How do hospitals cope with sustained slow growth in Medicare prices?
To estimate the effects of changes in Medicare inpatient hospital prices on hospitals' overall revenues, operating expenses, profits, assets, and staffing. Medicare hospital cost reports (1996-2009). For each hospital, we quantify the year-to-year price impacts from changes in the Medicare payment formula. We use cumulative simulated price impacts as instruments for Medicare inpatient revenues. We use a series of two-stage least squares panel data regressions to estimate the effects of changes in Medicare revenues among all hospitals, and separately among not-for-profit versus for-profit hospitals, and among hospitals experiencing real price increases ("gainers") versus decreases ("losers"). Medicare price cuts are associated with reductions in overall revenues even larger than the direct Medicare price effect, consistent with price spillovers. Among not-for-profit hospitals, revenue reductions are fully offset by reductions in operating expenses, and profits are unchanged. Among for-profit hospitals, revenue reductions decrease profits one-for-one. Responses of gainers and losers are roughly symmetrical. On average, hospitals do not appear to make up for Medicare cuts by "cost shifting," but by adjusting their operating expenses over the long run. The Medicare price cuts in the Affordable Care Act will "bend the curve," that is, significantly slow the growth in hospitals' total revenues and operating expenses.


The simcyp population based simulator: architecture, implementation, and quality assurance.
Developing a user-friendly platform that can handle a vast number of complex physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models both for conventional small molecules and larger biologic drugs is a substantial challenge. Over the last decade the Simcyp Population Based Simulator has gained popularity in major pharmaceutical companies (70% of top 40 - in term of R&D spending). Under the Simcyp Consortium guidance, it has evolved from a simple drug-drug interaction tool to a sophisticated and comprehensive Model Based Drug Development (MBDD) platform that covers a broad range of applications spanning from early drug discovery to late drug development. This article provides an update on the latest architectural and implementation developments within the Simulator. Interconnection between peripheral modules, the dynamic model building process and compound and population data handling are all described. The Simcyp Data Management (SDM) system, which contains the system and drug databases, can help with implementing quality standards by seamless integration and tracking of any changes. This also helps with internal approval procedures, validation and auto-testing of the new implemented models and algorithms, an area of high interest to regulatory bodies.


Change in prescription pattern as a potential marker for adverse drug reactions of angiotensin converting enzyme inhibitors.
Angiotensin converting enzyme inhibitors (ACEIs) are among the most frequently prescribed groups of medications. ACEI-induced adverse drug reactions (ADRs) are the main reason to discontinue or switch ACEI treatment. ADRs information is not available in prescription databases. OBJECTIVE :To identify a proxy for ACEI-induced ADRs in prescription databases. The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the Netherlands and has included 14,926 subjects aged 45 years or older. All ACEI starters from 2000 to 2011 were identified using prescription data within the Rotterdam Study. Participants were classified into 4 mutually exclusive groups: continuing, discontinuing, switching to angiotensin receptor blockers (ARBs), and switching to other antihypertensives. For categorization, the maximum time-interval between two prescription periods was set at 3 and 6 months. Subsequently, primary care physician files were searched and clinical events were classified as definite ADRs, probable ADRs, possible ADRs and definite non-ADRs. Finally the accuracy of different prescription patterns as indicators of ADRs was evaluated. Main outcome measure Positive predictive values (PPVs), negative predictive values (NPVs), sensitivity and specificity of the prescription patterns of the 4 groups were calculated. Totally, 1132 ACEI starters were included. The PPV for a definite ADR was 56.1 % for switchers to ARB, while the PPVs for switchers to other antihypertensives, and discontinuation were 39.5 and 19.5 %, respectively. After including probable ADRs and possible ADRs, PPVs for switchers to ARB increased to 68.3 and 90.5 %. A 6-month interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1 % higher). The differences in NPVs between 3 and 6-months interval groups were approximately 1.0 %. Switching ACEIs to ARBs is the best marker for ACEI-induced ADRs in prescription databases.


Complexity of terminal airspace geometry assessed by computed tomography in asthma.
Low attenuation areas in computed tomography images from patients with chronic obstructive pulmonary disease have been reported to represent macroscopic and/or microscopic emphysema. The cumulative size distribution of the clusters has been shown to follow a power law characterized by the exponent D, a measure of the complexity of the terminal airspace geometry. We have previously found increased low attenuation areas in nonsmoking subjects with asthma. We examined the size distribution of the clusters in nonsmoking subjects with asthma compared with both nonsmoking control subjects and subjects with asthma with a smoking history. The percentage of lung field occupied by low attenuation areas (LAA%) and D in subjects with asthma with a smoking history differed significantly from nonsmoking subjects with asthma and control subjects. In nonsmoking subjects with asthma, both parameters differed significantly between severe asthma and mild or moderate asthma. The LAA% differed significantly between moderate and mild asthma, but D did not. In mild and moderate asthma, a highly significant correlation between LAA% and D was observed in patients with a smoking history, but not in nonsmoking subjects with asthma. Our results suggest that decreased D is mostly related to emphysematous change, and both measurements of LAA% and D may provide useful information to characterize low attenuation areas in subjects with asthma.


Surface-plasmon-coupled emission of quantum dots.
We studied surface plasmon-coupled emission (SPCE) of semiconductor quantum dots (QDs). These QDs are water-soluble ZnS-capped CdSe nanoparticles stabilized using lysine cross-linked mercaptoundecanoic acid. The QDs were spin-coated from 0.75% PVA solution on a glass slide covered with 50 nm of silver and a 5-nm protective SiO(2) layer. Excited QDs induced surface plasmons in a thin silver layer. Surface plasmons emitted a hollow cone of radiation into an attached hemispherical glass prism at a narrow angle of 48.5 degrees. This directional radiation (SPCE) preserves the spectral properties of QD emission and is highly p-polarized irrespective of the excitation polarization. The SPCE spectrum depends on the observation angle because of the intrinsic dispersive properties of SPCE phenomenon. The remarkable photostability can make QDs superior to organic fluorophores when long exposure to the intense excitation is needed. The nanosize QDs also introduce a roughness near the metal layer, which results in a many-fold increase of the coupling of the incident light to the surface plasmons. This scattered incident illumination transformed into directional, polarized radiation can be used simultaneously with SPCE to develop devices based on both quantum dot emission and light scattered from surface plasmons on a rough surface.


The Effect of a Whey Protein Supplement on Bone Mass in Older Caucasian Adults.
It has been assumed that the increase in urine calcium (Ca) that accompanies an increase in dietary protein was due to increased bone resorption. However, studies using stable Ca isotopes have found that dietary protein increases Ca absorption without increasing bone resorption. The objective of the study was to investigate the impact of a moderately high protein diet on bone mineral density (BMD). This was a randomized, double-blind, placebo-controlled trial of protein supplementation daily for 18 months. The study was conducted at two institutional research centers. Two hundred eight older women and men with a body mass index between 19 and 32 kg/m(2) and a self-reported protein intake between 0.6 and 1.0 g/kg participated in the study. Subjects were asked to incorporate either a 45-g whey protein or isocaloric maltodextrin supplement into their usual diet for 18 months. BMD by dual-energy x-ray absorptiometry, body composition, and markers of skeletal and mineral metabolism were measured at baseline and at 9 and 18 months. There were no significant differences between groups for changes in L-spine BMD (primary outcome) or the other skeletal sites of interest. Truncal lean mass was significantly higher in the protein group at 18 months (P = .048). C-terminal telopeptide (P = .0414), IGF-1 (P = .0054), and urinary urea (P < .001) were also higher in the protein group at the end of the study period. There was no difference in estimated glomerular filtration rate at 18 months. Our data suggest that protein supplementation above the recommended dietary allowance (0.8 g/kg) may preserve fat-free mass without adversely affecting skeletal health or renal function in healthy older adults.


Segmentation of nodules on chest computed tomography for growth assessment.
Several segmentation methods to evaluate growth of small isolated pulmonary nodules on chest computed tomography (CT) are presented. The segmentation methods are based on adaptively thresholding attenuation levels and use measures of nodule shape. The segmentation methods were first tested on a realistic chest phantom to evaluate their performance with respect to specific nodule characteristics. The segmentation methods were also tested on sequential CT scans of patients. The methods' estimation of nodule growth were compared to the volume change calculated by a chest radiologist. The best method segmented nodules on average 43% smaller or larger than the actual nodule when errors were computed across all nodule variations on the phantom. Some methods achieved smaller errors when examined with respect to certain nodule properties. In particular, on the phantom individual methods segmented solid nodules to within 23% of their actual size and nodules with 60.7 mm3 volumes to within 14%. On the clinical data, none of the methods examined showed a statistically significant difference in growth estimation from the radiologist.


Hepatic organic anion uptake in the rat.
The hepatic uptake of bilirubin (BR), indocyanine green (ICG), and sulfobromophthalein (BSP) was studied in 350 anesthetized Sprague-Dawley rats by determining the initial plasma disappearance rate (V) of various doses of unlabeled ICG, or of tracer quantities of [3H]BR or [35S]BSP injected into the jugular vein simultaneously with varying amounts of unlabeled BR or BSP. Similar studies were also performed involving the simultaneous injection of potential inhibitors of hepatic uptake. The results indicate that: (a) hepatic uptake determined by direct tissue measurement could be accurately estimated from the plasma disappearance data; (b) saturation of hepatic uptake with increasing dose was readily demonstrated for each of these three organic anions, and in each instance a plot of V versus dose took the form of a rectangular hyperbola analyzable in terms of Michaelis-Menten kinetics; (c) for BR, the saturable uptake process showed a Vmax more than 100 times the normal net transfer rate from plasma to bile; (d) hepatic uptake of BR, BSP, and ICG showed relatively selective, mutually competitive inhibition; glycoholic acid did not inhibit hepatic uptake of any of these substances; and (e) "counter-transport" could be demonstrated for each of the three test substances. These data are compatible with the existence of a carrier-mediated transport process for hepatic uptake of each of these three organic anions and clarify the relationship of hepatic BR uptake to its overall transport from plasma to bile.


New strategies for prevention and early diagnosis of iodinated contrast-induced nephropathy: a systematic review
Iodinated contrast-induced nephropathy is one of the most feared complications of percutaneous coronary interventions and is associated with increased cardio-vascular mortality and a faster progression towards end stage renal disease. The effects of the iodinated contrast medium on intra-renal hemodynamics and its direct cytotoxic action on proximal tubular cells contribute synergistically to the pathophysiology of renal damage. Since the therapeutic options are extremely limited, the rapid identification of risk factors and the timely implementation of preventive strategies are mandatory to reduce the incidence of iodinated contrast-induced nephropathy. To date, the criteria for defining and staging contrast medium nephropathy are still based on the increase of serum creatinine and/or contraction of diuresis, which are lacking in specificity and therefore do not allow early diagnosis. The aim of this review is to report the latest evidence on the pathophysiological mechanisms that contribute to renal damage by iodinated contrast medium, on the risk stratification tools and on the new early biomarkers of contrast-induced nephropathy, while also focusing on the most validated prevention strategies.


Self-assembly of magnesium-seamed hexameric pyrogallol[4]arene nanocapsules.
The solvothermal synthesis of a metal-seamed hexameric nanocapsule from pyrogallol[4]arenes and magnesium is reported. The unique non-toxic and biocompatible nature of divalent magnesium cations in addition to the large inherent cavities make these nanocapsules promising for potential application in biomedicine. In addition, we show that these nanocapsules can form cocrystals with pyridine molecules through hydrogen bonding, which sheds light to cocrystallization of supramolecular nanocapsules with small pharmaceutics.


Biology of the rice rat (Oryzomys palustris natator) in a laboratory environment. VII. Pre-weaning growth of the body.
Body growth using weight and length parameters have been examined following the introduction of the rice rat to laboratory conditions and a history of breeding covering some 15 generations. The pattern of growth shows a characteristic enphasic form which appears to be determined by the interplay of the external environment and the genetic endowment. The external environmental factors include the waxing and waning of the lactational performance of the mother and the intake of solid food, resulting in the first phase being mainly controlled by the maternal environment, the second phase being mainly controlled by a lessening maternal environment + external (solid food) environment + some genetics, the third phase being influenced by external environment + genetic endowment.


Helical CT cholangiography with three-dimensional volume rendering using an oral biliary contrast agent: feasibility of a novel technique.
We evaluated the feasibility and image quality of a new noninvasive biliary imaging technique: helical CT cholangiography with three-dimensional volume rendering using an oral biliary contrast agent. Nineteen subjects including five healthy volunteers and 14 patients underwent helical CT cholangiography. Subjects ingested 6.0 g of iopanoic acid 6-10 hr before undergoing imaging. Axial data were used to construct three-dimensional volume-rendered cholangiograms. Two radiologists, an endoscopist, and a laparoscopic surgeon reviewed the images and evaluated overall image quality. In the 14 patients, findings from CT cholangiography were compared with those from ERCP, surgery, and intraoperative cholangiography. All segments of the biliary tree were opacified in all volunteers except one, in whom the intrahepatic ducts were not opacified. Image quality was good to excellent in all volunteers. Anomalous cystic duct insertions were seen in two volunteers. Opacification of the biliary tree was rated as acceptable to excellent in nine patients and suboptimal in five. In five patients with good or excellent opacification, the biliary anatomy correlated with findings on intraoperative cholangiography or ERCP. CT cholangiography revealed additional conditions (gallbladder varices and acute pancreatitis) and variant anatomy in three patients. Results of this pilot project suggest that obtaining CT cholangiograms using an oral biliary contrast agent is a feasible, noninvasive method for revealing biliary anatomy. However, visualization of the biliary tree was suboptimal in 36% of the patients, which represents a limitation of this technique.


BI-BII transitions in B-DNA.
Molecular modelling is used to study the conformational and energetic aspects of BI-BII transitions within the backbone of a B-DNA dodecamer d(CATGACGTCATG) whose fine structure has previously been determined by molecular modelling combined with NMR spectroscopy. It is shown that while the dodecamer under investigation does not contain any BII junctions, the central CpG step can most easily undergo the transition. More generally, it is also found that the base sequence and hence the backbone geometry of a DNA segment, strongly influences both the conformational impact of the transition, the associated energy barrier and the stability of the resulting BII state.


Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.
Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.


Ensuring Patient Safety by using Colored Petri Net Simulation in the Design of Heterogeneous, Multi-Vendor, Integrated, Life-Critical Wireless (802.x) Patient Care Device Networks.
Hospitals and manufacturers are designing and deploying the IEEE 802.x wireless technologies in medical devices to promote patient mobility and flexible facility use. There is little information, however, on the reliability or ultimate safety of connecting multiple wireless life-critical medical devices from multiple vendors using commercial 802.11a, 802.11b, 802.11g or pre-802.11n devices. It is believed that 802.11-type devices can introduce unintended life-threatening risks unless delivery of critical patient alarms to central monitoring systems and/or clinical personnel is assured by proper use of 802.11e Quality of Service (QoS) methods. Petri net tools can be used to simulate all possible states and transitions between devices and/or systems in a wireless device network, and can identify failure modes in advance. Colored Petri Net (CPN) tools are ideal, in fact, as they allow tracking and controlling each message in a network based on pre-selected criteria. This paper describes a research project using CPN to simulate and validate alarm integrity in a small multi-modality wireless patient monitoring system. A 20-monitor wireless patient monitoring network is created in two versions: one with non-prioritized 802.x CSM protocols and the second with simulated Quality of Service (QoS) capabilities similar to 802.11e (i.e., the second network allows message priority management.) In the standard 802.x network, dangerous heart arrhythmia and pulse oximetry alarms could not be reliably and rapidly communicated, but the second network's QoS priority management reduced that risk significantly.


Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters.
Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross-resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp)-mediated drug efflux. To address this problem, new agents have been sought that are less prone to inducing resistance and less likely to serve as substrates for Pgp efflux. An alternative to this approach is to deliver established agents as molecular transporter conjugates into cells through a mechanism that circumvents Pgp-mediated efflux and allows for release of free drug only after cell entry. Here we report that the widely used chemotherapeutic agent Taxol, ineffective against Taxol-resistant human ovarian cancer cell lines, can be incorporated into a releasable octaarginine conjugate that is effective against the same Taxol-resistant cell lines. It is significant that the ability of the Taxol conjugates to overcome Taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with coelenterazine, a Pgp substrate. Although coelenterazine itself does not enter cells because of Pgp efflux, its octaarginine conjugate does so readily. This approach shows generality for overcoming the multidrug resistance elicited by small-molecule cancer chemotherapeutics and could improve the prognosis for many patients with cancer and fundamentally alter search strategies for novel therapeutic agents that are effective against resistant disease.


Screen media usage, sleep time and academic performance in adolescents: clustering a self-organizing maps analysis.
Screen media usage, sleep time and socio-demographic features are related to adolescents' academic performance, but interrelations are little explored. This paper describes these interrelations and behavioral profiles clustered in low and high academic performance. A nationally representative sample of 3,095 Spanish adolescents, aged 12 to 18, was surveyed on 15 variables linked to the purpose of the study. A Self-Organizing Maps analysis established non-linear interrelationships among these variables and identified behavior patterns in subsequent cluster analyses. Topological interrelationships established from the 15 emerging maps indicated that boys used more passive videogames and computers for playing than girls, who tended to use mobile phones to communicate with others. Adolescents with the highest academic performance were the youngest. They slept more and spent less time using sedentary screen media when compared to those with the lowest performance, and they also showed topological relationships with higher socioeconomic status adolescents. Cluster 1 grouped boys who spent more than 5.5 hours daily using sedentary screen media. Their academic performance was low and they slept an average of 8 hours daily. Cluster 2 gathered girls with an excellent academic performance, who slept nearly 9 hours per day, and devoted less time daily to sedentary screen media. Academic performance was directly related to sleep time and socioeconomic status, but inversely related to overall sedentary screen media usage. Profiles from the two clusters were strongly differentiated by gender, age, sedentary screen media usage, sleep time and academic achievement. Girls with the highest academic results had a medium socioeconomic status in Cluster 2. Findings may contribute to establishing recommendations about the timing and duration of screen media usage in adolescents and appropriate sleep time needed to successfully meet the demands of school academics and to improve interventions targeting to affect behavioral change.


Caffeine induced changes in cerebral circulation.
While the caffeine induced cerebral vasoconstriction is well documented, the effects of oral ingestion of the drug in a dose range comparable to the quantities in which it is usually consumed and the intensity and duration of the associated reduction in cerebral circulation are unknown. Cerebral blood flow was measured via the 133Xenon inhalation technique before and thirty and ninety minutes after the oral administration of 250 mg of caffeine or a placebo, under double-blind conditions. Caffeine ingestion was found to be associated with significant reductions in cerebral perfusion thirty and ninety minutes later. The placebo group showed no differences between the three sets of cerebral blood flow values.


Sex reassignment surgery: a study of 141 Dutch transsexuals.
This is an evaluation of the therapeutic effect of sex reassignment surgery on 36 female-to-male transsexuals and 105 male-to-female transsexuals in the Netherlands. Data were collected by means of structured interviews. The evaluation was made on the basis of subjective data only, that is on what the persons themselves reported on their gender identity, gender role, and physical condition. Allowing for the restrictive methodology of the (ex post facto) study, it is concluded that there is no reason to doubt the therapeutic effect of sex reassignment surgery. No specific differences were found between those who were still in medical treatment and those who had completed treatment. The findings obtained in the female-to-male transsexuals compare favorably with those obtained in male-to-female transsexuals. Finally, the conclusion is drawn that more attention ought to be paid to psychosocial guidance in addition to medical guidance.


Toward a Natural Language Interface for EHR Questions.
This paper presents a pilot study on the process of manually annotating natural language EHR questions with a formal meaning representation. This formal representation could then be used as a structured query as part of a natural language interface for electronic health records. This study analyzes the challenges of representing EHR questions as structured queries as well as the feasibility of creating a sufficiently large corpus of manually annotated structured queries for EHR questions. A set of 100 EHR questions, sampled from actual questions asked by ICU physicians[1], is used to perform the analysis. The ultimate goal of this research is to enable automatic methods for understanding EHR questions for use in a natural language EHR interface.


Racial and Ethnic Differences Over Time in Outcomes of Infants Born Less Than 30 Weeks' Gestation.
To examine changes in care practices over time by race and ethnicity and whether the decrease in hospital mortality and severe morbidities has benefited infants of minority over infants of white mothers. Infants 22 to 29 weeks' gestation born between January 2006 and December 2017 at a Vermont Oxford Network center in the United States were studied. We examined mortality and morbidity rate differences and 95% confidence intervals for African American and Hispanic versus white infants by birth year. We tested temporal differences in mortality and morbidity rates between white and African American or Hispanic infants using a likelihood ratio test on nested binomial regression models. Disparities for certain care practices such as antenatal corticosteroids and for some in-hospital outcomes have narrowed over time for minority infants. Compared with white infants, African American infants had a faster decline for mortality, hypothermia, necrotizing enterocolitis, and late-onset sepsis, whereas Hispanic infants had a faster decline for mortality, respiratory distress syndrome, and pneumothorax. Other morbidities showed a constant rate difference between African American and Hispanic versus white infants over time. Despite the improvements, outcomes including hypothermia, mortality, necrotizing enterocolitis, late-onset sepsis, and severe intraventricular hemorrhage remained elevated by the end of the study period, especially among African American infants. Racial and ethnic disparities in vital care practices and certain outcomes have decreased. That the quality deficit among minority infants occurred for several care practice measures and potentially modifiable outcomes suggests a critical role for quality improvement initiatives tailored for minority-serving hospitals.


Dynamic nuclear polarization using frequency modulation at 3.34 T.
During dynamic nuclear polarization (DNP) experiments polarization is transferred from unpaired electrons to their neighboring nuclear spins, resulting in dramatic enhancement of the NMR signals. While in most cases this is achieved by continuous wave (cw) irradiation applied to samples in fixed external magnetic fields, here we show that DNP enhancement of static samples can improve by modulating the microwave (MW) frequency at a constant field of 3.34 T. The efficiency of triangular shaped modulation is explored by monitoring the (1)H signal enhancement in frozen solutions containing different TEMPOL radical concentrations at different temperatures. The optimal modulation parameters are examined experimentally and under the most favorable conditions a threefold enhancement is obtained with respect to constant frequency DNP in samples with low radical concentrations. The results are interpreted using numerical simulations on small spin systems. In particular, it is shown experimentally and explained theoretically that: (i) The optimal modulation frequency is higher than the electron spin-lattice relaxation rate. (ii) The optimal modulation amplitude must be smaller than the nuclear Larmor frequency and the EPR line-width, as expected. (iii) The MW frequencies corresponding to the enhancement maxima and minima are shifted away from one another when using frequency modulation, relative to the constant frequency experiments.


Coexistence and within-host evolution of diversified lineages of hypermutable Pseudomonas aeruginosa in long-term cystic fibrosis infections.
The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic fibrosis (CF) patients have indicated high bacterial population diversity. Such diversity may be driven by hypermutability resulting from DNA mismatch repair system (MRS) deficiency, a common trait evolved by P. aeruginosa strains in CF infections. No studies to date have utilized whole-genome sequencing to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was ∼100 SNPs/year-∼40-fold higher than rates in normo-mutable populations. Comparison of the genomes of 11 isolates from the same sample showed extensive within-patient genomic diversification; the populations were composed of different sub-lineages that had coexisted for many years since the initial colonization of the patient. Analysis of the mutations identified genes that underwent convergent evolution across lineages and sub-lineages, suggesting that the genes were targeted by mutation to optimize pathogenic fitness. Parallel evolution was observed in reduction of overall catabolic capacity of the populations. These findings are useful for understanding the evolution of pathogen populations and identifying new targets for control of chronic infections.


Initiating and imaging the coherent surface dynamics of charge carriers in real space.
The tip of a scanning tunnelling microscope is an atomic-scale source of electrons and holes. As the injected charge spreads out, it can induce adsorbed molecules to react. By comparing large-scale 'before' and 'after' images of an adsorbate covered surface, the spatial extent of the nonlocal manipulation is revealed. Here, we measure the nonlocal manipulation of toluene molecules on the Si(111)-7 × 7 surface at room temperature. Both the range and probability of nonlocal manipulation have a voltage dependence. A region within 5-15 nm of the injection site shows a marked reduction in manipulation. We propose that this region marks the extent of the initial coherent (that is, ballistic) time-dependent evolution of the injected charge carrier. Using scanning tunnelling spectroscopy, we develop a model of this time-dependent expansion of the initially localized hole wavepacket within a particular surface state and deduce a quantum coherence (ballistic) lifetime of ∼10 fs.


Effect of polycations on the function of the isolated perfused rat kidney.
1. In minimal change nephrotic syndrome the occurrence of heavy proteinuria can be explained on the basis of a reduction in charge selectivity of the glomerular filtration barrier, and it has been proposed that this might be caused by the neutralization of anionic groups by a circulating polycationic factor. 2. The effects of two polycations, protamine and poly-L-lysine, on the function of the isolated perfused rat kidney have been examined. 3. Poly-L-lysine polymers of relatively high molecular weight (8800 and 17,800) induced heavy proteinuria, while simultaneously causing a marked increase in renal vascular resistance and a fall in filtration rate. Protamine (approximate molecular weight 7000) at relatively high concentration induced modest proteinuria in the absence of effects on vascular resistance or filtration rate. 4. A poly-L-lysine polymer of lower molecular weight (3800) did not induce proteinuria. Protamine at a concentration of 40 micrograms/ml and below did not affect protein excretion either. Both provoked substantial natriuresis. This appeared to be largely due to an effect on the tubular handling of sodium since the filtration rate remained steady while fractional sodium excretion rose markedly. 5. The natriuretic effect of protamine was blocked by heparin, but not by indomethacin or verapamil, suggesting that the mechanism of natriuresis did not depend upon either prostaglandin production or entry of calcium through verapamil-sensitive channels.


Change of School in Early Adolescence and Adverse Obesity-Related Dietary Behavior: A Longitudinal Cohort Study, Victoria, Australia, 2013-2014.
Environments that facilitate energy-dense, nutrient-poor diets are associated with childhood obesity. We examined the effect of a change of school environment on the prevalence of obesity and related dietary behavior in early adolescence. Fifteen schools in Victoria, Australia, were recruited at random from the bottom 2 strata of a 5-level socioeconomic scale. In 9 schools, students in grade 6 primary school transitioned to different schools for grade 7 secondary school, whereas in 6 schools, students remained in the same school from grade 6 to grade 7. Time 1 measures were collected from students (N = 245) in grade 6 (aged 11-13 y). Time 2 data were collected from 243 (99%) of the original cohort in grade 7. Data collected were dietary recall self-reported by students via questionnaire, measured height and weight of students, and aspects of the school food environment via school staff survey. Comparative and mixed model regression analyses were conducted. Of 243 students, 63% (n = 152) changed schools from time 1 to time 2, with no significant difference in weight status. Students who changed schools reported an increase in purchases of after-school snack food, greater sweetened beverage intake, fewer fruit-and-vegetable classroom breaks, and less encouragement for healthy eating compared with students who remained in the same school. School staff surveys showed that more primary than secondary schools had written healthy canteen policies and fewer days of canteen or food services operation. A change of school environment has negative effects on children's obesity-related dietary behavior. Consistent policy is needed across school types to support healthy eating in school environments.


Transition models to assess risk factors for new and persistent trypanosome infections in cattle-analysis of longitudinal data from the Ghibe Valley, southwest Ethiopia.
The objective of this study was to apply transition models to distinguish between factors associated with both incident and persistent trypanosome infections. Data collected from 1561 cattle were analyzed from a long-term study involving 8 herds in which both trypanosome infections (a total of 56,931 cattle sampling-months) and tsetse (Glossina spp.) challenge were monitored monthly from March 1986 to March 1998. Both pour-on and insecticide-target tsetse control programs and mass treatment with diminazene aceturate before tsetse control were associated with significant decreases in both incidence and persistence of trypanosome infection relative to noncontrol periods, as were seasonal and sex effects. The magnitudes of the effects were, however, often different for new and persistent infections. For persistence of infection, there were 2 trends. In general, the duration of infection increased during the study, despite the regular treatment with diminazene aceturate. The transition model had 2 major benefits. The first was to identify an increasing duration of infections with time, taking into account other factors associated with increasing infection risk. The second was to highlight different patterns in the effects of certain factors on new and persistent trypanosome infections.


Reduction of body weight by dietary garlic is associated with an increase in uncoupling protein mRNA expression and activation of AMP-activated protein kinase in diet-induced obese mice.
This study investigated the antiobesity effect of garlic in diet-induced obese mice. Male C57BL/6J mice were fed a high-fat diet (45% fat) for 8 wk to induce obesity. Subsequently, they were fed a high-fat control diet, high-fat diets supplemented with 2%, or 5% garlic (wt:wt) for another 7 wk. Dietary garlic reduced body weight and the mass of various white adipose tissue deposits and also ameliorated the high-fat diet-induced abnormal plasma and liver lipid profiles. Garlic supplementation significantly decreased the mRNA levels of adipogenic genes in white adipose tissues (WAT). However, consumption of garlic increased the expression of mRNA for uncoupling proteins in brown adipose tissue (BAT), liver, WAT, and skeletal muscle. Mice treated with garlic maintained a significantly higher body temperature than untreated mice during a 6-h, 4°C cold challenge and, notably, AMP-activated protein kinase (AMPK) activity was stimulated in BAT, liver, WAT, and skeletal muscle. These results suggest that the antiobesity effects of garlic were at least partially mediated via activation of AMPK, increased thermogenesis, and decreased expression of multiple genes involved in adipogenesis.


Restructuring of poly(2-ethyl-2-oxazoline)/tannic acid multilayers into fibers.
H-Bonded, pH-responsive poly(2-ethyl-2-oxazoline) (PEOX) and tannic acid (TA) multilayers were prepared by layer-by-layer deposition. Free-floating PEOX/TA multilayers were shown to restructure in a pH3 phosphate buffer solution to H-bonded, pH-responsive PEOX/TA fibers. This restructuring was also evident during the growth of multilayers thicker than 15 bilayers (BL). The growth profile of 30 BL-thick films showed a significant decrease in the film thickness from 118 nm to 85 nm between 15 BL and 20 BL, after which the growth trend was regained with some small fluctuations. This decrease was associated with the detachment of film patches from the top surface of the film. The rinse solutions consisted of fibrous aggregates, which were formed by the restructuring of the detached multilayer patches. These fibers were characterized by TGA, XPS, FTIR and SEM measurements which showed that the fibers consisted of H-bonded PEOX and TA molecules. As such, the fibers were pH-responsive and disintegrated at pH > 8.5. Scanning electron microscopy images indicated that the fibers might have been formed by the curling of planar LbL film patches and the dried fibers looked like collapsed hollow tubes on solid substrates. These results contribute to our understanding of the stability of LbL films in various chemical conditions and the ways to modify the morphology of self-assembled structures. pH-responsive fibrous aggregates are important in a variety of biomedical applications, from controlled release to sensors.


Regulation of Cox-2 by cyclic AMP response element binding protein in prostate cancer: potential role for nexrutine.
We recently showed that Nexrutine, a Phellodendron amurense bark extract, suppresses proliferation of prostate cancer cell lines and tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Our data also indicate that the anti-proliferative effects of Nexrutine are emediated in part by Akt and Cyclic AMP response element binding protein (CREB). Cyclooxygenase (Cox-2), a pro-inflammatory mediator, is a CREB target that induces prostaglandin E(2) (PGE(2)) and suppresses apoptosis. Treatment of LNCaP cells with Nexrutine reduced tumor necrosis factor alpha-induced enzymatic as well as promoter activities of Cox-2. Nexrutine also reduced the expression and promoter activity of Cox-2 in PC-3 cells that express high constitutive levels of Cox-2. Deletion analysis coupled with mutational analysis of the Cox-2 promoter identified CRE as being sufficient for mediating Nexrutine response. Immunohistochemical analysis of human prostate tumors show increased expression of CREB and DNA binding activity in high-grade tumors (three-fold higher in human prostate tumors compared to normal prostate; P = .01). We have identified CREB-mediated activation of Cox-2 as a potential signaling pathway in prostate cancer which can be blocked with a nontoxic, cost-effective dietary supplement like Nexrutine, demonstrating a prospective for development of Nexrutine for prostate cancer management.


Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis.
Atorvastatin and other members of the statin family are widely used for the treatment of hypercholesterolaemia in order to reduce the risk of atherosclerosis and cardiovascular disease. Atorvastatin-induced adverse events are mostly mild and only a few cases of lupus-like syndrome or severe acute hepatitis have been documented. In this case report we describe a patient who developed an atorvastatin-induced severe autoimmune hepatitis. In addition, this patient presented with a concomitant systemic lupus-like syndrome which has been already described for statins but not in association with severe liver disease. Although the drug was immediately withdrawn the disease persisted and even deteriorated to a fulminant disease with evidence of acute hepatic failure. The patient failed to respond to conventional immunosuppression with corticosteroids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery of the patient. Interestingly, the patient was HLA DR3- and HLA DR4-positive, which are well-known genetic factors associated with autoimmune diseases. This case is the first report of a drug-induced lupus-likesyndrome concomitant with a severe autoimmune hepatitis in a genetically predisposed patient.


A case of lupus-associated pancreatitis in Jamaica.
Pancreatitis complicating a diagnosis of systemic lupus erythematosus (SLE) is rarely reported in the literature and there are no known published cases thus far in the Caribbean. A 50-year old female diagnosed with SLE and discoid lupus erythematosus (DLE) since 1990, presented in February, 2009, to the University Hospital of the West Indies (UHWI), Kingston, Jamaica, with symptoms suggestive of lupus pancreatitis. Serum amylase level was 2341 IU/L and serum lipase was 203 IU/L. Pancreatitis has a 3-8% rate of occurrence in adult patients with SLE. Aetiology and management of this entity remains controversial in these cases, but one must bear the diagnosis in mind, when faced with a SLE patient presenting with abdominal pain, vomiting and diarrhoea.


Accelerated telomere shortening in β-thalassemia/HbE patients.
β-Thalassemia/HbE disease is caused by a defective β-globin synthesis that leads to accumulation of excess unbound α-globins, and consequently oxidative stress, ineffective erythropoiesis and chronic anemia. Cell replication and oxidative stress are factors contributing to erosion of telomeres responsible for maintaining genomic stability and cell replication capability. In this study, the rate of telomere shortening in β-thalassemia/HbE patients was compared to the rate of telomere shortening in normal individuals. Telomere length was determined from peripheral blood mononuclear cells of 43 β-thalassemia/HbE patients and 22 normal controls using Flow-FISH analysis. The telomere length was shown to be age-dependent in normal group (rs = 0.715, P = 0.002), whereas severity-dependent telomere shortening was observed in the patients. The telomere length of patients who had severe clinical symptoms (10.07 ± 2.15%) was shorter than that of patients who showed mild symptoms (15.59 ± 2.27%), moderate symptoms (14.50 ± 1.41%) and those in the normal group (14.75 ± 3.11%, P < 0.05). Additionally, reticulocyte count and oxidative stress were correlated with telomere length. This indicates that increased oxidative stress and markedly enhanced erythropoiesis in β-thalassemia/HbE patients leads to accelerated telomere erosion in clinically severe patients.


Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.
Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.


PSD95 suppresses dendritic arbor development in mature hippocampal neurons by occluding the clustering of NR2B-NMDA receptors.
Considerable evidence indicates that the NMDA receptor (NMDAR) subunits NR2A and NR2B are critical mediators of synaptic plasticity and dendritogenesis; however, how they differentially regulate these processes is unclear. Here we investigate the roles of the NR2A and NR2B subunits, and of their scaffolding proteins PSD-95 and SAP102, in remodeling the dendritic architecture of developing hippocampal neurons (2-25 DIV). Analysis of the dendritic architecture and the temporal and spatial expression patterns of the NMDARs and anchoring proteins in immature cultures revealed a strong positive correlation between synaptic expression of the NR2B subunit and dendritogenesis. With maturation, the pruning of dendritic branches was paralleled by a strong reduction in overall and synaptic expression of NR2B, and a significant elevation in synaptic expression of NR2A and PSD95. Using constructs that alter the synaptic composition, we found that either over-expression of NR2B or knock-down of PSD95 by shRNA-PSD95 augmented dendritogenesis in immature neurons. Reactivation of dendritogenesis could also be achieved in mature cultured neurons, but required both manipulations simultaneously, and was accompanied by increased dendritic clustering of NR2B. Our results indicate that the developmental increase in synaptic expression of PSD95 obstructs the synaptic clustering of NR2B-NMDARs, and thereby restricts reactivation of dendritic branching. Experiments with shRNA-PSD95 and chimeric NR2A/NR2B constructs further revealed that C-terminus of the NR2B subunit (tail) was sufficient to induce robust dendritic branching in mature hippocampal neurons, and suggest that the NR2B tail is important in recruiting calcium-dependent signaling proteins and scaffolding proteins necessary for dendritogenesis.


Evolution over a 10 year period of the epidemiological profile of 1,726 newly diagnosed HCV patients in Belgium.
In order to evaluate the future burden of hepatitis C, there is a need to quantify the evolution with time of some crucial parameters such as disease frequency and age, modes of infection and infecting genotypes of patients presenting for the first time at consultation. The yearly evolution of these parameters was analyzed retrospectively in a cohort of 1,726 patients living in Belgium, who were diagnosed as hepatitis C virus (HCV) carriers by polymerase chain reaction (PCR) between 1992 and 2002. The epidemiological profile of HCV patients showed significant changes during this period. The number of new patients increased with time. The proportion of patients under 50 increased linearly at a rate of 3% per year. The rate of newly presenting patients infected by transfusion before 1990 decreased, but only by 2.7% per year. The proportion of intravenous (IV) drug users increased by 2.5% per year. Patients presenting "undefined" risk factors increased by 2.1% per year. Nosocomial acquisition of HCV infection exhibited a disturbing relative stability in time whereas dialysis tended to disappear as a cause of infection. There was a significant linear annual decrease of 2.3% in the frequency of genotype 1b, which was counterbalanced by a significant increase of 0.7% for genotype 1a and 1.1% for genotype 4. Genotypes 2 and 3 did not vary significantly with time. Such figures are useful for evaluating the epidemiological changes of C virus infection and for anticipating the future economical cost of hepatitis C treatment in the next few years.


Effects of cigarette smoking, caffeine consumption, and alcohol intake on fecundability.
Data from the Ontario Farm Family Health Study were analyzed to determine whether smoking, caffeine, or alcohol use among men and women affect fecundability (the monthly probability of conception). In this retrospective cohort study of farm couples in Ontario, Canada, the farm operator, husband, and wife completed questionnaires during 1991-1992, yielding information on 2,607 planned pregnancies that had occurred over the previous 30 years. Fecundability ratios were calculated using an analog of the Cox proportional hazards model. Cigarette smoking among women and men was associated with decreased fecundability (fecundability ratio = 0.90, 95% confidence interval (CI) 0.82-0.98 and fecundability ratio = 0.88, 95% CI 0.81-0.95, respectively). Caffeine consumption of 100 mg or less versus more than 100 mg in women and men was not associated with fecundability (fecundability ratio = 0.98, 95% CI 0.91-1.07 and fecundability ratio = 1.05, 95% CI 0.97-1.14, respectively). Decreases were observed among women who were coffee drinkers (fecundability ratio = 0.92, 95% CI 0.84-1.00) and men who were heavy tea drinkers (fecundability ratio = 0.85, 95% CI 0.69-1.05), regardless of caffeine content. Alcohol use among women and men was not associated with fecundability. These data are consistent with previous studies of the adverse effect of tobacco on fecundability in female smokers and suggest an effect of smoking among males. Continued evaluation of coffee and tea is warranted to address constituents other than caffeine.


Strength, Functional Outcome, and Postural Stability After Anterior Cruciate Ligament Reconstruction.
OBJECTIVE: To compare postural stability, single-leg hop, and isokinetic strength measurements in subjects after anterior cruciate ligament (ACL) reconstruction with an age- and activity-matched control group. DESIGN AND SETTING: Subjects reported to a sports medicine/athletic training research laboratory for testing. Subjects reported for one testing session for a total test time of 1 hour. SUBJECTS: Twenty subjects with ACL reconstructions (ACLRs) and 20 age- and activity-matched controls were selected to participate in this study. An arthroscopically assisted central one-third bone-patellar tendon procedure was used to repair the ACLs. MEASUREMENTS: We measured concentric and eccentric peak torque (Nm) measurements of the knee extensors and flexors at 120 degrees and 240 degrees /second on an isokinetic dynamometer. Unilateral and bilateral dynamic postural stability was measured as a stability index in the anterior-posterior and medial-lateral planes with the Biodex Stability System. We tested single-leg hop for distance to measure objective function. RESULTS: We found no significant difference between the ACLR and control subjects for stability index or knee-flexion peak torque scores. On the single-leg hop for distance, the ACLR subjects hopped significantly shorter distances with the involved limb than the uninvolved limb. Furthermore, the ACLR subjects' single-leg hop distance was significantly less when the involved limb was compared with the control-group matched involved limb, and the ACLR subjects performed significantly better when the uninvolved limb was compared with the control-group matched uninvolved limb. The ACLR subjects produced significantly greater torque in the uninvolved leg than in the involved leg. In addition, the peak torque was significantly less for the involved limb in the ACLR group when compared with the matched involved limb of the control group. CONCLUSIONS: After ACLR (mean = 18 +/- 10 months), single-leg hop-for-distance scores and quadriceps strength were not within normal limits when compared with the contralateral limb. Our results suggest that bilateral and single-limb postural stability in the ACLR group was not significantly different than the control group at an average follow-up of 18 months after surgery.


Effects of chromium on basal and insulin-induced tyrosine phosphorylation in H4 hepatoma cells: comparison with phorbol-12-myristate-13-acetate and sodium orthovanadate.
Chromium, in its various forms, is recognized both as a human carcinogen and as a nutrient essential in glucose homeostasis. Although the genotoxicity of this element is associated with its carcinogenic properties, the manner in which chromium mediates its epigenetic effects on cells, including its ability to potentiate insulin action, is not known. In the current studies, Western blotting with antiphosphotyrosine antibodies was used to study the effects of chromium on protein tyrosine phosphorylation in intact H4 rat hepatoma cells. Treatment of cells with hexavalent chromium [Cr(VI)] was found to induce the tyrosine phosphorylation of three prominent sets of proteins, having median molecular masses of 210, 125, and 87 kDa. Cr(VI) pretreatment also inhibited the insulin-induced tyrosine phosphorylation of the major substrate of the insulin receptor kinase, insulin receptor substrate-1, and its subsequent association with the 85-kDa regulatory subunit (p85) of phosphatidylinositol 3'-kinase. Furthermore, Cr(VI) was found to alter the pattern of other p85-binding (insulin-induced) phosphoproteins that were distributed throughout the soluble and particulate fractions of cells. Virtually all of the alterations in basal and insulin-induced phosphorylations associated with Cr(VI) treatment were also observed in cells treated with the protein kinase C (PKC) agonist phorbol-12-myristate-13-acetate. However, the effects of Cr(VI) were determined to be independent of PKC activity, because they were sustained in PKC-depleted cells. The pattern of phosphoproteins induced by Cr(VI) also had similarities to the pattern generated in response to the phosphatase inhibitor sodium orthovanadate. However, several specific differences, including the ability of vanadate to increase insulin receptor beta subunit autophosphorylation [i.e., an effect not observed with Cr(VI)], indicated that these agents modulate phosphorylation by distinct mechanisms. The ability of Cr(VI) to alter the phosphorylation state of key regulatory proteins in a manner similar to that of other biologically active agents suggests a mechanism by which this element can modulate the growth and metabolism of cells.


Convergence of cells from the progenitor fraction of adult olfactory bulb tissue to remyelinating glia in demyelinating spinal cord lesions.
Progenitor cells isolated from adult brain tissue are important tools for experimental studies of remyelination. Cells harvested from neurogenic regions in the adult brain such as the subependymal zone have demonstrated remyelination potential. Multipotent cells from the progenitor fraction have been isolated from the adult olfactory bulb (OB) but their potential to remyelinate has not been studied. We used the buoyant density gradient centrifugation method to isolate the progenitor fraction and harvest self-renewing multipotent neural cells grown in monolayers from the adult green-fluorescent protein (GFP) transgenic rat OB. OB tissue was mechanically and chemically dissociated and the resultant cell suspension fractionated on a Percoll gradient. The progenitor fraction was isolated and these cells were plated in growth media with serum for 24 hrs. Cells were then propagated in N2 supplemented serum-free media containing b-FGF. Cells at passage 4 (P4) were introduced into a demyelinated spinal cord lesion. The GFP(+) cells survived and integrated into the lesion, and extensive remyelination was observed in plastic sections. Immunohistochemistry revealed GFP(+) cells in the spinal cord to be glial fibrillary acidic protein (GFAP), neuronal nuclei (NeuN), and neurofilament negative. The GFP(+) cells were found among primarily P0(+) myelin profiles, although some myelin basic protein (MBP) profiles were present. Immuno-electron microscopy for GFP revealed GFP(+) cell bodies adjacent to and surrounding peripheral-type myelin rings. We report that neural cells from the progenitor fraction of the adult rat OB grown in monolayers can be expanded for several passages in culture and that upon transplantation into a demyelinated spinal cord lesion provide extensive remyelination without ectopic neuronal differentiation.


Talbot effect by a photorefractive volume phase grating.
In our proposal a light intensity distribution generated by an incoherently illuminated planar amplitude grating is projected into a photorefractive crystal. This 3D distribution is mapped as an index refractive perturbation via the photorefractive effect thereby generating a volume phase grating. The self-imaging phenomenon in the Fresnel field of this volume phase grating coherently illuminated is theoretically and experimentally analyzed. A model to simulate this volume grating that considers the 3D light intensity distribution formed in the crystal combined with the photorefractive grating formation theory is proposed. A path-integral approach to calculate the self-image patterns which account for the inhomogeneous propagation through the photorefractive grating is employed. The experimental and theoretical results show that the self-images location coincides with that of the self-images generated by planar phase grating of the same period. Moreover, the self-images visibility depends on three parameters: the exit pupil diameter of the incoherent recording optical system, the external electric field applied on the crystal, and the crystal thickness. To study the visibility behavior, a phase parameter which includes the three mentioned parameters is proposed. The self-images visibility shows the typical sinusoidal dependence found in planar phase grating. A good agreement between theoretical and experimental results is observed.


Refined crystal structures of "aged" and "non-aged" organophosphoryl conjugates of gamma-chymotrypsin.
"Aged" organophosphoryl conjugates of serine hydrolases differ from the corresponding "non-aged" conjugates in their striking resistance to nucleophilic reactivation. The refined X-ray structures of "aged" and "non-aged" organophosphoryl conjugates of gamma-chymotrypsin were compared in order to understand the molecular basis for this resistance of "aged" conjugates. "Aged" and "non-aged" crystalline organophosphoryl-gamma-chymotrypsin conjugates were obtained by prolonged soaking of native gamma-chymotrypsin crystals with appropriate organophosphates. Thus, a representative "non-aged" conjugate, diethylphosphoryl-gamma-chymotrypsin, was obtained by soaking native crystals with paraoxon (diethyl-p-nitrophenyl phosphate), and a closely related "aged" conjugate, monoisopropyl-gamma-chymotrypsin, was obtained by soaking with diisopropylphosphorofluoridate. In both crystalline conjugates, the refined structures clearly reveal a high occupancy of the active site by the appropriate organophosphoryl moiety within covalent bonding distance of Ser195 O gamma. Whereas in the "non-aged" conjugate both ethyl groups can be visualized clearly, in the putative "aged" conjugate, as expected, only one isopropyl group is present. There is virtually no difference between the "aged" and "non-aged" conjugates either with respect to the conformation of the polypeptide backbone as a whole or with respect to the positioning of the side-chains within the active site. In the "aged" conjugate, however, close proximity (2.6 A) of the negatively charged phosphate oxygen atom of the dealkylated organophosphoryl group to His57 N epsilon 2 indicates the presence of a salt bridge between these two moieties. In contrast, in the "non-aged" conjugate the DEP moiety retains its two alkyl groups; thus, lacking a negative oxygen atom, it does not enter into such a charge-charge interaction and its nearest oxygen atom is 3.6 A away from His57 N epsilon 2. It is suggested that steric constraints imposed by the salt bridge in the "aged" conjugate lie at the basis of its resistance to reactivation.


The 'indirect costs' of underfunding foreign partners in global health research: A case study.
This study of a global health research partnership assesses how U.S. fiscal administrative policies impact capacity building at foreign partner institutions. We conducted a case study of a research collaboration between Mbarara University of Science and Technology (MUST) in Mbarara, Uganda, and originally the University of California San Francisco (UCSF), but now Massachusetts General Hospital (MGH). Our case study is based on three of the authors' experiences directing and working with this partnership from its inception in 2003 through 2015. The collaboration established an independent Ugandan non-profit to act as a local fiscal agent and grants administrator and to assure compliance with the Ugandan labour and tax law. This structure, combined with low indirect cost reimbursements from U.S. federal grants, failed to strengthen institutional capacity at MUST. In response to problems with this model, the collaboration established a contracts and grants office at MUST. This office has built administrative capacity at MUST but has also generated new risks and expenses for MGH. We argue that U.S. fiscal administrative practices may drain rather than build capacity at African universities by underfunding the administrative costs of global health research, circumventing host country institutions, and externalising legal and financial risks associated with international work. MGH: Massachusetts General Hospital; MUST: Mbarara University of Science and Technology; NIH: National Institutes of Health; UCSF: University of California San Francisco; URI: Uganda Research Institute.


Non-invasive investigation of myocardial energetics in cardiac disease using 31P magnetic resonance spectroscopy.
Cardiac metabolism and function are intrinsically linked. High-energy phosphates occupy a central and obligate position in cardiac metabolism, coupling oxygen and substrate fuel delivery to the myocardium with external work. This insight underlies the widespread clinical use of ischaemia testing. However, other deficits in high-energy phosphate metabolism (not secondary to supply-demand mismatch of oxygen and substrate fuels) may also be documented, and are of particular interest when found in the context of structural heart disease. This review introduces the scope of deficits in high-energy phosphate metabolism that may be observed in the myocardium, how to assess for them, and how they might be interpreted.


Lessons from a search for leaf mutants in Arabidopsis thaliana.
Large-scale exploratory approaches to understanding gene function laid the foundations for the -omics era. Based on modern technologies for the structural and functional characterization of genomes, these curiosity-driven approaches allow systematic accumulation of vast amounts of data, enabling subsequent hypothesis-driven research. Some years before the dawn of genomics, exploratory approaches were already furthering our understanding of gene function in the form of saturation mutagenesis experiments aimed at the identification of all genes that mutate to a given phenotype. Forward genetic approaches, conducted on experimental organisms such as Drosophila melanogaster and Caenorhabditis elegans, have led to the isolation of mutants affected in specific developmental processes, whose cellular and molecular characterization has unraveled the underlying genetic mechanisms of animal development. To shed light on the making of plant leaves, in 1993 we initiated an attempt to identify as many viable and fertile mutants with abnormal leaf morphology as possible, using the Arabidopsis thaliana model organism. We identified 25 fast-neutron- and 153 ethyl-methane sulfonate-induced mutations, which fell into eight and 94 complementation groups, respectively. We also studied 115 publicly available mutant lines isolated by previous authors, which fell into 37 complementation groups. Although we did not reach saturation of the Arabidopsis thaliana genome, the broad spectrum of leaf morphological alterations identified is facilitating the dissection of specific leaf developmental processes. In a complementary approach, we also analyzed leaf architecture in natural accessions and two populations of recombinant inbred lines. Using a high-throughput gene mapping method, we have already cloned 25 of the genes identified by mutation, in some cases in collaboration with other groups. The products of these genes participate in various developmental processes, such as polar cell expansion, transduction of hormonal signals, gene regulation, plastid biogenesis, and chromatin remodeling, among others. The range of phenotypes and processes identified reveal the complexity of leaf ontogeny and will help explain the diversity of leaf morphology in nature.


Ultrasonographic measurement of fetal growth parameters over three successive pregnancies in a captive Malayan tapir (Tapirus indicus).
This study was conducted to establish representative curves that allow evaluation of fetal growth and estimation of gestational age from measurement of fetal structures by ultrasound in Malayan tapirs (Tapirus indicus). Three pregnancies (i.e. 3 fetuses) were examined in one female Malayan tapir. Transabdominal ultrasonographic examination was performed without anesthesia from 79 ± 8 days to 281 ± 48 days (mean ± S.D.) post mating. To assess fetal growth attempts were made to measure biparietal diameter (BPD), head length (HL), thorax diameter A (TDA), thorax height A (THA), thorax diameter B (TDB), thorax height B (THB), abdomen diameter (AD), abdomen height (AH), humerus length (HUL) and Crown rump length (CRL). The value of each parameter as an estimator of gestational age was assessed by ease of observation and the length of time the parameter was measurable throughout gestation. The most precise predictors for gestational age in this study were BPD and CRL (weeks 10-20 of gestation), as well as AD and AH (weeks 14-43 of gestation). The parameters TDB, THB and HUL (weeks 15-41 of gestation) gave almost as good predictions. Fetal viability was assessed by identifying a fetal heartbeat and movement. All pregnancies resulted in normal deliveries and healthy offspring. The ultrasound examination was well tolerated by the female. The gestation lengths (399 ± 3 days) were within reported ranges. The serial transabdominal ultrasound, without the need for anesthesia, was an effective method to evaluate fetal growth, development and well being in a Malayan tapir.


Neurovascular risks of anteroinferior clavicular plating.
Anteroinferior plating has been described for internal fixation of clavicular fractures, citing improved bicortical fixation, less hardware prominence, and safer drill trajectories compared with other plate configurations. This anatomic study defined structures at risk during anteroinferior clavicular plating. Four paired cadaveric specimens (8 clavicles) from ages 75 to 93 years were systematically dissected. Using the screw paths associated with an anteroinferior plate (anteroinferior to superoposterior), the distance from the posterior clavicle cortex to the nearest vital structure was measured at 5 different positions along the clavicle. In the medial half of the clavicle, the subclavian artery is in closest proximity to the clavicle, measuring, on average, 22.95 mm and 15.10 mm at point A and B. At the lateral three-fifths point of the clavicle (point C), the brachial plexus is 12.76 mm from the posterior clavicle and is more at risk than the subclavian artery. Lateral to the three-fifth point of the clavicle, there were no vital structures that could be injured by overdrilling. Our results suggest that more care should be observed with placement of screws in the medial half of the clavicle where subclavian artery damage is more likely.


Carotenoid cation formation and the regulation of photosynthetic light harvesting.
Photosynthetic light harvesting in excess light is regulated by a process known as feedback deexcitation. Femtosecond transient absorption measurements on thylakoid membranes show selective formation of a carotenoid radical cation upon excitation of chlorophyll under conditions of maximum, steady-state feedback deexcitation. Studies on transgenic Arabidopsis thaliana plants confirmed that this carotenoid radical cation formation is correlated with feedback deexcitation and requires the presence of zeaxanthin, the specific carotenoid synthesized during high light exposure. These results indicate that energy transfer from chlorophyll molecules to a chlorophyllzeaxanthin heterodimer, which then undergoes charge separation, is the mechanism for excess energy dissipation during feedback deexcitation.


The antitumour agent 5,6-dimethylxanthenone-4-acetic acid acts in vitro on human mononuclear cells as a co-stimulator with other inducers of tumour necrosis factor.
5,6-dimethylxanthenone-4-acetic acid (DMXAA), currently in phase I trials, demonstrates excellent activity against transplantable murine tumours with established vasculature. The induction of cytokines, particularly of tumour necrosis factor (TNF), appears to be critical to its action. We investigated TNF induction by DMXAA in cultured human peripheral blood leucocytes (HPBL). TNF was measured by an enzyme-linked immunosorbent assay after 8 h, and NF-kappaB induction by electrophoretic mobility shift assays (EMSA) after 2 h. DMXAA (800 microg/ml) had no effect alone on TNF production but augmented, by up to 4-fold, the ability of bacterial lipopolysaccharide (LPS) to induce TNF. Previously reported results showing TNF production by DMXAA alone were traced to the presence in an earlier batch of DMXAA of a small amount of LPS, the action of which could be blocked by polymyxin B. DMXAA stimulated TNF production by deacylated LPS, which alone had little effect. An antibody (MEM-18) to the CD14 receptor, while blocking the induction of TNF by LPS, enabled DMXAA to both synthesise TNF and induce NF-kappaB. The structurally related drug, flavone acetic acid (FAA), did not induce TNF or synergise with anti-CD14 antibody. DMXAA strongly augmented the ability of suboptimal concentrations of interleukin-1 (IL-1) (25 ng/ml), okadaic acid (OA) (20 ng/ml) and phorbol-12-myristate-13-acetate (PMA) (5 ng/ml) to induce TNF production, suggesting that it affects multiple pathways converging on NF-kappaB activation. Sodium salicylate, a drug reported to inhibit the beta-subunit of IkappaB kinase (IKK), appeared to competitively inhibit TNF production by DMXAA in the presence of anti-CD14 antibody. Taken together, the results indicate DMXAA acts in vitro on HPBL to co-stimulate TNF production by a wide variety of agents, and suggests that IKK is the target that mediates this action.


Th2 differentiation in distinct lymph nodes influences the site of mucosal Th2 immune-inflammatory responses.
Allergic individuals rarely present with concurrent multiple-organ disease but, rather, with manifestations that privilege a specific site such as the lung, skin, or gastrointestinal tract. Whether the site of allergic sensitization influences the localization of Th2 immune-inflammatory responses and, ultimately, the organ-specific expression of disease, remains to be determined. In this study, we investigated whether both the site of initial Ag exposure and concomitant Th2 differentiation in specific lymph nodes (LNs) privileges Th2 memory responses to mucosal and nonmucosal sites, and whether this restriction is associated with a differential expression in tissue-specific homing molecules. In mice exposed to Ag (OVA) via the peritoneum, lung, or skin, we examined several local and distal LNs to determine the site of Ag-specific proliferation and Th2 differentiation. Whereas respiratory and cutaneous Ag exposure led to Ag-specific proliferation and Th2 differentiation exclusively in lung- and skin-draining LNs, respectively, Ag delivery to the peritoneum evoked responses in gut-associated, as well as distal thoracic, LNs. Importantly, only mice that underwent Th2 differentiation in thoracic- or gut-associated LNs mounted Th2 immune-inflammatory responses upon respiratory or gastric Ag challenge, respectively, whereas cutaneous Th2 recall responses were evoked irrespective of the site of initial sensitization. In addition, we observed the differential expression of gut homing molecules (CCR9, alpha(4), beta(7)) in gut-associated LNs and, unexpectedly, a universal induction of skin-related homing molecules (CCR4, CCR10) in all LNs. These data suggest that the site of initial Th2 differentiation and differential homing molecule expression restricts Th2 immune-inflammatory responses to mucosal, but not cutaneous, tissues.


Real-time diagnosis and visualization of tumor margins in excised breast specimens using fluorescence lifetime imaging and machine learning.
Tumor-free surgical margins are critical in breast-conserving surgery. In up to 38% of the cases, however, patients undergo a second surgery since malignant cells are found at the margins of the excised resection specimen. Thus, advanced imaging tools are needed to ensure clear margins at the time of surgery. The objective of this study was to evaluate a random forest classifier that makes use of parameters derived from point-scanning label-free fluorescence lifetime imaging (FLIm) measurements of breast specimens as a means to diagnose tumor at the resection margins and to enable an intuitive visualization of a probabilistic classifier on tissue specimen. FLIm data from fresh lumpectomy and mastectomy specimens from 18 patients were used in this study. The supervised training was based on a previously developed registration technique between autofluorescence imaging data and cross-sectional histology slides. A pathologist's histology annotations provide the ground truth to distinguish between adipose, fibrous, and tumor tissue. Current results demonstrate the ability of this approach to classify the tumor with 89% sensitivity and 93% specificity and to rapidly (∼ 20 frames per second) overlay the probabilistic classifier overlaid on excised breast specimens using an intuitive color scheme. Furthermore, we show an iterative imaging refinement that allows surgeons to switch between rapid scans with a customized, low spatial resolution to quickly cover the specimen and slower scans with enhanced resolution (400 μm per point measurement) in suspicious regions where more details are required. In summary, this technique provides high diagnostic prediction accuracy, rapid acquisition, adaptive resolution, nondestructive probing, and facile interpretation of images, thus holding potential for clinical breast imaging based on label-free FLIm.


Resisting decay: On disposal, valuation, and care in a dementia nursing home in Denmark.
This paper approaches institutionalized dementia care as a site of societal disposal, valuation, and care for human life. Drawing upon six weeks of ethnographic fieldwork and ten qualitative interviews carried out in a Danish dementia nursing home in 2014, we analyze how nursing home staff, through everyday care, uphold the value of life for residents in severe mental and physical decline. We argue that life's worth is established when residents gain qualities of personhood and agency through substitution processes carried out by staff. Yet the persistent absence of conventional personhood and autonomous agency in residents (i.e. capacities for memory, consciousness, language, and mobility) evokes experiences of ambiguity in staff and relatives of residents. We close the article with a discussion of this ambiguity and the significance of the nursing home as care institution in the welfare state. Dementia care, we propose, is not only about preserving the lives of people with dementia. At stake in the daily care practices around severely disabled residents in the nursing home is the very continuance of the main principles of the welfare society.


Laboratory prototype for experimental validation of MR-guided radiofrequency head and neck hyperthermia.
Clinical studies have established a strong benefit from adjuvant mild hyperthermia (HT) to radio- and chemotherapy for many tumor sites, including the head and neck (H&N). The recently developed HYPERcollar allows the application of local radiofrequency HT to tumors in the entire H&N. Treatment quality is optimized using electromagnetic and thermal simulators and, whenever placement risk is tolerable, assessed using invasively placed thermometers. To replace the current invasive procedure, we are investigating whether magnetic resonance (MR) thermometry can be exploited for continuous and 3D thermal dose assessment. In this work, we used our simulation tools to design an MR compatible laboratory prototype applicator. By simulations and measurements, we showed that the redesigned patch antennas are well matched to 50 Ω (S11<-10 dB). Simulations also show that, using 300 W input power, a maximum specific absorption rate (SAR) of 100 W kg(-1) and a temperature increase of 4.5 °C in 6 min is feasible at the center of a cylindrical fat/muscle phantom. Temperature measurements using the MR scanner confirmed the focused heating capabilities and MR compatibility of the setup. We conclude that the laboratory applicator provides the possibility for experimental assessment of the feasibility of hybrid MR-HT in the H&N region. This versatile design allows rigorous analysis of MR thermometry accuracy in increasingly complex phantoms that mimic patients' anatomies and thermodynamic characteristics.


Non-coding RNAs and hypertension-unveiling unexpected mechanisms of hypertension by the dark matter of the genome.
Hypertension is a major risk factor of cardiovascular diseases and a most important health problem in developed countries. Investigations on pathophysiology of hypertension have been based on gene products from coding region that occupies only about 1% of total genome region. On the other hand, non-coding region that occupies almost 99% of human genome has been regarded as "junk" for a long time and went unnoticed until these days. But recently, it turned out that noncoding region is extensively transcribed to non-coding RNAs and has various functions. This review highlights recent updates on the significance of non-coding RNAs such as micro RNAs and long non-coding RNAs (lncRNAs) on the pathogenesis of hypertension, also providing an introduction to basic biology of noncoding RNAs. For example, microRNAs are associated with hypertension via neuro-fumoral factor, sympathetic nerve activity, ion transporters in kidneys, endothelial function, vascular smooth muscle phenotype transformation, or communication between cells. Although reports of lncRNAs on pathogenesis of hypertension are scarce at the moment, new lncRNAs in relation to hypertension are being discovered at a rapid pace owing to novel techniques such as microarray or next-generation sequencing. In the clinical settings, clinical use of non-coding RNAs in identifying cardiovascular risks or developing novel tools for treating hypertension such as molecular decoy or mimicks is promising, although improvement in chemical modification or drug delivery system is necessary.


Diagnosis of pancreatic cancer by 2[18F]-fluoro-2-deoxy-D-glucose positron emission tomography.
The detection of pancreatic cancer or the discrimination between pancreatic cancer and chronic pancreatitis remains an important diagnostic problem. The increased glucose metabolism in malignant tumours formed the basis for this investigation, which focused on the role of positron emission tomography (PET) with 2[18F]-fluoro-2-deoxy-D-glucose (FDG) in the detection of pancreatic cancer and its differentiation from chronic pancreatitis. Eighty patients admitted for elective pancreatic surgery received preoperatively 250-350 mBq FDG intravenously and emission scans were recorded 45 minutes later. Intense focal activity in the pancreatic region was taken at the time of scanning as showing the presence of pancreatic cancer. The presence of cancer was later confirmed by histological examination of the surgical specimens and histological findings were compared with the preoperative PET results. Forty one patients with pancreatic cancer (group I: n = 42) had a focally increased FDG uptake in the pancreatic region. Two patients with a periampullary carcinoma (group II: n = 6) failed to develop FDG accumulation. In 28 patients with chronic pancreatitis (group III: n = 32) no FDG accumulation occurred. Overall sensitivity and specificity of PET for malignancy (group I + II) were 94% (45 of 48) and 88% (28 of 32), respectively. The standard uptake value of the patients with pancreatic carcinoma was significantly higher than in patients with chronic pancreatitis (3.09 (2.18) v 0.87 (0.56); p < 0.001; median (interquartile range)). These findings show that FDG-PET represents a new and non-invasive diagnostic procedure for the diagnosis of pancreatic cancer and to differentiate pancreatic cancer from chronic pancreatitis. However, the diagnostic potential of this technique requires further evaluation.


Example-Based Image Synthesis via Randomized Patch-Matching.
Image and texture synthesis is a challenging task that has long been drawing attention in the fields of image processing, graphics, and machine learning. This problem consists of modeling the desired type of images, either through training examples or via a parametric modeling, and then generating images that belong to the same statistical origin. This paper addresses the image synthesis task, focusing on two specific families of images-handwritten digits and face images. This paper offers two main contributions. First, we suggest a simple and intuitive algorithm capable of generating such images in a unified way. The proposed approach taken is pyramidal, consisting of upscaling and refining the estimated image several times. For each upscaling stage, the algorithm randomly draws small patches from a patch database and merges these to form a coherent and novel image with high visual quality. The second contribution is a general framework for the evaluation of the generation performance, which combines three aspects: the likelihood, the originality, and the spread of the synthesized images. We assess the proposed synthesis scheme and show that the results are similar in nature, and yet different from the ones found in the training set, suggesting that true synthesis effect has been obtained.


Heart coherence: a new tool in the management of stress on professionals and family caregivers of patients with dementia.
We describe a stress management intervention intended to reduce the damage and stress impact on the heart physiology and function of a group of caregivers (professional and non-professional) who work with patients with dementia. The intervention consisted in applying heart coherence techniques in a population of 72 caregivers of patients with dementia (42 professional and 29 non-professional caregivers) who had high scores in heart stress and burden tests. Six months after the training they were able to generate appropriate patterns of heart coherence, with a statistically significant decrease in their heart overload. We conclude that training in techniques of heart coherence and positive psychology had effective results on the stress management of the participant caregivers. This was a simple, inexpensive technique with lasting results. To our knowledge this is the first research in Spain studying the application of heart coherence techniques to caregivers of people with dementia.


Active compounds and distinctive sensory features provided by American ginseng (Panax quinquefolius L.) extract in a new functional milk beverage.
American ginseng (Panax quinquefolius L.) has recognized neurocognitive effects, and a ginsenoside-rich extract of the root of the plant has been shown to improve cognitive functions in young adults. This study aimed at assessing the chemical and sensory profiles of a UHT-treated, low-lactose functional milk containing American ginseng. Individual ginsenosides in the milk were analyzed by HPLC. Descriptive sensory analysis was performed by a trained panel to quantitatively document sensory changes resulting from the addition of ginseng and the UHT process on flavored and unflavored milks. Consumer acceptance of the product was also investigated. Total ginsenoside content in the UHT-treated milk enriched with the ginseng extract after UHT process treatment was 7.52 mg/100 g of milk, corresponding to a recovery of 67.6% compared with the content in the unprocessed extract. The intake of 150 to 300 mL of this ginseng-enriched milk provides the amount of total ginsenosides (11.5 to 23 mg) necessary to improve cognitive function after its consumption. Both the presence of ginsenosides and their thermal treatment affected some sensory properties of the milk, most notably an increase in bitterness and metallic taste, the appearance of a brownish color, and a decrease in milky flavor. Levels of brown color, bitterness, and metallic taste were highest in the industrially processed ginseng-enriched milk. The bitterness attributable to ginseng extract was reduced by addition of vanilla flavor and sucralose. A consumer exploratory study revealed that a niche of consumers exists who are willing to consume this type of product.


Surgical treatment of scoliosis in a rare disease: arthrogryposis.
The reported incidence of scoliosis in arthrogryposis varies from 30% to 67% and, in most cases, the curves progress rapidly and become stiff from early age.The authors report six cases of scoliosis in arthrogryposis to assess the role of surgical treatment. Six cases (3 males, 3 females; mean age at surgery 13.2 years) with arthrogryposis multiplex congenita associated with the characteristic amyoplasia were reviewed: they were operated on for scoliosis at the authors' Spine Surgery Department between 1987 and 2008.Surgery was performed using the Harrington-Luque instrumentation (2 cases), the Luque system (1), a hybrid segmental technique with hooks and screws (1) and spinal anchoring with pedicle screws (2). The patients were clinically and radiologically reviewed at a mean follow-up of 4.2 years, ± 2.7 (range, 1 to 9 years). Three minor postoperative complications were encountered; a long-term pulmonary complication was seen in one case after reintervention and was successfully resolved after 10 days. Surgery was successful in the other 5 cases, where solid arthrodesis was achieved and no significant curve progression was observed at follow-up. The experience acquired with the present case series leads the authors to assert that prompt action should be taken when treating such aggressive forms of scoliosis. In case of mild spinal deformities in arthrogryposis, brace treatment should be attempted, the evolution of the curves being unpredictable; however, when the curve exceeds 40° and presents with marked hyperkyphosis, hyperlordosis or pelvic obliquity, surgery should not be delayed.


[Pharmacoeconomic study of chemotherapy for gastric cancer: analysis of medical costs for oral fluoropyrimidine TS-1 and conventional i.v therapy].
To evaluate the economic impact of TS-1, an oral fluoropyrimidine, on the treatment of gastric cancer, the medical costs required for TS-1 treatment were compared with those for the conventional chemotherapy employed before the launch of TS-1 in patients with advanced and recurrent gastric cancer. The medical costs for 13 patients receiving TS-1 and 10 patients undergoing the conventional chemotherapy were extracted from the ordering system data, and the costs were compared using the fee schedule of the Japanese national health insurance. The monthly medical costs for the TS-1 group and conventional chemotherapy group were 327, 640 +/- 47,647 (mean +/- SE) yen and 852,874 +/- 62,412 yen, respectively. Medical costs appeared to have decreased because TS-1 is an oral preparation, permitting an easy transfer from inpatient treatment to ambulatory treatment, and because only small amounts of medication and blood transfusion were used for supportive care. Consequently, the medical costs for the TS-1 group were significantly lower than for the conventional chemotherapy group. Therefore, the administration of TS-1 leads to a reduction in medical costs.


Galactofuranose in Mycoplasma mycoides is important for membrane integrity and conceals adhesins but does not contribute to serum resistance.
Mycoplasma mycoides subsp. capri (Mmc) and subsp. mycoides (Mmm) are important ruminant pathogens worldwide causing diseases such as pleuropneumonia, mastitis and septicaemia. They express galactofuranose residues on their surface, but their role in pathogenesis has not yet been determined. The M. mycoides genomes contain up to several copies of the glf gene, which encodes an enzyme catalysing the last step in the synthesis of galactofuranose. We generated a deletion of the glf gene in a strain of Mmc using genome transplantation and tandem repeat endonuclease coupled cleavage (TREC) with yeast as an intermediary host for the genome editing. As expected, the resulting YCp1.1-Δglf strain did not produce the galactofuranose-containing glycans as shown by immunoblots and immuno-electronmicroscopy employing a galactofuranose specific monoclonal antibody. The mutant lacking galactofuranose exhibited a decreased growth rate and a significantly enhanced adhesion to small ruminant cells. The mutant was also 'leaking' as revealed by a β-galactosidase-based assay employing a membrane impermeable substrate. These findings indicate that galactofuranose-containing polysaccharides conceal adhesins and are important for membrane integrity. Unexpectedly, the mutant strain showed increased serum resistance.


Varicocele: a dilemma in adolescent males.
Varicoceles are the most common cause of infertility in men. Despite the high prevalence of varicoceles, only a small percentage of men with varicoceles have subfertility or infertility. In adolescents, the prevalence of varicoceles increases dramatically during puberty to reach adult prevalence rates. The development of varicoceles during puberty can impair testicular growth and function. Data on hormonal and semen parameters in adolescents with varicoceles are limited, making it harder to determine which varicoceles are associated with infertility and which may benefit from surgery. The main indications for varicocelectomy in adolescents with varicoceles include a volume differential between unaffected and affected testes or abnormality in semen analysis.


Dietary mushrooms reduce blood pressure in spontaneously hypertensive rats (SHR).
The blood pressure of spontaneously hypertensive rats (SHR) were significantly reduced by Maitake feeding for 8 weeks period beginning at a time when the animals were 10 weeks of age with well-established high blood pressure. There was no difference in the plasma total and free cholesterol, triglyceride and phospholipid levels between the Maitake fed animals and the control. On the other hand, Shiitake mushroom did not reduce the blood pressure, but significantly lower the plasma free cholesterol, triglyceride and phospholipid in compared with the control. The results suggest that dietary Maitake mushroom reduce the blood pressure.


Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.