Quantitative structure-biodegradation relationships for ortho-substituted biphenyl compounds oxidized by Methylosinus trichosporium OB3b.
Methanotrophs, bacteria that thrive in the presence of stable methane and oxygen concentrations, can cometabolically oxidize ortho-substituted biphenyls to yield a variety of hydroxylated products. Despite awareness of the susceptibility of ortho-substituted biphenyls and other aromatic compounds to methanotrophic oxidation, the molecular properties relevant for predicting rates of methanotrophic oxidation are unknown. To this end, we have developed quantitative structure-biodegradation relationships using oxygen uptake activity by the type 2 methanotroph. Methylosinus trichosporium OB3b, expressing the soluble form of methane monooxygenase and in the presence of nine ortho-substituted biphenyls. Multivariate analysis yielded the strongest correlations using the initial slope of the oxygen uptake rate versus substrate concentration curve as the dependent variable. Quantum mechanical descriptors, including the sum of carbon charges on the substituted ring, the charge on the substituted carbon, and the width of compound calculated using computationally derived bond lengths and dihedral angles, correlated more strongly with oxygen uptake activity than did empirically derived electronic descriptors. The resulting models suggest a significant influence of substituent electronic nature and size and the involvement of the substituted carbon site in the oxidation of these compounds by M. trichosporium OB3b.


[Corneal stromal layer changes of senile cataract patients with phacoemulsification in vivo].
To observe and investigate corneal stromal layer's changes of healthy elderly with phacoemulsification operation. The experimental design was prospective, one replicated measurement, one interventional method case series. Analysis of central corneal stromal layer's changes (including corneal thickness, keratocyte density of anterior and posterior corneal stromal layer and morphological changes) of 19 patients (22 eyes) just before operation and 1 week, 1 month, 3 months and 6 months after operation with CMTF and NCSM. The statistical test method of the three parameter groups was least significant difference. The significant sterling was P <0.05. (1) Corneal thickness: 1 week after operation, corneal thickness was significantly thicker than before operation as well as 1 month, 3 months and 6 months after operation (P < 0.05). Comparisons of the differences of other pairs of corneal thickness showed no significant differences (P> 0.05). (2) Keratocyte density: Keratocyte density in the posterior stromal before operation was (627 +/- 184)/mm2 and only the 1 month after operation group was significantly higher than before operation (P <0.05). Keratocyte density in the anterior stromal before operation was (859 +/- 137)/mm2. Comparisons of the differences of each pair of groups before and after operation showed no significant differences (P >0.05). (3) CMTF images displayed microfolds (4 eyes) in the middle and posterior stromal layers before operation. Different changes in stromal edema at an early stage after operation were observed within 3 months after operation, including different degrees of high-reflecting images and pathological microfolds (16 eyes). Keratocyte activation and fibroblast-like cells could also be found after operation. Phacoemulsification can injure the corneal stromal layers. CMTF test is a useful method to reveal corneal pathological changes in four-dimension space (three-dimension space + time).


Chick embryo inoculation as a pathogenicity test for Candida species.
The lesions produced by six Candida species on the chorioallantoic membrane (CAM) of the developing chick are described and compared. It is suggested that CAM inoculation be used as a pathogenicity test for Candida species.


[Most advance on chemical and biological investigations of gorgonian-octocorals].
This review presents the most recent chemical and biological investigations on one of the marine invertebrates, gorgonian octocoral. It summarizes all 432 new compounds published in 2002-2009, which consists of 46 sesquiterpenoids (including 2 new natural products, NNP), 282 diterpenoids (including 4 from Pennatulacea octocoral and one artifact), 76 steroids, and 29 alkaloids or other types (2 NNP included). In this paper, according to the structure division, the new compounds are described in combination with the taxonomy of the investigated animals, and its simultaneous bioactivity results. Novel skeletons and complex structures are paid most emphasis on its features, means of structural elucidation and the proposed biogenesis pathway. The source of all new compounds and the different diterpenoid skeleton types are all listed and analyzed, as well as the commonly used Chinese names or some proposed ones for diterpenoid skeletons. Furthermore, this papers deals with all biological test toward the gorgonian new metabolites, i.e. anti-cancer, anti-inflammatory, anti-bacterial(against Staphylococcus aureus bacteria, Mycobacterium tuberculosis etc), anti-malaria, and anti-fouling as well, in which anti-cancer activity and cytotoxicity were additionally, a discussion and prospect are proposed regarding chemical overview on gorgonian. This review, hopefully, can be useful in proving data and references for further chemical and biological research of China sea gorgonian, for the studies on chemical ecology, and for the discovery of new and bioactive compounds or the marine-derived leading targets.


Fertility levels, trends, and differentials in sub-Saharan Africa in the 1980s and 1990s.
This study presents an assessment of fertility trends in 23 countries of sub-Saharan Africa. It examines trends and differentials in proximate determinants and fertility preferences. Findings from the Demographic and Health Surveys for these countries over a period of 15 years show that desired family size has decreased significantly. Two-thirds of the countries examined show evidence of fertility decline, a particularly rapid decline in the cases of Kenya and Zimbabwe. Areas with higher education for women and lower child mortality experienced larger reductions in fertility and desired family size. Contraceptive use far exceeds other proximate determinants in explaining these changes. The striking regularity in fertility reduction across all ages indicates that contraception is practiced mostly for birth spacing and that contraceptive methods have gained wide acceptance among younger cohorts. Good prospects are seen for further intensification of fertility declines in East Africa and urban West Africa. However, low levels of education and high child mortality make rapid changes unlikely in rural West Africa.


Evaluating the program of a smoking cessation support group for adult smokers: a longitudinal pilot study.
Tobacco use is the leading cause of preventable death in Taiwan. In order to increase cessation rates among adult smokers, the Department of Health in Taiwan has begun providing financial support for nicotine replacement therapy (NRT). However, therapies based on multiple interventions can lead to significantly higher cessation rates than NRT alone. This study develops and evaluates the outcomes of a smoking cessation program that provides a combination of physiological and psychological treatment in the context of a short-term support group. In this study, ten adult smokers were recruited by means of advertisements broadcast on local television over a seven-day period and one thousand flyers that advertised free assistance with quitting smoking. The smoking cessation support group was carried in Tainan County, in southern Taiwan. The three-month program consisted of three, monthly group sessions, free nicotine patches, telephone counseling by public health nurses, and telephone interviews by community health volunteers. Those participating in the group were encouraged to keep a record of all smoking behavior and its "triggers" in a diary, list the personal benefits of quitting, draw up a quitting contract, and enlist significant family members to monitor their quitting behavior. Participants were also trained in behavioral strategies to avoid smoking, including imagery rehearsal, relaxation techniques, exercise, and distraction. The outcome of the project was assessed by the following two criteria: (1) carbon monoxide (CO) level in the breath before and after the three-month program, as measured by percentage of carboxyhemoglobin (%COHB), and (2) the self-reported number of cigarettes smoked per month, taken at the outset of the three-month program, at the conclusion of the program, and six months after the termination of the program. The Wilcoxon signed-rank and Friedman tests respectively revealed that there were significant decreases both in the subjects' %COHB level at the 3-month data-point, and in the number of cigarettes smoked at one month from the pretest, at the 3-month test and at the 9-month follow-up test. At the 9-month follow-up, five of the ten participants (50%) were abstinent, and three (30%) had decreased cigarette consumption by at least 49% of their pretest levels. Eighty percent of participants had, therefore, changed their smoking behavior. These results demonstrate the promise of integrated smoking cessation therapy in a group support context and indicate the need to pursue implementation and evaluation of this type of therapy on a larger scale.


Rhodopsin: insights from recent structural studies.
The recent report of the crystal structure of rhodopsin provides insights concerning structure-activity relationships in visual pigments and related G protein-coupled receptors (GPCRs). The seven transmembrane helices of rhodopsin are interrupted or kinked at multiple sites. An extensive network of interhelical interactions stabilizes the ground state of the receptor. The ligand-binding pocket of rhodopsin is remarkably compact, and several chromophore-protein interactions were not predicted from mutagenesis or spectroscopic studies. The helix movement model of receptor activation, which likely applies to all GPCRs of the rhodopsin family, is supported by several structural elements that suggest how light-induced conformational changes in the ligand-binding pocket are transmitted to the cytoplasmic surface. The cytoplasmic domain of the receptor includes a helical domain extending from the seventh transmembrane segment parallel to the bilayer surface. The cytoplasmic surface appears to be approximately large enough to bind to the transducin heterotrimer in a one-to-one complex. The structural basis for several unique biophysical properties of rhodopsin, including its extremely low dark noise level and high quantum efficiency, can now be addressed using a combination of structural biology and various spectroscopic methods. Future high-resolution structural studies of rhodopsin and other GPCRs will form the basis to elucidate the detailed molecular mechanism of GPCR-mediated signal transduction.


Novel Cu@Ag Micro/Nanoparticle Hybrid Paste and Its Rapid Sintering Technique via Electromagnetic Induction for High-Power Electronics.
Due to the harsh working environments up to 600 °C, the exploration of high-temperature interconnection materials is significantly important for high-power devices. In this study, a hybrid paste including Cu@Ag core-shell microparticles (MPs) and Ag nanoparticles (NPs) was designed to achieve Cu-Cu bonding. The Cu@Ag MPs exhibited excellent oxidation stability in an air atmosphere with the Ag layer coating on the Cu core. Ag NPs fill the pores among the Cu@Ag MPs and reduce the sintering temperature of the hybrid paste. The Cu-hybrid paste-Cu joints were formed via electromagnetic induction heating within approximately 15 s. When sintered at 26 kW, the shear strength of the joint reached 48 MPa, the porosity decreased to 0.73%, and the resistivity was down to 13.25 μΩ·cm. Furthermore, a possible interconnection mechanism at the contact interface between the Cu substrate and the sintered hybrid paste was proposed, which is related to the melting point of metal particles and the effect of magnetic eddy currents. This fast bonding technology inspires a new approach to interconnection for high-power devices under high operation temperatures.


Pharmacokinetic effects of conversion to a new formulation of cyclosporin A in rheumatoid arthritis patients.
In this study we aimed at evaluating the modifications in the pharmacokinetic profile of cyclosporin A (CyA) after conversion from standard formulation (CyA-ST) to a new formulation (CyA-NF, Sandimmun Neoral) in patients with rheumatoid arthritis (RA). It was an open, crossover study that involved 15 RA patients who were on stabilized treatment with CyA-ST. The patient continued receiving CyA-ST (mean dose of 3.0 +/- 0.7 mg/kg per day) for 3 weeks and then converted 1:1 to CyA-NF for a further 3 weeks. CyA pharmacokinetics were established on day 1 (CyA-ST evaluation) and +21 (CyA-NF evaluation). The results showed that the bioavailability of CyA-NF was greater than that of CyA-ST (AUC tau, bss: 3335 +/- 1300 vs 2667 +/- 1155 ng.h/ml, P = 0.0073; AUC tau, bss ratio 1.26 +/- 0.40 vs 1.0 as reference, P < 0.05), with higher and earlier peak blood concentrations (Cmax: 677 +/- 256 vs 475 +/- 213 ng/ml, P = 0.0329; tmax: 1.5 +/- 0.7 vs 2.6 +/- 1.6 h, P = 0.0720). The pharmacokinetic profile of CyA-NF showed greater between-patient reproducibility (lower CV% for all of the considered parameters). In conclusion, when using CyA-NF instead of CyA-ST, greater and more constant exposure to CyA should be expected.


Non-activation MOF arrays as a coating layer to fabricate a stable superhydrophobic micro/nano flower-like architecture.
Non-activation metal-organic framework (MOF) arrays are directly applied as a coating layer to fabricate a stable superhydrophobic micro/nano flower-like architecture. The MOF functionalized surfaces can be synthesized easily on different substrates without any activation procedure or modification by low free energy materials, which exhibit attractive performance in oil/water separation.


Performance of the classification criteria in patients with late-onset axial spondyloarthritis.
To evaluate the performance of four different classification criteria for spondyloarthritis (SpA) in patients with late-onset symptoms and to compare the clinical, laboratory and radiographic outcomes among the patients with symptoms before and after 45 years of age. A total of 329 patients with SpA were enrolled in this prospective cohort. Patients with psoriatic arthritis, reactive arthritis, colitis associated arthritis and peripheral or undifferentiated SpA were excluded. The remaining individuals were divided into two groups based on their ages at the time of onset of symptoms: from 16 to 45 years of age (adult-onset, A-O) and after 45 years of age (late-onset, L-O). The clinical data were collected, including BASDAI, BASFI, BASMI, mSASSS, ASDAS, as were concomitant diseases and medications, efficacy and safety data. The performance of four SpA classification criteria, including modified New York, ESSG, Amor and ASAS, was evaluated in both groups. p value <.05 was considered as significant. Thirty-two patients (9.72%) had L-O axial SpA. Mean age of diagnosis and symptoms were 57.6 (8.0) years and 7.6 (5.1) years, respectively. L-O patients had statistically worse functional impairment and higher disease activity. However, they had lower radiographic sacroiliac and spine damage (p < .001). Our data showed that almost 10% of the patients with SpA had late-onset of symptoms. Moreover, they had higher disease activity, worse physical function and lower spine radiographic damage than A-O SpA patients. Additionally, the ASAS classification criteria had the best performance and might be used in clinical practice.


Association Between Body Mass Index and Results of Rehabilitation in Patients After Stroke: A 3-Month Observational Follow-Up Study.
BACKGROUND We assessed the relationship between body mass index and results of rehabilitation in stroke patients. MATERIAL AND METHODS The study was carried out at the Clinical Rehabilitation Ward with Early Neurological Rehabilitation Unit at the Clinical Hospital. The examinations were performed 3 times. Based on inclusion and exclusion criteria, 128 subjects were qualified for the first examination, the second examination involved 114 subjects, and 100 stroke patients participated in the third examination. Body mass was examined with an accuracy of 0.1 kg, using a Tanita MC-780 MA body composition analyser. Body mass index (BMI) was calculated for all of the subjects. Effects of rehabilitation were assessed with the Barthel index and Ashworth scale. RESULTS Higher functional status in daily life, measured with the Barthel scale, was found in patients with normal body mass, compared to the overweight and obese subjects (examination I, II, and II). Exam I showed that before rehabilitation the overweight patients obtained significantly higher results in assessment of upper limbs, based on the Ashworth scale (mean=0.35±0.54) compared to the obese patients (mean=0.03±0.32) and those with normal body weight (mean=0.24±0.75). CONCLUSIONS Following hospital-based rehabilitation, patients with normal body mass achieved greater functional efficiency. The findings also show a trend towards normalization of BMI. The positive effect of rehabilitation was sustained for 3 months (Exam III), which may contribute to decreased risk of cardiovascular diseases and complications such as stroke.


Metformin: actions and indications for use in non-insulin-dependent diabetes mellitus.
Metformin (N,N-dimethylbiguanide) is about to be introduced into the United States. The drug, a potent blood glucose-lowering agent, is rapidly absorbed through the small intestine, has a circulating t 1/2 in plasma of 1.7 to 2.5 hours, and is 90% cleared through the kidneys in 12 hours. The drug does not cause hypoglycemia in nondiabetic patients and is effective in both obese and nonobese patients with non-insulin-dependent diabetes mellitus (NIDDM). The drug does not act through stimulation of endogenous insulin secretion. It seems to act at multiple sites, with a small effect on the inhibition of intestinal glucose transport, a moderate effect on inhibition of hepatic glucose output, and a major effect on enhancement of peripheral glucose uptake by muscle and adipose tissues. In addition to its glucose-lowering potency, metformin causes weight loss in obese patients with NIDDM and lowers total cholesterol, very-low-density lipoprotein cholesterol, total triglycerides, and very-low-density lipoprotein triglyceride levels as well as causing an increase in high-density lipoprotein cholesterol level. The drug is ideally suited for obese patients with NIDDM who are unresponsive to diet alone, and it is effective in combination with sulfonylureas. The major risk associated with use of metformin is the development of lactic acidosis. Patients predisposed toward the development of lactic acidosis are those with hepatic or renal disease or with tissue ischemia, in whom the drug should not be prescribed.


Effect of hyposalivation on mastication and mandibular movements during speech.
The aim of this study was to evaluate whether patients with hyposalivation present damaged mastication or mandibular movements during speech. Forty subjects composed 2 groups: control and hyposalivation. Masticatory performance was assessed with a silicon-based artificial material and a 10-sieve method. Mandibular movements during speech were observed with a 3D jaw-tracking device. Data were analyzed with Student's t-test or the Mann-Whitney method (P < 0.05). The masticatory performance (mm) of control and hyposalivation were 4.40 ± 0.62 and 4.74 ± 1.34, respectively. Outcomes for speech movements (mm) were as follows: maximum vertical opening amplitude (10.8 ± 4.2; 9.9 ± 2.7) and displacements to the right (1.0 ± 0.8; 0.5 ± 0.6), left (1.8 ± 1.4; 2.3 ± 1.2), or anterior-posterior (2.8 ± 1.1; 2.9 ± 1.0) for control and hyposalivation, respectively. No statistical difference was found between groups for any variable. The results indicated that hyposalivation did not affect masticatory performance or mandibular movements during speech.


Surface Characteristics and Biofilm Development on Selected Dental Ceramic Materials.
Intraoral adjustment and polishing of dental ceramics often affect their surface characteristics, promoting increased roughness and consequent biofilm growth. This study correlated surface roughness to biofilm development with four commercially available ceramic materials. Four ceramic materials (Vita Enamic®, Lava™ Ultimate, Vitablocs Mark II, and Wieland Reflex®) were prepared as per manufacturer instructions. Seventeen specimens of each material were adjusted and polished to simulate clinical intraoral procedures and another seventeen remained unaltered. Specimens were analysed by SEM imaging, confocal microscopy, and crystal violet assay. SEM images showed more irregular surface topography in adjusted specimens than their respective controls. Surface roughness (Ra ) values were greater in all materials following adjustments. All adjusted materials with the exception of Vitablocs Mark II promoted significantly greater biofilm growth relative to controls. Simulated intraoral polishing methods resulted in greater surface roughness and increased biofilm accumulation.


Factors affecting the location and shape of face seal leak sites on half-mask respirators.
While there have been a number of studies on the effect of leak site and shape on the magnitude of measured leakage through respirator face seals, there have been very few studies to identify the location and size of these leaks. In a previous study we used a method of identifying the location and shape of respirator leaks on a half-mask respirator by the deposition of a fluorescent tracer during a fit test, and testing for their association with facial dimensions. The purpose of this study was to apply that methodology to conduct multiple fit tests to determine if gender, respirator brand, repeated fit tests, and test exercises affected the location and shape of face seal leak sites. Categorical analysis found that none of these factors had a significant effect on the location and shape of leaks. General linear model analysis found some significant effects of the study factors on leaks, but facial dimensions had a greater effect, and there were significant differences between facial dimensions of subjects with a leak and those without. Significant differences in leak site distributions between this and the previous study may have been due to differences in facial dimensions and racial/ethnic composition. Twice as many diffuse leaks as point leaks were observed in both studies, indicating that slit-like leaks would be most appropriate on mannequins used in laboratory respirator leakage studies, and in respirator flow and penetration models. That the study factors had no significant effects in the categorical analysis, significant effects for facial dimensions were found in the linear analysis, and leak site distribution differences between this and our previous study may have been affected by differences in facial dimensions, indicate that, in addition to size, the shape of an individual's face may be an important determinant of leak sites on a half-mask respirator. This would have implications for the design of respirator facepieces and in the selection of respirators for individual wearers.


Minimal in situ conjunctival incision for segmental scleral buckling surgery.
To introduce a modified technique for minimal segmental buckling through a small in situ conjunctival opening for minimally invasive repair of uncomplicated rhegmatogenous retinal detachment. This technique was performed in 46 eyes of 46 patients with primary retinal detachment. Transconjunctival traction sutures were placed in four rectus muscles after retrobulbar anesthesia was administered. After transconjunctival location of the retinal break, a 5- to 6-mm radial conjunctival incision was performed corresponding to the retinal break without cutting the limbal conjunctiva-Tenon's capsule. After cryopexy, a minimal explant was fixed with one to two sutures through the conjunctival opening, expanded by a pediatric speculum. The incision was closed via layered closure. Retinal reattachments were achieved with correct buckle positions in all 46 cases, with rapid cosmetic recovery. This modified minimal segmental buckling technique simplifies the buckling procedure, minimizes surgical invasiveness, and preserves an intact limbal conjunctiva.


Switchable three-state fluorescence of a nonconjugated donor-acceptor triarylborane.
A nonconjugated fluorescent molecule with a triarylboron acceptor and an alkylamine donor has been found to display bright green fluorescence due to charge transfer through space, which can be reversibly deactivated by blocking either the donor or acceptor site. Binding of the fluoride ion to boron switches the fluorescence color to sky blue, while protonation of the amine with acid switches the emission color to the purple fluorescence of the acceptor chromophore.


[Diagnosis of strangulated Spiegel hernia based on CT scan: about a case].
We report a case of a 86-year old woman with Spiegel hernia complicated by occlusion whose diagnosis was based on CT scan. She was examined in the Emergency Surgery Department for brutal onset of pain in the right iliac fossa associated with vomiting. On physical examination the patient was febrile (38.2° C). It showed hard, sensitive and mobile mass located in the right iliac fossa, with respect to both planes. Abdominal CT scan showed a hernia sac with the neck measuring 13 mm in the right iliac fossa, in front of the aponeurosis of the external oblique muscle. It contained fat and a small bowel loop (curved arrow) with two zones of transition giving a double beak-like appearance at the level of the neck. CT scan showed a lack of enhancement of the wall of the loop after administration of contrast material. The diagnosis of strangulated spiegel hernia associated with sign of arterial ischemia of the digestive wall was retained. Surgery was perfomed with simple postoperative management.


DNA Structural Correlation in Short and Long Ranges.
Recent single-molecule measurements have revealed the DNA allostery in protein/DNA binding. MD simulations showed that this allosteric effect is associated with the deformation properties of DNA. In this study, we used MD simulations to further investigate the mechanism of DNA structural correlation, its dependence on DNA sequence, and the chemical modification of the bases. Besides a random sequence, poly d(AT) and poly d(GC) are also used as simpler model systems, which show the different bending and twisting flexibilities. The base-stacking interactions and the methyl group on the 5-carbon site of thymine causes local structures and flexibility to be very different for the two model systems, which further lead to obviously different tendencies of the conformational deformations, including the long-range allosteric effects.


Relation of High-Sensitivity Cardiac Troponin I and Obstructive Coronary Artery Disease in Patients Without Acute Myocardial Infarction.
The relation of high-sensitivity cardiac troponin I (hs-cTnI) concentration and presence of obstructive coronary artery disease (CAD) in patients without myocardial infarction (MI) is unclear. Study participants selected from patients free of MI who underwent coronary angiography with or without intervention were enrolled, and hs-cTnI measured. A gradient boosting model was implemented to build a model for detection of CAD. Cox proportional hazard regression was used to assess the association of hs-cTnI and adverse cardiovascular (CV) outcome. Among 978 study participants, 607 patients (62%) had CAD. Higher concentrations of hs-cTnI were associated with chronic kidney disease, heart failure, CAD, male gender, current tobacco use, anemia, age, and low-density lipoprotein cholesterol. History of CAD, male gender, type 2 diabetes mellitus, hs-cTnI, anemia, age, and high-density lipoprotein cholesterol were the most influential factors for detection of CAD. The gradient boosting model had an area under the curve of 0.82, accuracy of 75%, sensitivity of 88%, specificity of 52%, positive predictive value of 76%, and negative predictive value of 72% for detection of CAD. Increase in 1 log unit of hs-cTnI was significantly associated with increased risk of incident MI (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.22 to 1.47, p <0.001), CV mortality (HR 1. 24, 95% CI 1.11 to 1.39, p <0.001), and composite of incident MI or CV mortality (HR 1.29, 95% CI 1.20 to 1.40, p <0.001). In conclusion, among patients without acute MI and CAD, higher concentrations of hs-cTnI were associated with the presence of CAD and linked to increased risk of future CV events. ClinicalTrials.gov Identifier: NCT00842868.


Surge of dengue virus infection and chikungunya Fever in bali in 2010: the burden of mosquito-borne infectious diseases in a tourist destination.
Labor flow and travelers are important factors contributing to the spread of Dengue virus infection and chikungunya fever. Bali Province of Indonesia, a popular resort and tourist destination, has these factors and suffers from mosquito-borne infectious diseases. Using area study approach, a series of fieldwork was conducted in Bali to obtain up-to-date primary disease data, to learn more about public health measures, and to interview health officers, hotel personnel, and other resource persons. The national data including information on two other provinces were obtained for comparison. The health ministry reported 5,810 and 11,697 cases of dengue hemorrhagic fever in Bali in 2009 and 2010, respectively. Moreover, two densely populated tourist areas and one district have shown a particularly high incidence and sharp increases in 2010. Cases of chikungunya fever reported in Bali more than doubled in 2010 from the previous year. Our findings suggest that Bali can benefit from a significant reduction in vector populations and dissemination of disease preventive knowledge among both local residents and foreign visitors. This will require a concerted and trans-border approach, which may prove difficult in the province.


Relationships between Exciton Dissociation and Slow Recombination within ZnSe/CdS and CdSe/CdS Dot-in-Rod Heterostructures.
Type-II and quasi type-II heterostructure nanocrystals are known to exhibit extended excited-state lifetimes compared to their single material counterparts because of reduced wave function overlap between the electron and hole. However, due to fast and efficient hole trapping and nonuniform morphologies, the photophysics of dot-in-rod heterostructures are more rich and complex than this simple picture. Using transient absorption spectroscopy, we observe that the behavior of electrons in the CdS "rod" or "bulb" regions of nonuniform ZnSe/CdS and CdSe/CdS dot-in-rods is similar regardless of the "dot" material, which supports previous work demonstrating that hole trapping and particle morphology drive electron dynamics. Furthermore, we show that the longest lived state in these dot-in-rods is not generated by the type-II or quasi type-II band alignment between the dot and the rod, but rather by electron-hole dissociation that occurs due to fast hole trapping in the CdS rod and electron localization to the bulb. We propose that specific variations in particle morphology and surface chemistry determine the mechanism and efficiency of charge separation and recombination in these nanostructures, and therefore impact their excited-state dynamics to a greater extent than the heterostructure energy level alignment alone.


Online resources on 2009 pandemic influenza for clinicians.
Numerous resources relevant to the 2009 pandemic influenza are available on-line . A casual search in google using the phrase "swine flu resources" yields 9,180,000 items making a time-bound search less fruitful for an average health care professional. This review has summarized the contents useful to practicing clinician available in 12 websites which were selected based on their relevance to clinical care.


Treatment of collagen-induced arthritis with an anti-osteopontin monoclonal antibody through promotion of apoptosis of both murine and human activated T cells.
To test the effects of a novel monoclonal antibody (mAb) against human osteopontin (OPN) in the prevention and treatment of collagen-induced arthritis (CIA) and to elucidate the underlying mechanisms of these effects. DBA/1J mice immunized with type II collagen to induce CIA were monitored to assess the effects of anti-OPN mAb on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. The effects of anti-OPN mAb on survival of activated T cells from arthritic mice and from the synovial fluid of patients with rheumatoid arthritis (RA) were determined by TUNEL assay or annexin V assay. The levels of apoptosis-related proteins (Bim, Bax, and Bcl-2) and NF-kappaB were detected by immunoblot analysis. One anti-OPN mAb, 23C3, was effective in inhibiting the development of CIA and even reversing established disease in DBA/1J mice. Monoclonal antibody 23C3 reduced the levels of serum type II collagen-specific autoantibodies and proinflammatory cytokines, and suppressed T cell recall responses to type II collagen. Mechanistic studies demonstrated that OPN prevented the death of type II collagen-activated murine T cells and synovial T cells from RA patients. Monoclonal antibody 23C3 promoted apoptosis of the activated T cells, particularly CD4+ T cells, by inhibiting activation of NF-kappaB and by altering the balance among the proapoptotic proteins Bim and Bax and the antiapoptotic protein Bcl-2. Screening of a phage display peptide library led to identification of the epitope ATWLNPDPSQKQ as being recognized by this novel antibody. Because of its ability to effectively promote apoptosis of activated T cells, mAb 23C3 may be a novel therapeutic agent for the treatment of RA.


Gene signatures distinguish stage-specific prostate cancer stem cells isolated from transgenic adenocarcinoma of the mouse prostate lesions and predict the malignancy of human tumors.
The relevant social and economic impact of prostate adenocarcinoma, one of the leading causes of death in men, urges critical improvements in knowledge of the pathogenesis and cure of this disease. These can also be achieved by implementing in vitro and in vivo preclinical models by taking advantage of prostate cancer stem cells (PCSCs). The best-characterized mouse model of prostate cancer is the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice develop a progressive lesion called prostatic intraepithelial neoplasia that evolves into adenocarcinoma (AD) between 24 and 30 weeks of age. ADs often metastasize to lymph nodes, lung, bones, and kidneys. Eventually, approximately 5% of the mice develop an androgen-independent neuroendocrine adenocarcinoma. Here we report the establishment of long-term self-renewing PCSC lines from the different stages of TRAMP progression by application of the neurosphere assay. Stage-specific prostate cell lines were endowed with the critical features expected from malignant bona fide cancer stem cells, namely, self-renewal, multipotency, and tumorigenicity. Notably, transcriptome analysis of stage-specific PCSCs resulted in the generation of well-defined, meaningful gene signatures, which identify distinct stages of human tumor progression. As such, TRAMP-derived PCSCs represent a novel and valuable preclinical model for elucidating the pathogenetic mechanisms leading to prostate adenocarcinoma and for the identification of molecular mediators to be pursued as therapeutic targets.


Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15.
To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance. Patients with high-risk localized prostate cancer (tumor-node-metastasis >or= T(2b) or prostate-specific antigen >or= 15 ng/mL or Gleason glade >or= 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done. Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1beta. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone. Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-kappaB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.


Angiotensin II decreases glucose uptake by downregulation of GLUT1 in the cell membrane of the vascular smooth muscle cell line A10.
Recent evidence suggests a crosstalk between angiotensin II (Ang II) and insulin. However, whether this crosstalk affects glucose uptake, particularly in terms of actin filament involvement, has not yet been studied in vascular smooth muscle cells. Pretreatment of cells with either Ang II or cytochalasin D disarranged actin filaments in a time-dependent manner and inhibited glucose uptake. However, insulin increased actin reorganization and glucose uptake. Membrane fractionation studies showed that Ang II decreased GLUT-1 at the cell membrane, whereas it increased GLUT-1 in the cytoplasm, indicating that Ang II may cause internalization of GLUT-1 via actin disorganization, consequently decreasing glucose uptake. The effects of Ang II on glucose uptake and actin reorganization were blocked by AT1 receptor antagonist, but not by AT2 antagonist. Either P38 or ERK1/2 inhibitors partially reversed the Ang II-inhibited actin reorganization and glucose uptake, suggesting that MAPK signaling pathways could be involved as downstream events in Ang II signaling, and this signaling may interfere with insulin-induced actin reorganization and glucose uptake. These data imply that Ang II induces insulin resistance by decreasing glucose uptake via disarrangement of actin filaments, which provides a novel insight into understanding of insulin resistance by Ang II at the molecular level.


Post-Pancreaticoduodenectomy Outcomes and Epidural Analgesia: A 5-year Single-Institution Experience.
Optimal pain control post pancreaticoduodenectomy is a challenge. Epidural analgesia (EDA) is used increasingly, despite inherent risks and unclear effects on outcomes. All pancreaticoduodenectomies (PDs) performed from January 2013 through December 2017 were included. Clinical parameters were obtained from a retrospective review of a prospective clinical database, the American College of Surgeons NSQIP prospective institutional database, and medical record review. Chi-square, Fisher's exact test, and independent-samples t-tests were used for univariable analyses. Multivariable regression was performed. Six hundred and seventy-one consecutive PDs from a single institution were included (429 EDA, 242 non-EDA). On univariable analysis, EDA patients experienced significantly less wound disruption (0.2% vs 2.1%), unplanned intubation (3.0% vs 7.9%), pulmonary embolism (0.5% vs 2.5%), mechanical ventilation longer than 48 hours (2.1% vs 7.9%), septic shock (2.6% vs 5.8%), and lower pain scores. On multivariable regression (accounting for baseline group differences (ie sex, hypertension, preoperative transfusion, laboratory results, approach, and pancreatic duct size), EDA was associated with less superficial wound infections (odds ratio [OR] 0.34; 95% CI 0.14 to 0.83; p = 0.017), unplanned intubations (OR 0.36; 95% CI 0.14 to 0.88; p = 0.024), mechanical ventilation longer than 48 hours (OR 0.22; 95% CI 0.08 to 0.62; p = 0.004), and septic shock (OR 0.39; 95% CI 0.15 to 1.00; p = 0.050). Epidural analgesia improved pain scores post-PD days 1 to 3 (p < 0.001). No differences were seen in cardiac or renal complications; pancreatic fistula (B+C) or delayed gastric emptying, 30-/90-day mortality, length of stay, readmission, discharge destination, or unplanned reoperation. Based on the largest single-institution series published to date, our data support the use of EDA for optimization of pain control. More importantly, our data document that EDA improved infectious and pulmonary complications significantly.


An end-user's guide to the HEART score and pathway.
Chest pain accounts for a significant percentage of emergency department (ED) presentations. The HEART score and pathway have demonstrated an ability to appropriately risk stratify and discharge from the ED a significant proportion of patients. This review evaluates vital components of the HEART score and pathway, while discussing important considerations for current and future use. Chest pain is a common ED presentation, and several conditions associated with chest pain result in patient morbidity and mortality. One major disease is acute coronary syndrome (ACS). Despite the fear associated with this disease, it accounts for a minority of patients with chest pain in the ED. Emergency physicians rarely miss myocardial infarction (MI) or ACS, with miss rates<1%. Many have sought a score and pathway that allow physicians to safely and reliably risk stratify patients. The HEART score and pathway have revolutionized chest pain evaluation, as they can risk stratify a significant number of patients accurately into separate categories based on history, electrocardiogram (ECG), troponin, age, and risk factors while displaying high sensitivity for MACE. Several intricacies must be considered in the use of this score including risk factors, ECG, troponin, age, history, gestalt, follow up, borderline score, and shared decision making. The HEART pathway can supplement clinician decision making. Appropriate use of the HEART pathway reliably risk stratifies patients. Physicians must consider several key components when utilizing the HEART pathway, and future directions may incorporate other patient factors.


Detection of ultratrace phosphorus and sulfur by quadrupole ICPMS with dynamic reaction cell.
A method of detection of ultratrace phosphorus and sulfur that uses reaction with O2 in a dynamic reaction cell (DRC) to oxidize S+ and P+ to allow their detection as SO+ and PO+ is described. The method reduces the effect of polyatomic isobaric interferences at m/z = 31 and 32 by detecting P+ and S+ as the product oxide ions that are less interfered. Use of an axial field in the DRC improves transmission of the product oxide ions 4-6 times. With no axial field, detection limits (3sigma, 5-s integration) of 0.20 and 0.52 ng/mL, with background equivalent concentrations of 0.53 and 4.8 ng/mL, respectively, are achieved. At an optimum axial field potential (200 V), the detection limits are 0.06 ng/mL for P and 0.2 ng/mL for S, respectively. The method is used for determining the degree of phosphorylation of beta-casein, and regular and dephosphorylated alpha-caseins at 10-1000 fmol/microL concentration, with 5-10% v/v organic sample matrix (acetonitrile, formic acid, ammonium bicarbonate). The measured degree of phosphorylation for beta-casein (4.9 phosphorus atoms/molecule) and regular alpha-casein (8.8 phoshorus atoms/molecule) are in good agreement with the structural data for the proteins. The P/S ratio for regular alpha-casein (1.58) is in good agreement with the ratio of the number of phosphorylation sites to the number of sulfur-containing amino acid residues cysteine and methionine. The P/S ratio for commercially available dephosphorylated alpha-casein is measured at 0.41 (approximately 26% residual phosphate).


Role of magnesium alone or in combination with diltiazem and/or amiodarone in prevention of atrial fibrillation following off-pump coronary artery bypass grafting.
In this study the authors have tried to examine the role of magnesium alone or in combination with diltiazem and / or amiodarone in prevention of atrial fibrillation (AF) following off-pump coronary artery bypass grafting (CABG). AF after CABG is common and contributes to morbidity and mortality. Various pharmacological preventive measures including magnesium, amiodarone, diltiazem, and combination therapy among others have been tried to lower the incidence of AF. Most of the studies have been performed in patients undergoing conventional on-pump CABG. In this uncontrolled trial, efficacy of magnesium alone or in combination with amiodarone and / or diltiazem has been studied in patients undergoing off-pump CABG. One hundred and fifty patients undergoing off-pump CABG were divided into 3 groups, Group M (n=21) received intraoperative magnesium infusion at 30mg/ kg over 1 hour after midline sternotomy; Group MD (n=78) received magnesium infusion in similar manner with diltiazem infusion at 0.05 μg/kg/hr throughout the intraoperative period; Group AMD (n=51) received preoperative oral amiodarone at a dose of 200 mg three times a day for 3 days followed by 200 mg twice daily for another 3 days followed by 200 mg once daily till the day of surgery along with magnesium and diltiazem infusion as in other groups. AF lasting more than 10 min or requiring medical intervention was considered as AF. The overall incidence of postoperative AF was 12.6% with 11.7% in group AMD, 19% in group M, and 11.5% in group MD, which was not statistically significant. It is concluded that the use of amiodarone and/or diltiazem in addition to magnesium did not result in additional benefit of lowering the incidence of AF.


Changing attitudes in dementia care and the role of nurses.
Dementia care has been seen as a low priority, but with an estimated 700,000 people in the UK with dementia and an ageing population this is changing. The Alzheimer's Society will be holding events this week to raise awareness of dementia, sending a strong message to policy makers that dementia is a serious health issue. Nurses have also become active in fighting the old degenerative model of dementia and promoting the concept of person-centred care.


Conoidecyclics A-C from marine macroalga Turbinaria conoides: Newly described natural macrolides with prospective bioactive properties.
Intertidal marine brown alga Turbinaria conoides (J.Agardh) Kützing (family Sargassaceae) is considered as one of the largely abundant species, available in the coastal zones of the Indian subcontinent. Bioactivity-guided chromatographic fractionation of the organic extract of T. conoides resulted in three previously undescribed macrocyclic lactone homologues, named as conoidecyclics A-C. Conoidecyclic A displayed greater attenuation potential against cyclooxygenase-2 (IC50 1.75 mM) and 5-lipoxygenase (IC50 4.24 mM) in comparison with other analogues. Conoidecyclic A exhibited higher attenuation potential against 5-lipoxygenase than that displayed by an anti-inflammatory agent, ibuprofen (IC50 4.51 mM). The higher selectivity index of conoidecyclic A (1.79) recognized its selective attenuation potential against the inducible cyclooxygenase-2 enzyme. Inhibition potential of conoidecyclic A against angiotensin converting enzyme-I (IC50 1.23 mM) and protein tyrosine phosphatase-1B (IC50 1.39 mM) were non-competitive, as deduced by kinetic studies. In-silico molecular modeling study of conoidecyclic A with the allosteric sites of the targeted enzymes exhibited least binding energy of -14.51 to -11.27 kcal mol-1 compared to those exhibited by other studied macrolide homologues. Reaction kinetic studies of conoidecyclic A coupled with lesser apparent Vmax inferred that it could efficiently bind with the allosteric site of targeted enzymes in a non-competitive manner to diminish the reaction velocity resulting in enzyme inhibition. Drug-likeness and predictive pharmacokinetic parameters of conoidecyclic A exhibited an acceptable oral bioavailability. These reports inferred that conoidecyclic A encompassing pentacosa macrocyclic moiety could be a promising therapeutic lead to inhibit the enzymes related to the development and progression of pathological conditions leading to inflammation, hypertension and type-2 diabetes.


Exercise-induced bronchoconstriction and exercise-induced respiratory symptoms in nurses.
In order to assess prevalence and characteristics of exercise-induced respiratory symptoms (EIRSs) and exercise-induced bronchoconstriction (EIB) in health care workers, we performed a cross-sectional study including 48 female nurses from primary care settings and an equal number of female office workers studied as a control group. The evaluation of examined groups included completion of a questionnaire, skin prick tests to common inhalant allergens, spirometry, and exercise and histamine challenge. We found a similar prevalence of EIRSs and EIB in both groups. EIB was closely related to asthma, atopy, family history of asthma, and positive histamine challenge in either group, while the association between EIB and daily smoking in nurses was of borderline statistical significance. Bronchial reaction to exercise was significantly higher in nurses than in controls with EIB. With the exception of exercise induced wheezing, EIRSs were weakly associated with EIB in both groups with a large proportion of false positive results.


Furazolidone in chicken: case study of an incident of widespread contamination.
1. Furazolidone, a nitrofuran antibiotic, was prohibited from the use in food-producing animals in the European Union (EU) in 1997. In 2002, the EU restricted the import of poultry meat and aquaculture species from countries where furazolidone residues had been detected. 2. By 2004, however, residues of the side-chain metabolite, 3-amino-2-oxazolidinone (AOZ) of furazolidone, were detected in chicken meat produced in Northern Ireland. 3. With the random spread of positive results across farms of a single integrated organisation, including organically reared flocks, it seemed unlikely that the source of residues was due to illegal use of the drug, but more likely caused by a source of contamination. 4. Potential sources investigated were as follows: furazolidone contamination of feedstuffs, a "hot spot" of furazolidone in poultry houses, contamination occurring within breeding stocks and transferred with the birds to broiler growing houses, and furazolidone contamination of the water supply. 5. Furazolidone contamination was associated with birds reared in houses more than 10 years old. 6. Contamination was traced to the water supply of poultry houses, where un-dissolved furazolidone, legally administered prior to 1997, had settled to the bottom of water storage tanks. It remained un-disturbed until 2004 when the integrator changed the procedure for cleaning water tanks between crops of birds. 7. The use of Proxitane, a hydrogen peroxide disinfectant, caused effervescence within the tank such that small quantities of furazolidone were dissolved, delivered to birds via drinkers and subsequently caused residues in the broiler meat. 8. The environmental impact of the contamination was investigated by testing soil and grass from land adjacent to an organic poultry house to which birds had access. 9. Mechanisms of contamination and how residues may be spread throughout a large integrated poultry system are not restricted to furazolidone. Incidents of contamination are even more likely when using licensed drugs where the drugs may be present on-farm in large quantities.


Implementing services for Early Infant Diagnosis (EID) of HIV: a comparative descriptive analysis of national programs in four countries.
There is a significant increase in survival for HIV-infected children who have early access to diagnosis and treatment. The goal of this multi-country review was to examine when and where HIV-exposed infants and children are being diagnosed, and whether the EID service is being maximally utilized to improve health outcomes for HIV-exposed children. In four countries across Africa and Asia existing documents and data were reviewed and key informant interviews were conducted. EID testing data was gathered from the central testing laboratories and was then complemented by health facility level data extraction which took place using a standardized and validated questionnaire In the four countries reviewed from 2006 to 2009 EID sample volumes rose dramatically to an average of >100 samples per quarter in Cambodia and Senegal, >7,000 samples per quarter in Uganda, and >2,000 samples per quarter in Namibia. Geographic coverage of sites also rapidly expanded to 525 sites in Uganda, 205 in Namibia, 48 in Senegal, and 26 in Cambodia in 2009. However, only a small proportion of testing was done at lower-level health facilities: in Uganda Health Center IIs and IIIs comprised 47% of the EID collection sites, but only 11% of the total tests, and in Namibia 15% of EID sites collected >93% of all samples. In all countries except for Namibia, more than 50% of the EID testing was done after 2 months of age. Few sites had robust referral mechanisms between EID and ART. In a sub-sample of children, we noted significant attrition of infants along the continuum of care post testing. Only 22% (Senegal), 37% (Uganda), and 38% (Cambodia) of infants testing positive by PCR were subsequently initiated onto treatment. In Namibia, which had almost universal EID coverage, more than 70% of PCR-positive infants initiated ART in 2008. While EID testing has expanded dramatically, a large proportion of PCR- positive infants are initiated on treatment. As EID services continue to scale-up, more programmatic attention and support is needed to retain HIV-exposed infants in care and ensure that those testing positive initiate treatment in a timely manner. Namibia's experience demonstrates that it is feasible for a rural, low-income country to achieve high national coverage of infant testing and treatment.


Excited state tautomerization of azaindole.
Fluorescent tryptophan analogs, like azatryptophan, offer an advantage for exploring protein and peptide structure and dynamics. The chromophoric moieties, azaindole, of the azatryptophan analogs are investigated for their potential as fluorescent probes. The photophysical properties of 4-azaindole (4AI) and 5-azaindole (5AI) and their tautomers are characterized through computational and experimental methods. Both 4AI and 5AI undergo excited state tautomerization in the presence of 1 M NaOH. The protonated forms of 4AI and 5AI have a fluorescence emission of 415 and 410 nm, respectively, while the tautomers of 4AI and 5AI have a fluorescent emission of 480 and 450 nm, respectively. Gas phase computations (B3LYP/6-31+G**) show that the N1H azaindole tautomer is lower in energy in the ground state by as much as 12.5 kcal mol(-1), while the N(n)H azaindole tautomer is lower in energy in the excited state by as much as 18.1 kcal mol(-1). Solvent effects on the tautomer energy differences were computed using the isodensity polarized continuum model (IPCM). The polarity of the solvent helps to reduce the energy difference between the tautomers in the ground state by as much as 5.8 kcal mol(-1), but not enough to reverse the ground state tautomer preference.


Changes in County-Level Economic Prosperity Are Associated With Liver Disease-Related Mortality Among Working-Age Adults.
There is significant variability in county-level rates of liver disease-related mortality. Although this variability is explained partly by demographics, risk factors for liver disease, and access to specialty liver care, little is known about temporal changes in mortality, and its association with economic prosperity. Therefore, we sought to explore the association between changes in county-level economic prosperity and liver disease-related mortality. We performed a retrospective cohort study using county-level mortality data from the Centers for Disease Control and Prevention, economic prosperity measures from the Distressed Communities Index, and county-level markers of demographics, risk factors for liver disease, and access to health care. Primary analyses focused on adults aged 20 to 64 years of age. We used generalized linear mixed models (outcome = annual percentage change in age-adjusted liver disease-related mortality), with the primary exposure being an interaction between year and change in economic prosperity. There was an inverse relationship between county-level changes in economic prosperity and changes in county-level age-adjusted liver disease-related mortality rates (eg, counties with the smallest increase in economic prosperity had the biggest annual increase in liver disease-related mortality). In generalized linear mixed models accounting for county-level covariates, there was a significant association between economic prosperity and liver disease-related mortality, that is, for every 10-point higher mean rank for change in economic prosperity, there was an additional 0.65% decrease (95% CI, 0.19%-1.10%; P = .006) in mortality per year. County-level changes in economic prosperity, independent of other county-level clinical, demographic, and access-to-care variables, may play a role in population-level trends in liver disease-related deaths among the working age population.


Acute-phase protein haptoglobin is a cell migration factor involved in arterial restructuring.
Collagen turnover and cell migration are fundamental aspects of arterial restructuring. To identify mRNAs involved in blood flow-induced arterial restructuring, we performed subtraction polymerase chain reaction and found expression of haptoglobin mRNA in adventitial fibroblasts of rabbit arteries. Haptoglobin is highly expressed in liver, but its arterial expression and function are unknown. In vitro studies revealed that stimulation of haptoglobin expression by lipopolysaccharides in mice fibroblasts stimulated migration of wild-type fibroblasts but had no effect on migration of haptoglobin knockout fibroblasts. In vivo studies showed that flow-induced arterial restructuring was delayed in haptoglobin knockout mice. This new function of haptoglobin might be explained by facilitating cell migration through accumulation of a temporary gelatin matrix because cell culture showed that haptoglobin is involved in the breakdown of gelatin. We conclude that haptoglobin is highly expressed in arterial tissue and is involved in arterial restructuring. This new haptoglobin function may also apply to other functional and pathological restructuring processes such as angiogenesis, tissue repair, and tumor cell invasion.


An Unusual Presentation of Deep Tissue Injury, Do We Really Understand It? A Case Report and Literature Review
Deep tissue injury (DTI) is an injury to the soft tissue under the skin due to pressure and is usually over boney prominence. This injury is commonly seen in bedridden patients in hospitals and nursing homes. Although many efforts were made to elucidate the precise mechanism and clinical presentation, the pathogenesis and the final clinical outcome are yet to be determined. Although the current agreed upon presentation describes DTI as purple- or maroon-colored skin with ulceration, presented herein is an unusual case where DTI presented with only erythema and induration over the sacrum and right gluteal area.


Identification of hypoglycin A binding adsorbents as potential preventive measures in co-grazers of atypical myopathy affected horses.
Intestinal absorption of hypoglycin A (HGA) and its metabolism are considered major prerequisites for atypical myopathy (AM). The increasing incidence and the high mortality rate of AM urgently necessitate new therapeutic and/or preventative approaches. To identify a substance for oral administration capable of binding HGA in the intestinal lumen and effectively reducing the intestinal absorption of the toxin. Experimental in vitro study. Substances commonly used in equine practice (activated charcoal composition, di-tri-octahedral smectite, mineral oil and activated charcoal) were tested for their binding capacity for HGA using an in vitro incubation method. The substance most effective in binding HGA was subsequently tested for its potential to reduce intestinal HGA absorption. Jejunal tissues of 6 horses were incubated in Ussing chambers to determine mucosal uptake, tissue accumulation, and serosal release of HGA in the presence and absence of the target substance. Potential intestinal metabolism in methylenecyclopropyl acetic acid (MCPA)-conjugates was investigated by analysing their concentrations in samples from the Ussing chambers. Activated charcoal composition and activated charcoal were identified as potent HGA binding substances with dose and pH dependent binding capacity. There was no evidence of intestinal HGA metabolism. Binding capacity of adsorbents was tested in vitro using aqueous solutions, and in vivo factors such as transit time and composition of intestinal content, may affect adsorption capacity after oral administration. For the first time, this study identifies substances capable of reducing HGA intestinal absorption. This might have major implications as a preventive measure in cograzers of AM affected horses but also in horses at an early stage of intoxication.


Activin A induces phosphorylation of Smad2 but not complex formation of Smad2 with Smad4 in human colon cancer cell line HT-29.
Western blotting coupled with immunoprecipitation showed that activin A treatment induced phosphorylation of Smad2 but not complex formation of Smad2/4 in human colon cancer-derived HT-29 cells. Because HT-29 cells expressed neither Smad4 mRNA nor Smad4 protein, it is suggested that deletion of Smad4 leads to a defect of formation of Smad2/4 complex upon activin A stimulation in HT-29 cells.


Lay educators shore up diabetes DM efforts in Hispanic communities.
Diabetes impacts Hispanics at twice the rate of Caucasians, and traditional DM efforts are not adequately reaching this fast-growing minority group. However, a novel approach that makes use of 'lay educators' is showing promise at a number of sites across the country. And developers suggest that the model may have potential use in other minority groups as well.


The effect of alcohol intake and the use of oral corticosteroids on the risk of idiopathic osteonecrosis of the femoral head: a case-control study in Japan.
The systemic use of steroids and habitual alcohol intake are two major causative factors in the development of idiopathic osteonecrosis of the femoral head (ONFH). To examine any interaction between oral corticosteroid use and alcohol intake on the risk of ONFH, we conducted a hospital-based case-control study of 71 cases with ONFH (mean age 45 years (20 to 79)) and 227 matched controls (mean age 47 years (18 to 79)). Alcohol intake was positively associated with ONFH among all subjects: the adjusted odds ratio (OR) of subjects with ≥ 3032 drink-years was 3.93 (95% confidence interval (CI) 1.18 to 13.1) compared with never-drinkers. When stratified by steroid use, the OR of such drinkers was 11.1 (95% CI 1.30 to 95.5) among those who had never used steroids, but 1.10 (95% CI 0.21 to 4.79) among those who had. When we assessed any interaction based on a two-by-two table of alcohol and steroid use, the OR of those non-drinkers who did use steroids was markedly elevated (OR 31.5) compared with users of neither. However, no further increase in OR was noted for the effect of using both (OR 31.6). We detected neither a multiplicative nor an additive interaction (p for multiplicative interaction 0.19; synergy index 0.95), suggesting that the added effect of alcohol may be trivial compared with the overwhelming effect of steroids in the development of ONFH.


Development of a novel microplate for high-throughput screening and optimization of DHA producing strains based on CFD technology.
Microtiter plates are suitable for screening and process development of most microorganisms. They are currently the container of choice for high-throughput and small-scale microbial culture, but require optimization for specific work. In this research, a novel type of microtiter plate was developed using computational fluid dynamics (CFD) technology. The new plate provided high oxygen supply and optimal mixing effects for the fermentation culture of docosahexaenoic acid (DHA) producing strains, surpassing the conventional method of strain screening with shake flasks, which was insufficient. The shape of the microtiter plate was modified, and baffles were introduced to improve mass transfer and oxygen supply effects in the vibrating bioreactor. CFD technology was used to model the new plate's characteristics, establishing the superiority of hexagonal microtiter plates with six baffles. Parameters in the incubation process, such as vibration frequency and liquid load, were optimized, and the final result achieved an oxygen transfer coefficient (KL a) of 0.61 s-1 and a volume power input of 2364 w m-3 , which was four to five times better than the original 96-well plate. The culture results optimized by the model were also verified. Therefore, this new microtiter plate provides a powerful tool for future high-throughput screening of strains.


Granulocyte colony-stimulating factor and interleukin-6-producing lung cancer cell line, LCAM.
We describe a case of granulocyte colony-stimulating factor (GCSF) and interleukin-6 (IL-6)-producing lung cancer. A 53-year-old man underwent left upper lobectomy under diagnosis of lung cancer. The tumor obtained by a preoperative biopsy was analyzed. Preoperative data showed leukocytosis with left-shift of leukocytic morphology and thrombocytosis and an elevated serum GCSF level. Histological examination revealed poorly differentiated adenocarcinoma. A cell line, named LCAM, was established from the tumor and the cytokines in the culture medium were measured by enzyme immunoassay. GCSF and IL-6 were produced in large amounts by LCAM, but granulocyte-macrophage colony-stimulating factor (GMCSF) and interleukin-3 (IL-3) were not. A proportion of LCAM expressed GCSF receptor on the cell surface, but IL-6 receptor could not be detected. LCAM proliferation was inhibited in the culture with antihuman GCSF antibody in a dose-dependent manner. We suggest that LCAM proliferation is positively regulated by GCSF.


Utility and direct costs: ankylosing spondylitis compared with rheumatoid arthritis.
To compare utility and disease-specific direct costs between patients with ankylosing spondylitis (AS) and patients with rheumatoid arthritis (RA) in the Netherlands. Patients with AS and those with RA completed questions on disease characteristics, the EuroQol-5D (EQ-5D) to assess utility, and questionnaire resource utilisation. Resource utilisation was assessed prospectively in AS, but retrospectively in RA. True cost estimates (2003) were used to calculate the costs. Differences in disease characteristics between AS and RA were described, and determinants of EQ-5D utility and costs were explored by Cox proportional hazard regressions. 576 patients with RA and 132 with AS completed the questionnaires. EQ-5D utility (0.63 vs 0.7) was lower, and annual direct costs higher in RA (euro5167 vs euro2574). In multivariate Cox proportional hazard regressions, there was no difference in utility between the diagnostic groups, but patients with RA incurred higher direct costs after controlling for age, gender and disease duration. In patients with RA and patients with AS, who are under the care of a rheumatologist, utility is equally reduced, but healthcare costs are higher in RA after controlling for age, gender and disease duration. These data can be helpful to provide insights into the differences and similarities between the healthcare needs of both patient groups and to identify issues for further research and for policy in healthcare organisations.


Increased drinking following social isolation rearing: implications for polydipsia associated with schizophrenia.
Primary polydipsia, excessive drinking without known medical cause, is especially associated with a diagnosis of schizophrenia. We used animal models of schizophrenia-like symptoms to examine the effects on schedule-induced polydipsia: post-weaning social isolation rearing, subchronic MK-801 treatment (an NMDA-receptor antagonist) or the two combined. Male, Sprague-Dawley rats reared in groups or in isolation beginning at postnatal day 21 were further divided to receive subchronic MK-801 (0.5 mg/kg twice daily) or saline for 7 days beginning on postnatal day 62. Following a 4-day withdrawal period, all groups were trained on a schedule-induced polydipsia paradigm. Under food-restriction, animals reared in isolation and receiving food pellets at 1-min intervals developed significantly more drinking behavior than those reared with others. The addition of subchronic MK-801 treatment did not significantly augment the amount of water consumed. These findings suggest a predisposition to polydipsia is a schizophrenia-like behavioral effect of post-weaning social isolation.


Changes in cell surface hydrophobicity of Myxococcus xanthus are correlated with sporulation-related events in the developmental program.
Cell surface hydrophobicity was measured in the bacterium Myxococcus xanthus during vegetative growth, fruiting body formation, and glycerol-induced spore formation by the method of Rosenberg et al. (FEMS Microbiol. Lett. 9:29-33, 1980). A significant decrease in cell surface hydrophobicity was observed 12 to 36 h after fruiting body formation and 60 to 120 min after glycerol-induced sporulation. The hydrophilic shift was correlated with the ability of the cells to sporulate but not with their ability to aggregate. Sucrose gradient purification removed the hydrophilic substance from the fruiting body spores but not from the glycerol-induced spores. The change in cell surface hydrophobicity in M. xanthus should be a useful developmental marker.


The chronic fatigue syndrome (myalgic encephalomyelitis)--myth or mystery?
The chronic fatigue syndrome (CFS) or myalgic encephalomyelitis has caused great confusion, misunderstanding and perhaps even mismanagement of many persons presenting with a variety of combinations of ill-defined complaints. The history, possible pathogenesis and clinical features, of what is probably in most instances a post-viral infection syndrome, are reviewed. The recent Centers for Disease Control case definition is summarised and simplified. The need for such uniformity of definition, acceptable to most workers in the field, is emphasised in order to facilitate further studies into the cause, diagnosis, course and treatment of CFS. The difficulty in treating this condition and the currently recommended management are described. Double-blind controlled studies are essential in assessing any proposed new treatment.


Determining the Optimal Dose Prescription for the Planning Target Volume with Stereotactic Body Radiotherapy for Non- Small Cell Lung Cancer Patients.
The aim of this study was to determine a method of dose prescription that minimizes normal tissue irradiation outside the planning target volume (PTV) during stereotactic body radiotherapy (SBRT) for patients with non-small cell lung cancer. Previous research and patients with typical T1 lung tumors with peripheral lesions in the lung were selected for analysis. A PTV and several organs at risk (OARs) were constructed for the dose calculated; six treatment plans employing intensity modulated radiotherapy (IMRT) were produced, in which the dose was prescribed to encompass the PTV, with the prescription isodose level (PIL) set at 50, 60, 70, 80, 90 or 95% of the isocenter dose. Additionally, four OARs around the PTV were constructed to evaluate the dose received in adjacent tissues. The use of higher PILs for SBRT resulted in improved sparing of OARs, with the exception of the volume of lung treated with a lower dose. The use of lower PILs is likely to create significant inhomogeneity of the dose delivered to the target, which may be beneficial for the control of tumors with poor conformity indices.


Primary motor cortex of the parkinsonian monkey: altered encoding of active movement.
Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson's disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (-22%), speed (-40%), acceleration (-49%) and hand position (-33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (-50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes beginning in the 150-ms period that immediately preceded movement. Overall, the results are consistent with proposals that under-activation and abnormal timing of movement-related activity in M1 contribute to parkinsonian motor signs but are not consistent with the idea that a loss of functional specificity plays an important role. Given that pyramidal tract-type neurons form the primary efferent pathway that conveys motor commands to the spinal cord, the dysfunction of movement-related activity in pyramidal tract-type neurons is likely to be a central factor in the pathophysiology of parkinsonian motor signs.


An evaluation of hospitalizations for Kawasaki syndrome in Georgia.
To evaluate and describe the epidemiologic characteristics of Kawasaki syndrome (KS) hospitalizations in Georgia. We reviewed hospital discharge data and corresponding medical records for Georgian patients discharged with a KS diagnosis during 1997 and 1998. During the study period, 233 KS hospital discharges were recorded in Georgia; 177 (76%) were for children younger than 5 years. Twenty-one (9%) of 233 of the hospital discharges represented multiple hospitalizations. Medical records for 211 KS discharges (91%), representing 197 patients (93%), were reviewed. For those 189 patients whose medical records were reviewed and had sufficient information, 139 (74%) either had a documented illness that met the Centers for Disease Control and Prevention (CDC) definition for KS (n = 135) or had coronary artery abnormalities without meeting the CDC definition for KS (atypical KS; n = 4). Eight patients had only a history of KS. Excluding multiple hospitalizations and patients with only a history of KS, 158 hospitalizations were for patients younger than 5 years (14.0 per 100 000 children); 110 of these patients met the KS or atypical KS definition (9.8 per 100 000 children). Hospital discharge data are useful for KS surveillance. However, analysis of hospital discharge data may slightly overestimate the KS hospitalization rates because some discharges may represent multiple hospitalizations or hospitalizations of patients with only a history of KS. The incidence and epidemiology of KS in Georgia are consistent with findings from other continental US studies. Physicians should exercise their best clinical judgment in identifying and treating patients with KS who may not meet standard case definitions.


Effect of feeding on catabolism and activity of exogenous gastrin in dogs.
The effect of meal upon the catabolism and activity of exogenous gastrin was tested in 4 antrectomized and 4 non antrectomized dogs with Heidenhain pouches. In both antrectomized and non antrectomized dogs infused with exogenous gastrin, the meal decreased the serum gastrin level. This decrease amounted to about 20%, 60 minutes after feeding and the gastrinemia then returned gradually to control levels. In non antrectomized dogs, infusion of a near maximal dose of gastrin increased the acid response to the meal to a level above the maximal histamine acid output. Exogenous gastrin also increased the acid response to a meal in antrectomized dogs. These data indicate: 1) That feeding increases the metabolic clearance rate of exogenous gastrin. This effect could be at least partly related to changes in the intestinal blood flow. 2) That, after feeding, one or several hormones capable of stimulating the acid secretion but unrelated to gastrin are probably released. These hormones could be of major importance in the response of denervated pouches to feeding.


Resistance among Streptococcus pneumoniae: Implications for drug selection.
Streptococcus pneumoniae is an important pathogen in many community-acquired respiratory infections in the United States and a leading cause of morbidity and mortality worldwide. Unfortunately, S. pneumoniae is becoming increasingly resistant to a variety of antibiotics. Results of recent surveillance studies in the United States show that the prevalence of penicillin-nonsusceptible S. pneumoniae ranges from 25% to >50%, and rates of macrolide resistance among pneumococci are reported to be as high as 31%. A high prevalence of resistance to other antimicrobial classes is found among penicillin-resistant strains. Newer quinolones (e.g., gatifloxacin, gemifloxacin, and moxifloxacin) that have better antipneumococcal activity in vitro are the most active agents and therefore are attractive options for treatment of adults with community-acquired respiratory infections. Efforts should be made to prevent pneumococcal infections in high-risk patients through vaccination.


Multiscaling of noise-induced parametric instability.
We describe the statistical properties of growth rates of a linear oscillator driven by a parametric noise. We show that in general the fluctuations of local Lyapunov exponents are non-Gaussian and demonstrate multiscaling. Analytical calculations of the generalized Lyapunov exponents are complemented with approximative and numerical results; this allows us to identify the parameter range where the deviations from the Gaussian statistics become important.


Characterization of cell death pathways in murine retinal neurodegeneration implicates cytochrome c release, caspase activation, and bid cleavage.
Apoptosis is considered to be the final common pathway of photoreceptor cell death in different inherited retinal diseases. However, apoptosis encompasses diverse pathways of molecular interactions culminating in cellular demise. To begin dissecting these interactions, we have investigated key participants in the rd (retinal degeneration) model of retinal neurodegeneration. By Western blot analysis and immunocytochemistry, we found that cytochrome c release occurs in rd retinas concurrently with the activation of the proapoptotic protein Bid. Active forms of caspase-8 and the mitogen-activated protein kinase p38, both of which are capable of cleaving Bid, were detected in rd retinas at the peak time of photoreceptor death. In addition, the activated form of the cell death effector caspase-3 was detectable particularly at the photoreceptors in parallel with this peak degenerative phase. These data suggest that activation of both major apoptotic pathways occurs during photoreceptor degeneration in the rd mouse model of inherited blindness.


Investigation of Antiplasmodial Effects of Terpenoid Compounds Isolated from Myrrh.
As part of our ongoing search for antiprotozoal natural products from plants, we examined different resins from the Burseraceae family. The dichloromethane extract obtained from myrrh, the oleo-gum-resin of Commiphora species, showed promising in vitro activity against Plasmodium falciparum with an IC50 value of 1 µg/mL. Bioactivity-guided fractionation led to the isolation and characterization of 18 sesquiterpenoids, namely, β-elemene (1: ), elemyl acetate (2: ), curzerenone (3: ), 8-hydroxyisogermafurenolide (4: ), 2-methoxyisogermafurenolide (5: ), 8-epi-2-methoxyisogermafurenolide (6: ), furanodienone (7: ), 1(10)Z,4Z-furanodien-6-one (8: ), rel-2R-methyl-5S-acetoxy-4R-furanogermacr-1(10)Z-en-6-one (9: ), (1(10)E)-2-methoxy-8,12-epoxygermacra-1(10),7,11-trien-6-one (10: ), 2R-methoxyfuranodiene (11: ), 2-acetyloxyglechomanolide (12: ), 8-epi-2-acetyloxyglechomanolide (13: ), (1R,2R,4S)-1,2-epoxyfuranogermacr-10(15)-en-6-one (14: ), hydroxylindestrenolide (15: ), isohydroxylindestrenolide (16: ), myrrhone (17: ), and myrrhterpenoid O (18: ). Moreover, nine (nor-)triterpenoids were isolated: mansumbinol (19: ), mansumbinol epoxide (20: ), mansumbinone (21: ), mansumbin-13(17)-en-3,16-dione (22: ), 3,4-seco-mansumbinoic acid (23: ), rel-20S-hydroxy-dammar-24-en-3,16-dione (24: ), rel-(16S,20S)-dihydroxydammar-24-en-3-one (25: ), cycloart-24-en-1α,2α,3β-triol (26: ), and 3β-isovaleroyloxycycloart-24-en-1α,2α-diol (27: ). All compounds were identified by MS and NMR spectroscopic analyses. To the best of our knowledge, compounds 5, 6, 12, 13, 16, 18: , and 20: are reported for the first time. All isolated compounds were tested in vitro for activity against P. falciparum and cytotoxicity. The sesquiterpene 7: and the triterpene 25: were the most active compounds found in this study with IC50 values of 7.4 and 2.8 µM, respectively.


[The menstrual cycle after hormonal growth inhibition in girls].
Up to 1979 growth was inhibited with hormones in 43 girls in puberty with constitutional gigantism. The average reduction in size as compared to the calculated final body height was 7.5 cm, treatment having been started at a skeletal age of 12.3 years and with a treatment duration of 1.4 years. In over 90% of the cases, the first spontaneous menstruation after termination of therapy occurred within three months. During the first two years, cycles were likewise regular in 90% of the cases, with a duration of 4 +/- 1 weeks. Ovarian function in adolescence was thus found not to be impaired, but rather to be more stable as compared to the total population. It may be concluded from this that the preconditions for future fertility can be regarded as favorable.


Organ tropism in solid tumor metastasis: an updated review.
Tumors are equipped with a highly complex machinery of interrelated events so as to adapt to hazardous conditions, preserve a growing cell mass and thrive at the site of metastasis. Tumor cells display metastatic propensity toward specific organs where the stromal milieu is appropriate for their further colonization. Effective colonization relies on the plasticity of tumor cells in adapting to the conditions of the new area by reshaping their epigenetic landscape. Breast cancer cells, for instance, are able to adopt brain-like or epithelial/osteoid features in order to pursue effective metastasis into brain and bone, respectively. The aim of this review is to discuss recent insights into organ tropism in tumor metastasis, outlining potential strategies to address this driver of tumor aggressiveness.


Interleukin 1 alpha genetic polymorphisms as potential biomarkers for oral health-related quality of life in Para athletes.
To assess the impact of dental caries on OHRQoL in Para athletes and to evaluate whether interleukin 1 alpha (IL1A) (rs17561, rs1304037), interleukin 10 (IL10) (rs1800871), and interleukin 1 receptor antagonist (IL1RN) (rs9005) genes are potential biomarkers for OHRQoL in Para athletes. A cross-sectional study consisting of 264 Para athletes (athletics, 143; powerlifting, 61; and swimming, 60) aged between 14 and 79 years was conducted. The decayed-missing-filled teeth index was used for the clinical evaluation. The Brazilian version of the Oral Health Impact Profile (OHIP-14) was used to measure the OHRQoL. Genomic DNA was extracted from the saliva. Genetic polymorphisms were analyzed by real-time polymerase chain reaction. Descriptive and bivariate analyses were performed. The overall mean OHIP-14 score observed was 6.24 (standard deviation, 7.05) and 10.03 (standard deviation, 8.11) in Para athletes with no caries experience and with caries experience, respectively (p = .002). Para athletes with the A allele in the IL1A gene (rs17561), in a dominant model, had a significantly higher risk of poor psychological discomfort than those with the other allele (p = .03). Dental caries affected the OHRQoL in Para athletes. IL1A genetic polymorphisms were the potential biomarkers for OHRQoL in Para athletes.


[Depth profile of suspended particle scattering coefficient and its impact factors in Taihu Lake].
To acquire the depth profile of suspended particle scattering coefficient and the mechanism of surface reflection, three different depths of Taihu Lake scattering coefficient and backscattering coefficient are obtained in Nov. 2008, respectively. And their characteristic variation with depth is studied. Profiling distribution of the slope of particulate size distribution (PSD) is computed by the attenuation coefficient. Profiling distribution of the concentration and composition of suspended particle is computed according the relationship between the scattering coefficient and the suspended particle concentration. Impact dominant factors on scattering coefficient of the depth of water are divided according to the range of refractive index. At the three depths (0, 50, 100 cm), the particle scattering, with the percentage 14%, 17%, 12% of the samples are dominated by algae, respectively. 35%, 30%, 34% of the samples are dominated by inorganic particulate matter and Non-algal organic particulate matter,and 51%, 53%, 51% of the samples are dominated by the above all. The results can be concluded as: scattering and backscattering coefficient of Taihu Lake water body changes with depth slightly. The concentration of total suspended particles is of more diversity in different lake area, but there is less difference at different depths except those samples near the inflow rivers. The main factors of scattering coefficient of most aquatic scattering in Taihu Lake had little difference at different depths, except several samples beside the inflow rivers.


Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters.
Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.


Histone deacetylase inhibition decreases cholesterol levels in neuronal cells by modulating key genes in cholesterol synthesis, uptake and efflux.
Cholesterol is an essential component of the central nervous system and increasing evidence suggests an association between brain cholesterol metabolism dysfunction and the onset of neurodegenerative disorders. Interestingly, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) are emerging as promising therapeutic approaches in neurodegenerative diseases, but their effect on brain cholesterol metabolism is poorly understood. We have previously demonstrated that HDACi up-regulate CYP46A1 gene transcription, a key enzyme in neuronal cholesterol homeostasis. In this study, TSA was shown to modulate the transcription of other genes involved in cholesterol metabolism in human neuroblastoma cells, namely by up-regulating genes that control cholesterol efflux and down-regulating genes involved in cholesterol synthesis and uptake, thus leading to an overall decrease in total cholesterol content. Furthermore, co-treatment with the amphipathic drug U18666A that can mimic the intracellular cholesterol accumulation observed in cells of Niemman-Pick type C patients, revealed that TSA can ameliorate the phenotype induced by pathological cholesterol accumulation, by restoring the expression of key genes involved in cholesterol synthesis, uptake and efflux and promoting lysosomal cholesterol redistribution. These results clarify the role of TSA in the modulation of neuronal cholesterol metabolism at the transcriptional level, and emphasize the idea of HDAC inhibition as a promising therapeutic tool in neurodegenerative disorders with impaired cholesterol metabolism.


A new perceptual training strategy to improve vision impaired by central vision loss.
Patients with central vision loss depend on peripheral vision for everyday functions. A preferred retinal locus (PRL) on the intact retina is commonly trained as a new "fovea" to help. However, reprogramming the fovea-centered oculomotor control is difficult, so saccades often bring the defunct fovea to block the target. Aligning PRL with distant targets also requires multiple saccades and sometimes head movements. To overcome these problems, we attempted to train normal-sighted observers to form a preferred retinal annulus (PRA) around a simulated scotoma, so that they could rely on the same fovea-centered oculomotor system and make short saccades to align PRA with the target. Observers with an invisible simulated central scotoma (5° radius) practiced making saccades to see a tumbling-E target at 10° eccentricity. The otherwise blurred E target became clear when saccades brought a scotoma-abutting clear window (2° radius) to it. The location of the clear window was either fixed for PRL training, or changing among 12 locations for PRA training. Various cues aided the saccades through training. Practice quickly established a PRL or PRA. Comparing to PRL-trained observers whose first saccade persistently blocked the target with scotoma, PRA-trained observers produced more accurate first saccade. The benefits of more accurate PRA-based saccades also outweighed the costs of slower latency. PRA training may provide an efficient strategy to cope with central vision loss, especially for aging patients who have major difficulties adapting to a PRL.


In vitro models to study natural killer cell dynamics in the tumor microenvironment.
Immunotherapy is revolutionizing cancer therapy. The rapid development of new immunotherapeutic strategies to treat solid tumors is posing new challenges for preclinical research, demanding novel in vitro methods to test treatments. Such methods should meet specific requirements, such as enabling the evaluation of immune cell responses like cytotoxicity or cytokine release, and infiltration into the tumor microenvironment using cancer models representative of the original disease. They should allow high-throughput and high-content analysis, to evaluate the efficacy of treatments and understand immune-evasion processes to facilitate development of new therapeutic targets. Ideally, they should be suitable for personalized immunotherapy testing, providing information for patient stratification. Consequently, the application of in vitro 3-dimensional (3D) cell culture models, such as tumor spheroids and organoids, is rapidly expanding in the immunotherapeutic field, coupled with the development of novel imaging-based techniques and -omic analysis. In this paper, we review the recent advances in the development of in vitro 3D platforms applied to natural killer (NK) cell-based cancer immunotherapy studies, highlighting the benefits and limitations of the current methods, and discuss new concepts and future directions of the field.


Hypocholesterolemic agents IV: inhibition of beta-hydroxy-beta-methyglutaryl coenzyme A reductase by arylalkenyl and arylepoxy hydrogen succinates and glutarates.
Two series of half acid esters of succinic and glutaric acids were synthesized and assayed for inhibition of rat liver beta-hydroxy-beta-methylglutaryl coenzyme A reductase. Irreversible inhibition was studied by incorporation of a potential alkylating group (the epoxide function) into the side chain of the alcohol portion of the half acid esters. Incorporation of a terminal olefin function into the side chain of the alcohol portion of the half acid esters provided a group that could form a charge-transfer complex. Neither irreversible inhibition nor formation of a charge-transfer complex was indicated from these studies; however, the two series of half acid esters exhibited reversible inhibition.


Benchmarks for electronically excited states: time-dependent density functional theory and density functional theory based multireference configuration interaction.
Time-dependent density functional theory (TD-DFT) and DFT-based multireference configuration interaction (DFT/MRCI) calculations are reported for a recently proposed benchmark set of 28 medium-sized organic molecules. Vertical excitation energies, oscillator strengths, and excited-state dipole moments are computed using the same geometries (MP2/6-31G(*)) and basis set (TZVP) as in our previous ab initio benchmark study on electronically excited states. The results from TD-DFT (with the functionals BP86, B3LYP, and BHLYP) and from DFT/MRCI are compared against the previous high-level ab initio results, and, in particular, against the proposed best estimates for 104 singlet and 63 triplet vertical excitation energies. The statistical evaluation for the latter reference data gives the lowest mean absolute deviations for DFT/MRCI (0.22 eV for singlets and 0.24 eV for triplets) followed by TD-DFT/B3LYP (0.27 and 0.44 eV, respectively), whereas TD-DFT/BP86 and TD-DFT/BHLYP are significantly less accurate. The energies of singlet states with double excitation character are generally overestimated by TD-DFT, whereas triplet state energies are systematically underestimated by the currently investigated DFT-based methods.