglutination test (LAT) for antibodies to Toxoplasma gondii by using the LAT. Antibodies were found in 4.7% (31/ 665) of pigeons at a LAT titer of 1:32 or higher. The prevalence in Taiwan was highest in the northern areas (6.0%; 13/216) and lowest in the eastern areas (1.8%; 2/111).


Are Some Words Worth More than Others?
Current evaluation metrics for language modeling and generation rely heavily on the accuracy of predicted (or generated) words as compared to a reference ground truth. While important, token-level accuracy only captures one aspect of a language model's behavior, and ignores linguistic properties of words that may allow some mis-predicted tokens to be useful in practice. Furthermore, statistics directly tied to prediction accuracy (including perplexity) may be confounded by the Zipfian nature of written language, as the majority of the prediction attempts will occur with frequently-occurring types. A model's performance may vary greatly between high- and low-frequency words, which in practice could lead to failure modes such as repetitive and dull generated text being produced by a downstream consumer of a language model. To address this, we propose two new intrinsic evaluation measures within the framework of a simple word prediction task that are designed to give a more holistic picture of a language model's performance. We evaluate several commonly-used large English language models using our proposed metrics, and demonstrate that our approach reveals functional differences in performance between the models that are obscured by more traditional metrics.


Some observations on the Soviet health system.
The author wrote the following article after returning from a visit to the Soviet Union as a member of an HEW delegation. It identifies some of the underlying political and economic considerations that influenced health policy in the Soviet Union and comments on how the health system underpins the political system. The author also identifies some of the challenges being faced by the Soviet health system as consumer expectations increase, and how those challenges are causing the Soviets to ask many of the same questions currently being asked in the U.S. health system.


A computational approach to the functional screening of genomes.
Comparative genomics usually involves managing the functional aspects of genomes, by simply comparing gene-by-gene functions. Following this approach, Mushegian and Koonin proposed a hypothetical minimal genome, Minimal Gene Set (MGS), aiming for a possible oldest ancestor genome. They obtained MGS by comparing the genomes of two simple bacteria and eliminating duplicated or functionally identical genes. The authors raised the fundamental question of whether a hypothetical organism possessing MGS is able to live or not. We attacked this viability problem specifying in silico the metabolic pathways of the MGS-based prokaryote. We then performed a dynamic simulation of cellular metabolic activities in order to check whether the MGS-prokaryote reaches some equilibrium state and produces the necessary biomass. We assumed these two conditions to be necessary for a living organism. Our simulations clearly show that the MGS does not express an organism that is able to live. We then iteratively proceeded with functional replacements in order to obtain a genome composition that gives rise to equilibrium. We ruled out 76 of the original 254 genes in the MGS, because they resulted in duplication from a functional point of view. We also added seven genes not present in the MGS. These genes encode for enzymes involved in critical nodes of the metabolic network. These modifications led to a genome composed of 187 elements expressing a virtually living organism, Virtual Cell (ViCe), that exhibits homeostatic capabilities and produces biomass. Moreover, the steady-state distribution of the concentrations of virtual metabolites that resulted was similar to that experimentally measured in bacteria. We conclude then that ViCe is able to "live in silico."


Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts.
Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid.Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR.


Compassionate use of Gemzar in advanced pancreatic cancer: a Belgian experience.
Gemzar is a nucleoside analog that has been shown to be superior to 5-fluorouracil for the treatment of advanced pancreatic cancer in terms of both clinical benefit and survival. This open label program enrolled 214 patients. Patients eligible for this program had advanced or metastatic pancreatic cancer, received up to one previous chemotherapy, a baseline Karnofsky performance status (KPS) of at least 50, measurable or evaluable disease, adequate organ function defined as: absolute leucocyte count > 3 x 10(9)/L, platelet count > 100 x 10(9)/L, hemoglobin > 9 gr/dL, total bilirubin < 2 x upper limit of normal (ULN), creatinine < 2 x ULN, ALT and AST levels < 5 x ULN and were at least 18 years. A 1000 mg/m2 of Gemzar was administered weekly up to 7 weeks followed by a week of rest, then once weekly for 3 weeks out of every 4 weeks. The median age at inclusion was 64 years, 52% of the patients were male, 27% were 70 year or older, 66% had stage IV disease, 66% had a KPS of 80 or higher and 34% had received no prior chemotherapy. The overall response rate is 7%. A time-to-first-serious-event analysis was performed since only a limited number of dates of death were available. The first serious event (FSE) was considered as the earliest of the following: increase by at least 2 of the pain score, deterioration of KPS of at least 20, documentation of progressive disease or death. The median time to FSE was 4 months, the free FSE rate at 1 year was 14%. We conclude that the results observed in this program confirm the established efficacy of Gemzar in pancreatic cancer.


Muller's Ratchet and compensatory mutation in Caenorhabditis briggsae mitochondrial genome evolution.
The theory of Muller' Ratchet predicts that small asexual populations are doomed to accumulate ever-increasing deleterious mutation loads as a consequence of the magnified power of genetic drift and mutation that accompanies small population size. Evidence for Muller's Ratchet and knowledge on its underlying molecular mechanisms, however, are lacking for natural populations. We characterized mitochondrial genome evolutionary processes in Caenorhabditis briggsae natural isolates to show that numerous lineages experience a high incidence of nonsynonymous substitutions in protein-coding genes and accumulate unusual deleterious noncoding DNA stretches with associated heteroplasmic function-disrupting genome deletions. Isolate-specific deletion proportions correlated negatively with nematode fecundity, suggesting that these deletions might negatively affect C. briggsae fitness. However, putative compensatory mutations were also observed that are predicted to reduce heteroplasmy levels of deleterious deletions. Paradoxically, compensatory mutations were observed in one major intraspecific C. briggsae clade where population sizes are estimated to be very small (and selection is predicted to be relatively weak), but not in a second major clade where population size estimates are much larger and selection is expected to be more efficient. This study provides evidence that the mitochondrial genomes of animals evolving in nature are susceptible to Muller's Ratchet, suggests that context-dependent compensatory mutations can accumulate in small populations, and predicts that Muller's Ratchet can affect fundamental evolutionary forces such as the rate of mutation.


Factors associated with loneliness among mothers with 4-month-old or 18-month-old infants in an urban area in Japan.
The factors associated with loneliness in adults and elderly people have been revealed in previous studies. However, much less is known about these factors for mothers with infants. This article investigates the individual and environmental factors associated with loneliness among mothers with 4-month-old or 18-month-old infants in an urban area in Japan. This cross-sectional study was conducted using a self-reported questionnaire survey. Multiple linear regression analyses were undertaken with loneliness (UCLA Loneliness Scale Version 3) as the dependent variable; and demographics, individual factors (internal working model, child-care burden), and environmental factors (social network) as independent variables. The study population consisted of 125 mothers with 4-month-old infants and 123 mothers with 18-month-old infants who visited a Ward B health center in city A in 2012. Mothers of the 4-month-old infants with higher loneliness scores were significantly more likely to have an ambivalent type (β=.354, P<.001) or avoidant type (β=.331, P<.001) of internal working model, greater child-care burden (β=.180, P<.05), and a smaller social network of family (β=-.144, P<.05) and child-rearing friends (β=-.255, P<.01). Mothers of 18-month-old infants with higher loneliness scores were significantly more likely to have lower subjective health (β=-.191, P<.01), an ambivalent type (β=.297, P<.001) or avoidant type (β=.190, P<.05) of internal working model, greater child-care burden (β=.283, P<.001), and a smaller social network of child-rearing friends (β=-.213, P<.01). To prevent loneliness in mothers, it is important to build mothers' human relations through childcare, to enhance their ability to take advantage of childcare while receiving support, and to support community organizations for mothers with infants.


Offsetting the Effects of Neighborhood Disadvantage on Problem Drinking.
Residence in disadvantaged neighborhoods can amplify individual risk for adverse health conditions, including substance use disorders. Using data from a probability sample of problem drinkers in Northern California (N=616) interviewed at baseline and re-interviewed one year later, this study examines whether social support can buffer negative effects of neighborhood disadvantage on problem drinking. Living in a disadvantaged neighborhood increased the likelihood of problem drinking at follow-up (OR=2.33, p=0.015). Although baseline support for reducing drinking was unrelated to problem drinking at follow-up, there was a significant interaction between neighborhood disadvantage and support. Among those living in disadvantaged neighborhoods, baseline support significantly decreased the likelihood of problem drinking at follow-up (OR=0.19, p=0.048). Bolstering indigenous community resources where residents can interact with others in recovery or that foster sober activities may offset individual risk. Research is needed to determine whether this may also produce second-order neighborhood change.


Development of a clinical feeding assessment scale for very young infants in South Africa.
There is a need for validated neonatal feeding assessment instruments in South Africa. A locally developed instrument may contribute to standardised evaluation procedures of high-risk neonates and address needs in resource constrained developing settings. The aim of the study was to develop and validate the content of a clinical feeding assessment scale to diagnose oropharyngeal dysphagia (OPD) in neonates. The Neonatal Feeding Assessment Scale (NFAS) was developed using the Delphi method. Five international and South African speech-language therapists (SLTs) formed the expert panel, participating in two rounds of electronic questionnaires to develop and validate the content of the NFAS. All participants agreed on the need for the development of a valid clinical feeding assessment instrument to use with the neonatal population. The initial NFAS consisted of 240 items across 8 sections, and after the Delphi process was implemented, the final format was reduced to 211 items across 6 sections. The final format of the NFAS is scored using a binary scoring system guiding the clinician to diagnose the presence or absence of OPD. All members agreed on the format, the scoring system and the feeding constructs addressed in the revised final format of the NFAS. The Delphi method and the diverse clinical and research experience of participants could be integrated to develop the NFAS which may be used in clinical practice in South Africa or similar developing contexts. Because of demographically different work settings marked by developed versus developing contexts, participants did not have the same expectations of a clinical dysphagia assessment. The international participants contributed to evidence-based content development. Local participants considered the contextual challenges of South African SLTs entering the field with basic competencies in neonatal dysphagia management, thereby justifying a comprehensive clinical instrument. The NFAS is aimed at clinicians working in Neonatal Intensive Care Units where they manage large caseloads of high-risk neonates. Further validation of the NFAS is recommended to determine its criterion validity in comparison with a widely accepted standard such as the modified barium swallow study.


Fracture Classification Does Not Predict Functional Outcomes in Supracondylar Humerus Fractures: A Prospective Study.
Few studies have prospectively assessed functional outcomes after the surgical management of supracondylar humerus fractures (SCHFXs) and the relationship between fracture pattern and ultimate patient outcome has never been prospectively evaluated. The purpose of this study was to prospectively evaluate fracture classification and functional outcome in children with extension SCHFXs using validated outcome measures. An Institutional Review Board-approved prospective enrollment of consecutive patients with operative SCHFX was performed over a 3-year period. Fractures were classified by the treating surgeon using the modified Gartland classification. Functional outcome was assessed at final follow-up using the Pediatric Outcomes Data Collection Instruments (PODCI) and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) outcome measure. Patients with flexion-type fractures, multidirectionally unstable fractures and those with <10 weeks follow-up were excluded from analysis. Statistical analysis was used to determine the relationship between fracture classification/pattern and functional outcome. Seven hundred fifty-two patients were enrolled during the study period. One hundred thirty-two patients with extension-type injuries (average age 6.7 y) completed functional outcome measures at an average follow-up of 12.4 weeks. Forty-five (34%) were type II fractures and 87 (66%) were type III fractures. Forty-five (34%) of the fractures were posteromedially displaced, 43 (33%) were posterolaterally displaced, and 44 (33%) were posteriorly displaced without coronal plane deformity. The average PODCI global functioning scale score and QuickDASH scores for the entire cohort were 93.6 and 11.4, respectively, indicating excellent function. No differences in outcome scores were noted between patients with type II and III fractures. No difference in outcome was identified based upon direction of fracture displacement. This is the first study to prospectively analyze fracture classification and functional outcome using validated outcome measures following the operative treatment of pediatric extension-type SCHFX. Children generally have excellent functional outcomes following the operative treatment of SCHFX. Garland classification and direction of displacement do not influence functional outcomes. Level II-therapeutic.


The magnitude of oral health inequalities in Canada: findings of the Canadian health measures survey.
This study aimed to measure the magnitude of income-related inequality for four oral health outcomes in Canada. The degree of oral health inequality according to sex was also compared. Data for this study are from the year 2007 to 2009 Canadian Health Measure Survey (CHMS). The sample size consisted of 4951 Canadians aged 6-79 (2409 men and 2542 women). The oral health indicators used were the number of decayed teeth, number of missing teeth, number of filled teeth, and oral pain in the past year. Socioeconomic status was measured as equivalized household income. We used the relative concentration index to quantify health inequalities. Data analyses were performed using STATA 11.1 and ADePT (4.0). The number of decayed teeth, the number of missing teeth and the prevalence of oral pain decreased with increasing income, while the number of filled teeth increased with increasing income. The relative concentration indices for decayed teeth, missing teeth, filled teeth and for oral pain were -0.264, -0.157, 0.085, and -0.120, respectively. There was a statistically significant deviation from equality for the four oral health outcomes and this was generally present for both sexes. The relative concentration indices for decayed teeth were statistically significantly larger than other oral health outcomes. The relative concentration indices for women were greater than those of males indicating a greater magnitude of inequality among women. There was a higher concentration of decayed teeth, missing teeth and oral pain in the worse off, while the more affluent had a greater concentration of filled teeth. The numbers of decayed teeth was the most unequal aspect of oral health comparatively. There was a sex difference in the pattern of oral health inequalities with greater magnitude of inequality present among women in terms of the number of decayed and missing teeth. Health policymakers should consider the magnitude of health inequalities according to outcome and between sexes in their decision to tackle oral health inequalities.


The Inter-Valley Soil Comparative Survey: the ecology of Dry Valley edaphic microbial communities.
Recent applications of molecular genetics to edaphic microbial communities of the McMurdo Dry Valleys and elsewhere have rejected a long-held belief that Antarctic soils contain extremely limited microbial diversity. The Inter-Valley Soil Comparative Survey aims to elucidate the factors shaping these unique microbial communities and their biogeography by integrating molecular genetic approaches with biogeochemical analyses. Although the microbial communities of Dry Valley soils may be complex, there is little doubt that the ecosystem's food web is relatively simple, and evidence suggests that physicochemical conditions may have the dominant role in shaping microbial communities. To examine this hypothesis, bacterial communities from representative soil samples collected in four geographically disparate Dry Valleys were analyzed using molecular genetic tools, including pyrosequencing of 16S rRNA gene PCR amplicons. Results show that the four communities are structurally and phylogenetically distinct, and possess significantly different levels of diversity. Strikingly, only 2 of 214 phylotypes were found in all four valleys, challenging a widespread assumption that the microbiota of the Dry Valleys is composed of a few cosmopolitan species. Analysis of soil geochemical properties indicated that salt content, alongside altitude and Cu(2+), was significantly correlated with differences in microbial communities. Our results indicate that the microbial ecology of Dry Valley soils is highly localized and that physicochemical factors potentially have major roles in shaping the microbiology of ice-free areas of Antarctica. These findings hint at links between Dry Valley glacial geomorphology and microbial ecology, and raise previously unrecognized issues related to environmental management of this unique ecosystem.


Measuring the validity and reliability of the Lithuanian missed nursing care in infection prevention and control scales using Rasch analysis.
The aim was to translate and validate the Missed Nursing Care in Infection Prevention and Control Survey for its use in the Lithuanian context. A convenience sample of 331 nurses was surveyed. The study instrument explored missed care in the context of infection prevention and control practices. Rasch analysis was undertaken using Winsteps® Rasch measurement computer program and the generalized item response modelling software. The Missed Nursing Care in Infection Prevention and Control Survey in the Lithuanian language demonstrated unidimensionality and provided evidence of item fit to the modified instrument. The reliability of both sub-scales was 0.78 and 0.98, respectively. Differing consensus between the nurses based on their perceived frequencies and reasons of missed care was demonstrated. The final Lithuanian version of the Missed Nursing Care in Infection Prevention and Control Survey consists of 29 items that assess type and frequency of missed care and 17 items that identify reasons for missed care. Unit managers will be able to use the modified scales to generate evidence as to the sources of missed infection control practices in their clinical areas and the rationale for the breaks in the hierarchy of mandatory infection prevention.


Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation.
The calcineurin-nuclear factor of activated T-cell (NFAT) signal transduction pathway regulates the expression of a plethora of genes in the myocardium. Cytosolic calcium overloading occurs in atrial fibrillation (AF), and this fulfills the condition needed for activation of this pathway. We therefore investigated the NFAT pathway in atrial tissue in a porcine model of AF. AF was induced in eight adult pigs by rapid atrial pacing. Investigations on the calcineurin and NFAT pathway were performed on transmural left atrial tissue obtained 6 weeks after implantation of the pacemaker (pacing for 4 weeks, and AF without pacing for 2 weeks). In the AF group, the left atrial dimension increased significantly (26 +/- 4 mm vs 31 +/- 4 mm, respectively, p < 0.05 [mean +/- SD]). Calcineurin enzyme activity increased significantly in pigs with AF (n = 8) when compared to control pigs (n = 6) [0.143 +/- 0.034 vs 0.038 +/- 0.063 mmol PO(4)(-) released, p < 0.01]. We found that both NFAT-c3 and NFAT-c4, the downstream effectors of calcineurin, increased significantly in the nuclei in AF tissue using immunoblotting. Translocation of NFAT-c3 and NFAT-c4 into the nuclei was also demonstrated in AF tissue microsections using immunohistochemistry. The electrophoresis mobility shift assay further demonstrated that nuclear extracts from AF tissue had a significantly larger binding capacity for NFAT-specific oligonucleotide probes. Our results demonstrate that calcineurin activity was increased in AF with subsequent NFAT-c3 and NFAT-c4 translocation into the nucleus. Activation of this signal transduction pathway may play an important role in the pathogenesis of AF.


Intuitive wireless control of a robotic arm for people living with an upper body disability.
Assistive Technologies (ATs) also called extrinsic enablers are useful tools for people living with various disabilities. The key points when designing such useful devices not only concern their intended goal, but also the most suitable human-machine interface (HMI) that should be provided to users. This paper describes the design of a highly intuitive wireless controller for people living with upper body disabilities with a residual or complete control of their neck and their shoulders. Tested with JACO, a six-degree-of-freedom (6-DOF) assistive robotic arm with 3 flexible fingers on its end-effector, the system described in this article is made of low-cost commercial off-the-shelf components and allows a full emulation of JACO's standard controller, a 3 axis joystick with 7 user buttons. To do so, three nine-degree-of-freedom (9-DOF) inertial measurement units (IMUs) are connected to a microcontroller and help measuring the user's head and shoulders position, using a complementary filter approach. The results are then transmitted to a base-station via a 2.4-GHz low-power wireless transceiver and interpreted by the control algorithm running on a PC host. A dedicated software interface allows the user to quickly calibrate the controller, and translates the information into suitable commands for JACO. The proposed controller is thoroughly described, from the electronic design to implemented algorithms and user interfaces. Its performance and future improvements are discussed as well.


Natural Killer Cells: Angels and Devils for Immunotherapy.
In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR)-modified T cells. The discovery of donor NK cells' anti-tumor activity in acute myeloid leukemia patients receiving allogeneic stem cell transplantation (allo-SCT) was the trigger to conduct many clinical trials infusing NK cells. Surprisingly, many of these studies did not obtain optimal results, suggesting that many different NK cell parameters combined with the best clinical protocol need to be optimized. Various parameters including the high array of activating receptors that NK cells have, the source of NK cells selected to treat patients, different cytotoxic mechanisms that NK cells activate depending on the target cell and tumor cell survival mechanisms need to be considered before choosing the best immunotherapeutic strategy using NK cells. In this review, we will discuss these parameters to help improve current strategies using NK cells in cancer therapy. Moreover, the chimeric antigen receptor (CAR) modification, which has revolutionized the concept of immunotherapy, will be discussed in the context of NK cells. Lastly, the dark side of NK cells and their involvement in inflammation will also be discussed.


MitoGen: A Framework for Generating 3D Synthetic Time-Lapse Sequences of Cell Populations in Fluorescence Microscopy.
The proper analysis of biological microscopy images is an important and complex task. Therefore, it requires verification of all steps involved in the process, including image segmentation and tracking algorithms. It is generally better to verify algorithms with computer-generated ground truth datasets, which, compared to manually annotated data, nowadays have reached high quality and can be produced in large quantities even for 3D time-lapse image sequences. Here, we propose a novel framework, called MitoGen, which is capable of generating ground truth datasets with fully 3D time-lapse sequences of synthetic fluorescence-stained cell populations. MitoGen shows biologically justified cell motility, shape and texture changes as well as cell divisions. Standard fluorescence microscopy phenomena such as photobleaching, blur with real point spread function (PSF), and several types of noise, are simulated to obtain realistic images. The MitoGen framework is scalable in both space and time. MitoGen generates visually plausible data that shows good agreement with real data in terms of image descriptors and mean square displacement (MSD) trajectory analysis. Additionally, it is also shown in this paper that four publicly available segmentation and tracking algorithms exhibit similar performance on both real and MitoGen-generated data. The implementation of MitoGen is freely available.


Importance of the cytochrome P450 monooxygenase CYP52 family for the sophorolipid-producing yeast Candida bombicola.
Three cytochrome P450 monooxygenases belonging to the CYP52 family were isolated from the genome of the sophorolipid-producing yeast Candida bombicola using degenerate PCR and genomic walking. One gene displayed high identity with the CYP52E members and was classified into this group (CYP52E3), whereas the other genes belonged to new groups: CYP52M and CYP52N. CYP52E3 and CYP52N1 turned out to be of no relevance for sophorolipid production, but show clear upregulation when the yeast cells are grown on alkanes as the sole carbon source. On the other hand, CYP52M1 is clearly upregulated during sophorolipid synthesis and very likely takes part in sophorolipid formation.


Cancer incidence rates and environmental factors: an ecological study.
The environmental factors latitude, temperature, and water consumption have been correlatedwithcancerincidencerates. To date, there is noconsensus of opinion that explains how these environmental factors alter the incidence of cancer. A fluoride belt stretches across the north and east of Africa, through the Middle East, across Pakistan and India, into Southeast Asia, and the south of China. There appears to be an association between areas with low cancer incidence rates and high fluoride concentrations in the water supply. This ecologic study attempts to determine if fluoride is correlated with cancer incidence rates. If so, this study also attempts to determine whether fluoride is a factor in the correlation between latitude, temperature, and cancer incidence rates. Population groups with very high cancer incidence rates and population groups with very low cancer incidence rates are compared to identify environmental factors that might explain the correlation between cancer incidence rates and the environmental factors of latitude, temperature, and fluoride. There is a positive correlation between cancer incidence rates and latitude (r = 0.71). There is an inverse correlation between cancer incidence rates and temperature (r = -0.87). There is also an inverse correlation between cancer incidence rates and fluoride concentration in the drinking water (r = -0.75). Very low cancer incidence was found in areas with high fluoride concentrations in the drinking water.


Anesthesia information management systems: past, present, and future of anesthesia records.
Documenting a patient's anesthetic in the medical record is quite different from summarizing an office visit, writing a surgical procedure note, or recording other clinical encounters. Some of the biggest differences are the frequent sampling of physiologic data, volume of data, and diversity of data collected. The goal of the anesthesia record is to accurately and comprehensively capture a patient's anesthetic experience in a succinct format. Having ready access to physiologic trends is essential to allowing anesthesiologists to make proper diagnoses and treatment decisions. Although the value provided by anesthesia information management systems and their functions may be different than other electronic health records, the real benefits of an anesthesia information management system depend on having it fully integrated with the other health information technologies. An anesthesia information management system is built around the electronic anesthesia record and incorporates anesthesia-relevant data pulled from disparate systems such as laboratory, billing, imaging, communication, pharmacy, and scheduling. The ability of an anesthesia information management system to collect data automatically enables anesthesiologists to reliably create an accurate record at all times, regardless of other concurrent demands. These systems also have the potential to convert large volumes of data into actionable information for outcomes research and quality-improvement initiatives. Developing a system to validate the data is crucial in conducting outcomes research using large datasets. Technology innovations outside of healthcare, such as multitouch interfaces, near-instant software response times, powerful but simple search capabilities, and intuitive designs, have raised the bar for users' expectations of health information technology.


Blog/web log - a new easy and interactive website building tool for a non-net savvy radiologist.
Recently, there has been no escaping the mention of blogs in the media. Blogging has emerged as a social phenomenon, which has impacted politics, business, and communication. Blogging software has enabled people with limited knowledge of the Internet to publish their thoughts online and participate in a global conversation; whereas the Blogosphere has hyperaccelerated the spread of information. Technorati, a blog search engine is now tracking over 7.8 million Weblogs, and 937 million links, and reports that there are about 30,000 to 40,000 new blogs created a day. The majority of people who blog do so as a hobby, using blogs to publish their thoughts, feelings, and viewpoints on whatever topics interest them. Blogging software also enables people to post pictures, music, and more recently videos. For many people blogs are used as online journals or diaries; other people use blogs to communicate with their family and friends. Whether people generate revenue with their blogs or use them as a hobby the one thing they all have in common is that they are part of the Blogosphere, or network of blogs that gives people a voice and allows them to spread information at an unprecedented rate. Although searching PubMed produces few results for "blog" (6 relevant articles of 24), "weblog" (1 article), web log (8 entries of varying relevance), and "blogging" (4 articles) (none of which were in Radiology, RadioGraphics, AJR, or JVIR), blogging might well become an important means of information transfer in Radiology also. As radiology is an image-based science, a blog is a satisfying endeavor in that you can share your experiences with others instantaneously In this context, I would like to submit my experience with easy method for building a Web site known as blogging (maintaining a Web log). As a radiologist, I use my blog (http://www.sumerdoc.blogspot.com/; or http://www.indianradiology.com/) to post interesting cases from my routine practice along with any interesting abstracts I come across during my day-to-day work. The success of this project can be measured by the fact that in the last full year of "rad-blogging," more than 30,000 visitors came to the site from all over the world, with thousands of queries from patients, colleagues, and many interested students. Rad-blogging might well become a new easy method of information exchange and opinion building in Radiology.


Understanding the Risks and Harms of Management of Incidental Thyroid Nodules: A Review.
Incidental thyroid nodules are defined as nodules originally detected in a patient with no thyroid-related clinical symptoms, examination findings, or suspected thyroid disease. Medical imaging for diseases in the neck, chest, and spine is a common source of incidental thyroid nodules. They are easily detected but poorly characterized. The next step is to decide whether the incidental thyroid nodule should be further evaluated with ultrasonography. Indiscriminate workup of incidental thyroid nodules with ultrasonography is not cost-effective and is potentially harmful. Although the concern for malignant neoplasms drives workup, the risk for poor outcomes without evaluation is minimal. The rate of malignant tumors in patients with 1 or more thyroid nodules larger than 5 mm is only 1.6%, and most small thyroid cancers are indolent. Substantial evidence suggests that a reservoir of thyroid cancers does not progress, and workup after detection with imaging leads to epidemiologic overdiagnosis. Finally, a significant proportion of patients with benign nodules have cytologic results that are not definitive and require lobectomy. Evidence-based recommendations for incidental thyroid nodules detected at computed tomography, magnetic resonance imaging, nuclear medicine studies, and extrathyroidal ultrasonography include selection criteria for nodule workup based on suspicious imaging findings, patient age, and nodule size. In the absence of clinical risk factors or suspicious imaging findings, workup with dedicated thyroid ultrasonography is only recommended for nodules at least 1.5 cm in patients 35 years or older and for nodules at least 1.0 cm in patients younger than 35 years. Only a few select incidental thyroid nodules require further evaluation with ultrasonography based on recommendations that aim to diagnose clinically significant thyroid cancers while reducing unnecessary workup and provide guidance for clinical practice.


Multistep ion exchange processes of gradient refractive index rod lens.
A mathematical model for research on the refractive index profile (RIP) of multistep ion exchange processes (IEPs) of gradient refractive index rod lenses (GRINs) is established by the different initial condition and boundary condition, based on the Fickian diffusion equation. GRIN rod lenses have been fabricated using the three-step IEPs. Research results indicate that the experimental deviations of refractive index (DRI) are in good agreement with the theoretical data. The DRI of three-step IEPs is superior to the one- and two-step IEPs and smaller than 10(-5).


Association of Peak Changes in Plasma Cystatin C and Creatinine With Death After Cardiac Operations.
Acute kidney injury is a risk factor for death in cardiac surgical patients. Plasma cystatin C and creatinine have different temporal profiles in the postoperative setting, but the associations of simultaneous changes in both filtration markers compared with change in only one marker with prognosis after hospital discharge are not well described. This is a longitudinal study of 1,199 high-risk adult cardiac surgical patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium who survived hospitalization. We examined in-hospital peak changes of cystatin C and creatinine in the 3 days after cardiac operations. We evaluated associations of these filtration markers with death, adjusting for demographics, operative characteristics, medical comorbidities, preoperative estimated glomerular filtration rate, preoperative urinary albumin-to-creatinine ratio, and site. During the first 3 days of hospitalization, nearly twice as many patients had a 25% or higher rise in creatinine (30%) compared with a 25% or higher peak rise in cystatin C (15%). The risk of death was higher in those with elevations in cystatin C (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.4 to 2.37) or creatinine (adjusted HR, 1.90; 95% CI, 1.32 to 2.72) compared with patients who experienced a postoperative decrease in either filtration marker. Patients who had simultaneous elevations of 25% or higher in cystatin C and creatinine were at similar adjusted risk for 3-year mortality (HR, 1.79; 95% CI, 1.03 to 3.1) as those with a 25% or higher increase in cystatin C alone (HR, 2.2; 95% CI, 1.09 to 4.47). Elevations in creatinine postoperatively are more common than elevations in cystatin C. However, elevations in cystatin C appeared to be associated with a higher risk of death after hospital discharge.


Tumor Heterogeneity in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Gastric Cancer Assessed by CT Texture Analysis: Association with Survival after Trastuzumab Treatment.
Image texture analysis is a noninvasive technique for quantifying intratumoral heterogeneity, with derived texture features reported to be closely related to the treatment outcome of tumors. Gastric cancer is one of the most common tumors and the third leading cause of cancer-related deaths worldwide. Although trastuzumab is associated with a survival gain among patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, optimal patient selection is challenging. The purpose of this study was to determine whether CT texture features of HER2-positive gastric cancer were related to the survival rate after trastuzumab treatment. Patients diagnosed with HER2-positive advanced gastric cancer from February 2007 to August 2014 were retrospectively selected. Using in-house built software, histogram features (kurtosis and skewness) and gray-level co-occurrence matrices (GLCM) features (angular second moment [ASM], contrast, entropy, variance, and correlation) were derived from the CT images of HER2-positive advanced gastric cancer in 26 patients. All the patients were followed up for more than 6 months, with no confirmed deaths. The patients were dichotomized into a good and poor survival group based on cutoff points of overall survival of 12 months. A receiver-operating characteristics (ROC) analysis was performed to test the ability of each texture parameter to identify the good survival group. Kaplan-Meier curves for patients above and below each threshold were constructed. Using a threshold of >265.8480 for contrast, >488.3150 for variance, and ≤0.1319×10-3. for correlation, all of the area under the ROC curves showed fair accuracy (>0.7). Kaplan-Meier analysis showed statistically significant survival difference between two groups according to optimal cutoff values of contrast, variance, correlation and ASM. However, as this study had a small number of patients, a further study with a larger population will be needed to validate the results. Heterogeneous texture features on CT images were associated with better survival in patients with HER2-positive advanced gastric cancer who received trastuzumab-based treatment. Therefore, texture analysis shows potential to be a clinically useful imaging biomarker providing additional prognostic information for patient selection.


George Price's contributions to evolutionary genetics.
George Price studied evolutionary genetics for approximately seven years between 1967 and 1974. During that brief period Price made three lasting contributions to evolutionary theory; these were: (i) the Price Equation, a profound insight into the nature of selection and the basis for the modern theories of kin and group selection; (ii) the theory of games and animal behavior, based on the concept of the evolutionarily stable strategy; and (iii) the modern interpretation of Fisher's fundamental theorem of natural selection, Fisher's theorem being perhaps the most cited and least understood idea in the history of evolutionary genetics. This paper summarizes Price's contributions and briefly outlines why, toward the end of his painful intellectual journey, he chose to focus his deep humanistic feelings and sharp, analytical mind on abstract problems in evolutionary theory.


Comparative Accuracy of the InBios Scrub Typhus Detect IgM Rapid Test for the Detection of IgM Antibodies by Using Conventional Serology.
This study investigated the comparative accuracy of a recombinant 56-kDa type-specific antigen-based rapid diagnostic test (RDT) for scrub typhus for the detection of IgM antibodies by using conventional serology in well-characterized serum samples from undifferentiated febrile illness patients. The RDT showed high specificity and promising comparative accuracy, with 82% sensitivity and 98% specificity for samples defined positive at an IgM indirect immunofluorescence assay positivity cutoff titer of ≥1:1,600 versus 92% and 95% at ≥1:6,400, respectively.


Secretion of novel SEL1L endogenous variants is promoted by ER stress/UPR via endosomes and shed vesicles in human cancer cells.
We describe here two novel endogenous variants of the human endoplasmic reticulum (ER) cargo receptor SEL1LA, designated p38 and p28. Biochemical and RNA interference studies in tumorigenic and non-tumorigenic cells indicate that p38 and p28 are N-terminal, ER-anchorless and more stable relative to the canonical transmembrane SEL1LA. P38 is expressed and constitutively secreted, with increase after ER stress, in the KMS11 myeloma line and in the breast cancer lines MCF7 and SKBr3, but not in the non-tumorigenic breast epithelial MCF10A line. P28 is detected only in the poorly differentiated SKBr3 cell line, where it is secreted after ER stress. Consistently with the presence of p38 and p28 in culture media, morphological studies of SKBr3 and KMS11 cells detect N-terminal SEL1L immunolabeling in secretory/degradative compartments and extracellularly-released membrane vesicles. Our findings suggest that the two new SEL1L variants are engaged in endosomal trafficking and secretion via vesicles, which could contribute to relieve ER stress in tumorigenic cells. P38 and p28 could therefore be relevant as diagnostic markers and/or therapeutic targets in cancer.


Studies of endotoxin-induced decrease in lipoprotein lipase activity.
A variety of invasive stimuli have been shown to induce hyperlipidemia due to impaired removal of triglyceride from the circulation. The mechanism by which endotoxin induces a deficiency in the activity of the key enzyme of triglyceride metabolism, lipoprotein lipase (LPL), has been studied. In C3H/HeN (endotoxin-sensitive) mice, LPL activity in adipose tissue was markedly suppressed 16 h after endotoxin administration. In contrast, the endotoxin-resistant C3H/HeJ mice were less sensitive to the suppressive effect of endotoxin on LPL activity. After endotoxin administration, a transferable factor had been detected in the blood of C3H/HeN mice 2 h after the injection of endotoxin that causes a suppression of adipose tissue LPL activity in C3H/HeJ mice as well as in C3H/HeN mice. Conditioned medium from the cultures of peritoneal exudate cells of C3H/HeN mice incubated in endotoxin also suppresses adipose tissue LPL in C3H/HeJ mice. These studies demonstrate that exudate cells produce a humoral factor in response to endotoxin, which suppresses adipose tissue LPL.


A role for pericytes as microenvironmental regulators of human skin tissue regeneration.
The cellular and molecular microenvironment of epithelial stem and progenitor cells is poorly characterized despite well-documented roles in homeostatic tissue renewal, wound healing, and cancer progression. Here, we demonstrate that, in organotypic cocultures, dermal pericytes substantially enhanced the intrinsically low tissue-regenerative capacity of human epidermal cells that have committed to differentiate and that this enhancement was independent of angiogenesis. We used microarray analysis to identify genes expressed by human dermal pericytes that could potentially promote epidermal regeneration. Using this approach, we identified as a candidate the gene LAMA5, which encodes laminin alpha5, a subunit of the ECM component laminin-511/521 (LM-511/521). LAMA5 was of particular interest as we had previously shown that it promotes skin regeneration both in vitro and in vivo. Analysis using immunogold localization revealed that pericytes synthesized and secreted LAMA5 in human skin. Consistent with this observation, coculture with pericytes enhanced LM-511/521 deposition in the dermal-epidermal junction of organotypic cultures. We further showed that skin pericytes could also act as mesenchymal stem cells, exhibiting the capacity to differentiate into bone, fat, and cartilage lineages in vitro. This study suggests that pericytes represent a potent stem cell population in the skin that is capable of modifying the ECM microenvironment and promoting epidermal tissue renewal from non-stem cells, a previously unsuspected role for pericytes.


Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis.
To test the hypothesis that deimination of viral sequences containing Arg-Gly repeats could generate epitopes recognized by anti-citrullinated protein antibodies (ACPAs) that are present in rheumatoid arthritis (RA) sera. Multiple antigen peptides derived from Epstein-Barr virus (EBV)-encoded Epstein-Barr nuclear antigen 1 (EBNA-1) were synthesized, substituting the arginines with citrulline, and were used to screen RA sera. Anti-cyclic citrullinated peptide antibodies were purified by affinity chromatography and tested on a panel of in vitro deiminated proteins. Their ability to bind in vivo deiminated proteins was evaluated by immunoprecipitation, using EBV-infected cell lines. Antibodies specific for a peptide corresponding to the EBNA-1(35-58) sequence containing citrulline in place of arginine (viral citrullinated peptide [VCP]) were detected in 50% of RA sera and in <5% of normal and disease control sera. In addition, affinity-purified anti-VCP antibodies from RA sera reacted with filaggrin-derived citrullinated peptides, with deiminated fibrinogen, and with deiminated recombinant EBNA-1. Moreover, anti-VCP antibodies immunoprecipitated, from the lysate of calcium ionophore-stimulated lymphoblastoid cell lines, an 80-kd band that was reactive with a monoclonal anti-EBNA-1 antibody and with anti-modified citrulline antibodies. These data indicate that ACPAs react with a viral deiminated protein and suggest that EBV infection may play a role in the induction of these RA-specific antibodies.


A clinically relevant rodent model of the HIV antiretroviral drug stavudine induced painful peripheral neuropathy.
HIV-associated sensory neuropathy is the most frequent manifestation of HIV disease, afflicting 40-50% of patients whose HIV disease is otherwise controlled by antiretroviral therapy. It often presents with significant neuropathic pain and is consistently associated with previous exposure to nucleoside reverse transcriptase inhibitors including stavudine (d4T), which is widely used in resource-limited settings. Here we investigated complex pain-related behaviours associated with d4T treatment using ethologically relevant thigmotaxis and burrowing behaviours in adult rats. Detailed neuropathological response was also examined using neurochemistry, electron microscopy, and proteomics. After 2 intravenous injections of d4T (50 mg/kg, 4 days apart), rats developed hind paw mechanical hypersensitivity, which plateaued at 21 days after initial d4T injection, a time that these animals also had significant changes in thigmotaxis and burrowing behaviours when compared to the controls; reductions in hind paw intraepidermal nerve fibre density and CGRP/IB4 immunoreactivity in L5 spinal dorsal horn, suggesting injury to both the peripheral and central terminals of L5 dorsal root ganglion neurons; and increases in myelinated and unmyelinated axon diameters in the sural nerve, suggesting axonal swelling. However, no significant glial and inflammatory cell response to d4T treatment was observed. Sural nerve proteomics at 7 days after initial d4T injection revealed down-regulated proteins associated with mitochondrial function, highlighting distal axons vulnerability to d4T neurotoxicity. In summary, we have reported complex behavioural changes and a distinctive neuropathology in a clinically relevant rat model of d4T-induced sensory neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.


Identification, molecular characterization, and tissue expression of OVCOV1.
Key to the maternal-embryonic dialogue during early implantation are the extra embryonic trophoblast cells that play several critical roles including invasion of the maternal decidua. Cytotrophoblast proliferation and differentiation along an invasive pathway is regulated by a positive gradient of oxygen tension. We have employed transcript profiling to characterize the extra-embryonic tissues during early human implantation. We probed a cDNA library isolated from the ectoplacental cone region of stage 7.5 days post coitus mouse embryos with cDNA from hypoxic cultured human trophoblast cells. This identified the pattern of expression of a series of previously unknown genes that correlate to day 20 of human embryonic development. One EST was selected for further analysis since it is identical to the 1588-bp CGI-15 sequence assembled in silico. The human gene is organized into 10 exons 2063 bp in length. The open reading frame contains 1272 bp predicting protein composed of 365 amino acids. This gene is expressed in many tissues including those found in the reproductive tract. Its expression is regulated by oxygen tension and is unaffected by estradiol or progesterone treatment.


Characterisation of brain disorders and evaluation of therapy by functional and molecular magnetic resonance techniques.
To review advanced functional and molecular magnetic resonance techniques that are currently clinically useful or with potential clinical use in the near future. Literature search of Medline to December 2007 was conducted. Key words search terms were: 'magnetic resonance imaging', 'magnetic resonance spectroscopy', 'brain', 'functional', 'perfusion', 'diffusion', 'diffusion tensor', 'magnetic transfer', 'molecular imaging', 'superparamagnetic iron oxide'. Relevant original papers and review articles were retrieved. A total of 83 original papers and review articles were systematically analysed. The introduction of modern neuroimaging modalities in recent years has revolutionised investigation of the normal and diseased brain. Among others, magnetic resonance has emerged as the pre-eminent imaging modality, which can produce both high-resolution anatomical images and maps that reflect a variety of physiological parameters relevant to functional assessment and tissue characterisation. Magnetic resonance imaging techniques are now capable of visualising physiological and diseased processes at cellular and molecular levels, including cerebral blood flow, capillary perfusion and permeability, blood oxygenation level-dependent neuronal activation, microscopical motion of water (water diffusion), integrity of axonal fibres, and the molecular transfer of magnetisation within tissues. Magnetic resonance cell trafficking can evaluate the macrophage activity in areas of brain inflammation. Magnetic resonance cell-labelling strategies can be used to monitor the seeding and migration of embryonic stem cells. Magnetic resonance spectroscopy allows the detection of various metabolites that pertain to different biochemical processes in brain tissues. Such metabolites/spectra include: N-acetyl aspartate used as a neuronal marker, choline as a cell membrane metabolism marker, myo-inositol as a glial marker in proton spectrum, and phosphorous whose spectrum provides an in-vivo assessment of the bio-energetic status of tissues. Besides characterisation of brain disorders, magnetic resonance imaging and spectroscopy can improve the planning and monitoring of therapy and contribute to the development of new therapies. Advances in neuroimaging have made a great leap in the morphological, metabolic, and functional assessment of the neurological diseases, enabling better diagnosis and management of patients.


Symptoms, subtype, and suicidality in patients with schizophrenia spectrum disorders.
Suicide is the single largest cause of premature death among individuals with schizophrenia. This report examines the relationship between positive or negative symptoms, illness subtype, and suicidal behavior among patients with schizophrenia and schizophrenia spectrum disorders in a long-term follow-up cohort. Based on index admission records, patients from the Chestnut Lodge Follow-Up Study with schizophrenia (N = 187), schizoaffective disorder (N = 87), schizophreniform disorder (N = 15), and schizotypal personality disorder (N = 33) were retrospectively assessed with the Positive and Negative Syndrome Scale, classical subtype criteria, and criteria for the deficit syndrome. Completed suicide, suicide attempts, and suicidal ideation during the follow-up period (average = 19 years) were ascertained by means of interviews with patients and/or surviving relatives. Over the follow-up period, 40% of the patients reported suicidal ideation, 23% reported suicide attempts, and 6.4% died from suicide. Patients dead from suicide had significantly lower negative symptom severity at index admission than patients without suicidal behaviors. Two positive symptoms (suspiciousness and delusions), however, were more severe among successful suicides. The paranoid schizophrenia subtype was associated with an elevated risk (12%) and the deficit subtype was associated with a reduced risk (1.5%) of suicide. The impact of positive and negative symptoms on suicide risk has not been reported. These findings suggest that prominent negative symptoms, such as diminished drive, blunted affect, and social and emotional withdrawal, counter the emergence of suicidality in patients with schizophrenia spectrum disorders and that the deficit syndrome defines a group at relatively low risk for suicide. Prominent suspiciousness in the absence of negative symptoms defines a relatively high-risk group.


ACOG Committee Opinion Number 542: Access to emergency contraception.
Emergency contraception includes contraceptive methods used to prevent pregnancy in the first few days after unprotected intercourse, sexual assault, or contraceptive failure. Although the U.S. Food and Drug Administration approved the first dedicated product for emergency contraception in 1998, numerous barriers to access to emergency contraception remain. The purpose of this Committee Opinion is to examine the barriers to the use of oral emergency contraception methods and to highlight the importance of increasing access.


Tumorigenic and metastatic activity of human thyroid cancer stem cells.
Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. We show that the tumorigenic capacity in thyroid cancer is confined in a small subpopulation of stem-like cells with high aldehyde dehydrogenase (ALDH(high)) activity and unlimited replication potential. ALDH(high) cells can be expanded indefinitely in vitro as tumor spheres, which retain the tumorigenic potential upon delivery in immunocompromised mice. Orthotopic injection of minute numbers of thyroid cancer stem cells recapitulates the behavior of the parental tumor, including the aggressive metastatic features of undifferentiated thyroid carcinomas, which are sustained by constitutive activation of cMet and Akt in thyroid cancer stem cells. The identification of tumorigenic and metastagenic thyroid cancer cells may provide unprecedented preclinical tools for development and preclinical validation of novel targeted therapies.


Stroke incidence rates were unchanged, while fatality rates declined, during 1971-1987 in Göteborg, Sweden.
Stroke risk factors have been shown to change with time in several places; simultaneously, stroke incidence rates have increased in some and decreased in other places. In Göteborg, Sweden, cardiovascular epidemiological research has included stroke registration since 1971. From these data on stroke, incidence and fatality rates from a 17-year period are given. During the period 1971-1987 all cases of stroke occurring in people aged 15-65 years in the city of Göteborg were uniformly recorded, with an estimated case detection rate of 90% or more. Age-adjusted incidence rates of first-ever stroke by sex did not change during the period. Age-specific rates and rates for individual types of stroke (subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarction-unspecified stroke combined) were also largely unchanged. A slight increase in the incidence rate of intracerebral hemorrhage may be due to better detection after computed tomography came into use in 1976. Stroke fatality rates declined through the whole period in both sexes and all age groups, markedly so for intracerebral hemorrhage and subarachnoid hemorrhage. This conforms with vital statistics for Göteborg and for Sweden of declining stroke mortality during the period. The decline in stroke fatality rates may be related to decreases in smoking habits and blood pressure together with an increase in the percentage of people on antihypertensive treatment among middle-aged men, and to some extent even middle-aged women, reported from the same population. Why stroke incidence rates did not decline concomitantly is unexplained.


Evidence for CD8-independent T cell maturation in transgenic mice.
Double-negative (CD4-/CD8-) T cells expressing the alpha/beta transgenic TCR from the 2C cell line (anti-H-2Ld) were examined in the periphery of animals whose MHC type produces positive, negative, or no selection for differentiation of the TCR on single positive (CD8+) cells. Regardless of the selection haplotype the CD4-/CD8- cells are capable of activation by anticlonotypic mAb indicating that negative selection does not inactivate the "forbidden" TCR. Rather, the lack of response to H-2Ld in the negative haplotype is likely to absence of CD8 required to produce a functional response to H-2Ld. The similarity of surface phenotype and functional activity of these CD4-/CD8- cells maturing in different haplotypes suggests they may arise by an alternative lineage which, unlike the dominant TCR alpha/beta pathway, does not require coexpression of CD4/CD8.


Efficient solid-phase-based total synthesis of the bisintercalator TANDEM.
[reaction: see text] In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue of triostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation, introduction of chromophores, and disulfide bond formation on the solid phase, prior to a final solution-phase macrolactamization, to give the target molecule. Although pure TANDEM was obtained in an overall yield comparable to those for all syntheses to date, the yield of the final cyclization was low (11%). A more efficient approach involved removal from the solid phase prior to disulfide bond formation. The resulting linear peptide underwent macrolactamization under mild conditions and high dilution. Final disulfide bond formation was essentially quantitative and gave the target molecule, TANDEM, in an overall yield of 18%. The final compound was assessed for its ability to bind to 5'-TpA sequences on DNA by DNase I footprinting. This efficient synthesis sets the stage for a study of the structure-activity relationship of TANDEM and the natural product triostin A, with analogues containing "point mutations" at every site within the cyclic compounds.


Human immunity to the meningococcus. I. The role of humoral antibodies.
Susceptibility to systemic meningococcal disease is related to a selective deficiency of humoral antibodies to pathogenic strains of meningococci. In a study of the age-specific incidence of meningococcal meningitis in the United States, it was found that the proportion of individuals with serum bactericidal activity to meningococci of serogroups A, B, and C was reciprocally related to the incidence of disease. The prevalence of bactericidal activity was highest at birth and among adults, and lowest in infants between 6 and 24 months of age. Sera from 51 of 54 prospective cases of meningococcal disease among military recruits were deficient in antibodies to homologous and heterologous strains of pathogenic meningococci as determined by serum bactericidal activity and indirect immunofluorescence. Such sera, however, could support the bactericidal activity of purified human gamma globulin (Cohn fraction II), and such individuals could respond immunologically to infection with meningococci. The implication is that susceptible persons are deficient in antimeningococcal antibodies because they have not received significant exposure to meningococcal antigens in the past. The fate of individuals who lack bactericidal antibodies to pathogenic meningococci was determined during an outbreak of group C meningitis among military recruits. The incidence of disease was found to be primarily associated with the incidence of exposure of susceptibles to the pathogenic strains. Whereas 81.5% of the presumed susceptibles acquired a meningococcal strain, only 24.1% acquired an organism similar to the prevalent disease-producing strains. Of the exposed susceptibles, 38.5% developed systemic meningococcal disease.


The role of surgical expertise with regard to chronic postoperative inguinal pain (CPIP) after Lichtenstein correction of inguinal hernia: a systematic review.
The aim of this study was to evaluate whether a relation exists between surgical expertise and incidence of chronic postoperative inguinal pain (CPIP) after inguinal hernia repair using the Lichtenstein procedure . CPIP after inguinal hernia repair remains a major clinical problem despite many efforts to address this problem. Recently, case volume and specialisation have been found correlated to significant improvement of outcomes in other fields of surgery; to date these important factors have not been reviewed extensively enough in the context of inguinal hernia surgery. A systematic literature review was performed to identify randomised controlled trials reporting on the incidence of CPIP after the Lichtenstein procedure and including the expertise of the surgeon. Surgical expertise was subdivided into expert and non-expert. In a total of 16 studies 3086 Lichtenstein procedures were included. In the expert group the incidence of CPIP varied between 6.9 and 11.7 % versus an incidence of 18.1 and 39.4 % in the non-expert group. Due to the heterogeneity between groups no statistical significance could be demonstrated. The results of this evaluation suggest that an association between surgical expertise and CPIP is highly likely warranting further analysis in a prospectively designed study.


Dry needling for the treatment of poststroke muscle spasticity: a prospective case report.
Spasticity is a common symptom that can be detrimental to the quality of life and daily function of patients with stroke. To introduce the use of dry needling (DN) as a novel method for the treatment of affected upper limb spasticity in a patient with chronic ischemic stroke who was admitted at the Stroke Physiotherapy Clinic. The pronator teres (PT), flexor carpi radialis (FCR), and flexor carpi ulnaris (FCU) on the affected side were needled. The patient received deep DN for 1 session, and the duration of needling for each muscle was 1 minute. The main outcomes were the Modified Modified Ashworth Scale (MMAS) muscle spasticity score, and the Hmax/Mmax ratio which were measured before (T0), immediately after (T1), and 15 minutes after the end of needling (T2). The case was a 53-year-old man with a 13-year history of right hemiparesis poststroke. After DN, the spasticity scores improved and maintained as indicated in the MMAS grades (PT 3 to 2, finger flexors 1 to 0) and the Hmax/Mmax ratio (0.39, 0. 29, and 0.32 at T0, T1, and T2, respectively). The patient was able to voluntarily extend the wrist and fingers slightly after DN. The upper limb Brunnstrom recovery stage (3 to 4) and hand function (2 to 3) improved and maintained. The passive supination increased at T1 (75°) and T2 (50°) compared to T0 (38°). This prospective case report presents dry needling as a novel method in neurorehabilitation for the treatment of poststroke spasticity. Further research is recommended.


Commercial importation of prescription drugs in the United States: short-run implications.
The option of legalizing the commercial importation of prescription drugs is of continued policy interest as a way to reduce U.S. drug spending. Using IMS data, we estimate potential savings from commercial drug importation under assumptions about percentage of drugs likely to attract imports; potential supply from foreign countries; and share of savings passed on to payers. Our base case estimate is that $1.7 billion per year, or 0.6 percent of total drug spending, would be saved by payers; sensitivity analyses range from 0.2 to 2.5 percent under plausible assumptions and up to 17.4 percent under unrealistic assumptions about unlimited foreign supply, costless trade, and zero profits for intermediaries. Estimated savings to payers are less than the average price differentials between the United States and foreign countries because proposed legislation exempts certain drugs from importation; foreign markets are small relative to the United States; regulatory and other constraints may limit the volume of exports; trade is costly; and intermediaries will retain some savings. Although savings to U.S. payers/consumers would likely be small and have minimal impact on total U.S. health care spending, costs to other countries could be significant, due to reduced access and possibly higher prices. In the long run, reduced investment in R&D could adversely affect consumers globally.


Direct detection of polar structure formation in helium nanodroplets by beam deflection measurements.
Long-range intermolecular forces are able to steer polar molecules submerged in superfluid helium nanodroplets into highly polar metastable configurations. We demonstrate that the presence of such special structures can be identified, in a direct and determinative way, by electrostatic deflection of the doped nanodroplet beam. The measurement also establishes the structures' electric dipole moments. In consequence, the introduced approach is complementary to spectroscopic studies of low-temperature molecular assembly reactions. It is enabled by the fact that within the cold superfluid matrix the molecular dipoles become nearly completely oriented by the applied electric field. As a result, the massive (tens of thousands of helium atoms) nanodroplets undergo significant deflections. The method is illustrated here by an application to dimers and trimers of dimethyl sulfoxide (DMSO) molecules. We interpret the experimental results with ab initio theory, mapping the potential energy surface of DMSO complexes and simulating their low temperature aggregation dynamics.


Reactive oxygen species: impact on skeletal muscle.
It is well established that contracting muscles produce both reactive oxygen and nitrogen species. Although the sources of oxidant production during exercise continue to be debated, growing evidence suggests that mitochondria are not the dominant source. Regardless of the sources of oxidants in contracting muscles, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Further, oxidants regulate numerous cell signaling pathways and modulate the expression of many genes. This oxidant-mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species result in contractile dysfunction and fatigue. Ongoing research continues to explore the redox-sensitive targets in muscle that are responsible for both redox regulation of muscle adaptation and oxidant-mediated muscle fatigue.


Elder Abuse and Neglect in China: Prevalence, Co-occurrence, and Intergenerational Risk Factors.
The prevalence and patterns of elder abuse and neglect in China have been understudied. The objectives of this study were to examine the chronicity and prevalence of different patterns of elder abuse, and the influence of individual and contextual risk factors. We used data from a sample of 7,466 adults randomly recruited from six regions in China. The participants responded to a questionnaire about their demographic characteristics, childhood abuse experiences, and instances of abuse and neglect against their elderly parents. Logistic regression analysis was performed to examine the association of elder abuse and neglect with individual and contextual factors. The results showed that one in 10 participants reported that their elderly parents had experienced abuse or neglect in the past year. The elder victims were reported to have suffered different types of abuse and neglect on multiple occasions, ranging from 3.6 to 11.82 times on average. More than 5% of participants reported that their elderly parents had suffered two or more types of abuse and neglect in the past year, accounting for 40% of the elderly victims. The co-occurrence of elder abuse within elderly couples was also high. Reports of abuse and neglect of elderly parents were related to low socioeconomic status, living in rural areas, and the experience of childhood abuse of the participants. This study supports the model of intergenerational transmission of violence in the Chinese population. The high prevalence, chronicity, and co-occurrence of elder abuse and neglect underline the importance of screening for risk factors, and have implications for preventive practice and policy.


A randomized clinical trial to evaluate the preventive effect of cranberry juice (UR65) for patients with recurrent urinary tract infection.
We examined the rate of relapse, as a variable index, in patients with urinary tract infection (UTI) who suffered from multiple relapses when using cranberry juice (UR65). A randomized, placebo-controlled, double-blind study was conducted from October 2007 to September 2009 in Japan. The subjects were outpatients aged 20 to 79 years who were randomly divided into two groups. One group received cranberry juice (group A) and the other a placebo beverage (group P). To keep the conditions blind, the color and taste of the beverages were adjusted. The subjects drank 1 bottle (125 mL) of cranberry juice or the placebo beverage once daily, before going to sleep, for 24 weeks. The primary endpoint was relapse of UTI. In the group of females aged 50 years or more, there was a significant difference in the rate of relapse of UTI between groups A and P (log-rank test; p = 0.0425). In this subgroup analysis, relapse of UTI was observed in 16 of 55 (29.1 %) patients in group A and 31 of 63 (49.2 %) in group P. In this study, cranberry juice prevented the recurrence of UTI in a limited female population with 24-week intake of the beverage.


Efficient and robust RNA-seq process for cultured bacteria and complex community transcriptomes.
We have developed a process for transcriptome analysis of bacterial communities that accommodates both intact and fragmented starting RNA and combines efficient rRNA removal with strand-specific RNA-seq. We applied this approach to an RNA mixture derived from three diverse cultured bacterial species and to RNA isolated from clinical stool samples. The resulting expression profiles were highly reproducible, enriched up to 40-fold for non-rRNA transcripts, and correlated well with profiles representing undepleted total RNA.