Effect of membrane filtration of antimalarial drug solutions on in vitro activity against Plasmodium falciparum.
Antimalarial activities of chloroquine, mefloquine, amodiaquine, and quinine in vitro against Plasmodium falciparum were diminished as a consequence of membrane filtration. Filtered drug solutions gave ID(50) values up to 25-fold greater than those of non-filtered (ethanol-sterilized) drug solutions. Loss of activity by filtration was overcome by increasing the drug concentration prior to filtration. Water solutions filtered through Millex-GS filter units consistently showed an absorbance maximum at 277 nm, accompanied by a lesser peak at 225 nm. Water filtrates from Nucleopore and Millex-GV filters showed no absorbance at 277 nm and only slight absorbance was evident for the Gelman filter unit. Activity losses were attributed to extractable contaminating moieties in the membrane filters and/or drug binding to the membrane filters.


Optimal CCN4 Immunofluorescence for Tissue Microarray.
CCN4 (also known as WNT1-Inducible Signaling Pathway Protein 1 or WISP1) is a 367 amino acid, 40 kDa protein located on chromosome 8q24.1-8q24.3. Prior studies have provided support for a pro-inflammatory role for CCN4. We have shown recently that CCN4 expression is associated with advanced disease, epithelial-mesenchymal transition, and an inflamed tumor microenvironment in multiple solid tumors. We detail here the CCN4 tissue microarray immunofluorescence protocol related to these findings.


The neuroprotective effect of Withania somnifera root extract in MPTP-intoxicated mice: an analysis of behavioral and biochemical variables.
We studied the influence of Withania somnifera (Ws) root extract (100 mg/kg body weight) on parkinsonism induced by 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP; i.p, 20 mg/kg body weight for 4 days), via the analysis of behavioral features and the oxidant-antioxidant imbalance in the midbrain of mice. A significant alteration in behavior, increased levels of thiobarbituric acid reactive substance (TBARS), and increased activities of superoxide dismutase (SOD) and catalase (CAT) were noticed in this region of brain in MPTP-treated mice. Oral treatment with the root extract resulted in a significant improvement in the mice's behavior and antioxidant status, along with a significant reduction in the level of lipid peroxidation. The results indicated that at least part of the chronic stress-induced pathology may be due to oxidative stress, which is mitigated by Ws. Further studies are needed to assess the precise mechanism to support the clinical use of the plant as an antiparkinsonic drug.


Serum Uric Acid Concentrations and Risk of Adverse Outcomes in Patients With COVID-19.
Although hyperuricemia frequently associates with respiratory diseases, patients with severe coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) can show marked hypouricemia. Previous studies on the association of serum uric acid with risk of adverse outcomes related to COVID-19 have produced contradictory results. The precise relationship between admission serum uric acid and adverse outcomes in hospitalized patients is unknown. Data of patients affected by laboratory-confirmed COVID-19 and admitted to Leishenshan Hospital were retrospectively analyzed. The primary outcome was composite and comprised events, such as intensive care unit (ICU) admission, mechanical ventilation, or mortality. Logistic regression analysis was performed to explore the association between serum concentrations of uric acid and the composite outcome, as well as each of its components. To determine the association between serum uric acid and in-hospital adverse outcomes, serum uric acid was also categorized by restricted cubic spline, and the 95% confidence interval (CI) was used to estimate odds ratios (OR). The study cohort included 1854 patients (mean age, 58 years; 52% women). The overall mean ± SD of serum levels of uric acid was 308 ± 96 µmol/L. Among them, 95 patients were admitted to ICU, 75 patients received mechanical ventilation, and 38 died. In total, 114 patients reached composite end-points (have either ICU admission, mechanical ventilation or death) during hospitalization. Compared with a reference group with estimated baseline serum uric acid of 279-422 µmol/L, serum uric acid values ≥ 423 µmol/L were associated with an increased risk of composite outcome (OR, 2.60; 95% CI, 1.07- 6.29) and mechanical ventilation (OR, 3.01; 95% CI, 1.06- 8.51). Serum uric acid ≤ 278 µmol/L was associated with an increased risk of the composite outcome (OR, 2.07; 95% CI, 1.18- 3.65), ICU admission (OR, 2.18; 95% CI, 1.17- 4.05]), and mechanical ventilation (OR, 2.13; 95% CI, 1.06- 4.28), as assessed by multivariate analysis. This study shows that the association between admission serum uric acid and composite outcome of COVID-19 patients was U-shaped. In particular, we found that compared with baseline serum uric acid levels of 279-422 µmol/L, values ≥ 423 µmol/L were associated with an increased risk of composite outcome and mechanical ventilation, whereas levels ≤ 278 µmol/L associated with increased risk of composite outcome, ICU admission and mechanical ventilation.


Carnosine ameliorates lens protein turbidity formations by inhibiting calpain proteolysis and ultraviolet C-induced degradation.
Carnosine (CAR) is an endogenous peptide and present in lens, but there is little evidence for its effectiveness in calpain-induced proteolysis inhibition and its differential effects toward different wavelengths of ultraviolet (UV) irradiation. This study aimed to develop three in vitro cataract models to compare the mechanisms underlying the protective activities of CAR. Crude crystallins extracted from porcine lenses were used for antiproteolysis assays, and purified γ-crystallins were used for anti-UV assays. The turbidity in those in vitro models mimics cataract formation and was assayed by measuring optical density (OD) at 405 nm. The effectiveness of CAR on calpain-induced proteolysis was studied at 37 and 58 °C. Patterns of proteins were then analyzed by SDS-PAGE. The turbidity was reduced significantly (p<0.05) at 60 min measurements with the increased concentration of CAR (10-300 mM). SDS-PAGE showed that the decreased intensities at both ∼28 and ∼30 kDa protein bands in heat-enhanced assays were ameliorated by CAR at ≥10 mM concentrations. In UV-B studies, CAR (200, 300 mM) reduced the turbidity of γ-crystallin significantly (p<0.05) at 6 h observations. The turbidity of samples containing γ-crystallins was ameliorated while incubated with CAR (100, 300 mM) significantly (p<0.05) following 4 h of exposure to UV-C. SDS-PAGE showed that the presence of CAR reduced UV-B-induced aggregation of γ-crystallins at ∼44 kDa and resulted in less loss of γ-crystallin following UV-C exposure. The result of modeling also suggests that CAR acts as an inhibitor of calpain. In conclusion, CAR protects lens proteins more readily by inhibiting proteolysis and UV-C-induced degradation than aggregation induced by UV-B irradiation.


Histamine potentiation by hydroxylamines: structure-activity relations; inhibition of diamine oxidase.
Hydroxylamines potentiated the responses of the canine colonic epithelium to histamine but not to other agonists such as serotonin or carbachol. We tested the hypothesis that an inhibition of histamine catabolism could explain the observed potentiation. A clear structure activity relation was defined, active compounds having the structure NH2-O-R, R being a simple uncharged aliphatic group. Active compounds delayed the disappearance of histamine from the bathing solutions and inhibited colonic diamine oxidase, an effect mimicked by standard inhibitors aminoguanidine and semicarbazide. Histamine agonists that possessed an imidazole nucleus (2- and 4-methylhistamine) were affected, whereas impromidine, 2 pyridylethylamine, and dimaprit were not. Agonist specificity combined with the enzyme data suggest an inhibition of histamine catabolism as a possible mechanism for the potentiating effects observed.


Comparative analysis of resected prostate weight in diabetic and non-diabetic benign prostatic hyperplasia Patients.
Benign prostatic hyperplasia (BPH) is the most common benign tumor in men. The etiology of BPH is still unresolved and multiple systems are likely to be involved. The effects of diabetes on urinary system are a risk factor for BPH. We then assessed the effects of diabetes on the parameters related to BPH, especially weight and volume. This study was conducted on patients with BPH who underwent surgery during 2010-2013. The patients' demographic and clinical data including age, height, weight, history of diabetes, abdominal sonography, prostate-specific antigen(PSA), fasting blood sugar (FBS), triglyceride, and cholesterol, resected sample weight, and pathological diagnosis were extracted. The mean age of all 225 patients (35 (15.6%) diabetic patients and 190 (84.4%) non-diabetic patients) who entered the study was 71.5±8.7 years. The patients were divided in to 3 body mass index (BMI) groups: 48 (21.3%) were normal, 151 (67.1%) were overweight and 26 (11.6%) were obese. The mean weight of resected prostate was higher in diabetic patients (22.9±6.9 vs 21.7±14.3, P=0.02). The resected prostate weight had a significant relationship with BMI (P=0.001), prostate-specific antigen (PSA) level (P=0.001), and prostate volume sonography (P=0.001). No significant relationship was detected between resected prostate weight with age, FBS and triglyceride however, it is significant with cholesterol. We concluded that diabetes has a role in the development and progression of BPH with effect on prostate weight and volume. As well, BMI is a risk factor in BPH progression.


Renal transplant in HIV-positive patients: long-term outcomes and risk factors for graft loss.
In the highly active antiretroviral therapy era of improved survival for patients living with human immunodeficiency virus (HIV), chronic kidney disease now accounts for more than 10% of HIV-related deaths. The role of kidney transplant among HIV-positive patients with end-stage renal disease is under consideration, but concerns remain regarding allocation of kidneys to these patients when long-term benefit has not been firmly established. We evaluated 39,501 patients undergoing a renal transplant between January 1, 2004, and June 30, 2006, identified through the United Network for Organ Sharing national registry and found that, although long-term allograft survival is lower among HIV-positive recipients, controllable risk factors may explain this disparity. With proper donor selection and transplant recipient management, including the avoidance of prolonged cold ischemic time, use of living donors, and determination of optimal immunosuppression dosing before transplant, long-term graft survival comparable to that in HIV-negative patients can be achieved.


The role of neuropeptides in regulating airway function. Postsecretory metabolism of peptides.
Peptide hormones and neurotransmitters play an essential role in regulation of cellular metabolism. Once released from an endocrine cell or nerve ending, peptides encounter membrane-bound and soluble peptidases. The peptidases inactivate peptides or form fragments with novel biologic activity. Therefore, peptidases must play a major role in homeostatic control, but this aspect of regulation has been a neglected area. This review examines the postsecretory metabolism of biologically active peptides in the brain and alimentary tract, 2 organs in which peptide regulation is of crucial importance.


Predictive role of imaging in sentinel lymph node dissection for melanoma.
A retrospective study of 67 patients with metastatic melanoma was performed to evaluate if imaging from lymphoscintigraphy could predict a higher miss rate if only the most radioactive node were removed. Following protocol for sentinel node biopsy, the surgeon resected all lymph nodes containing radioactivity > 10% of the most radioactive node. A correlation was performed between the radioactive counts of the lymph nodes and the presence of metastases. The percentage of cases in which the most radioactive node was negative for metastasis on pathology was calculated. Two nuclear medicine physicians read the images from lymphoscintigraphy specifically to determine if the first lymph node visualized became less intense than other nodes on later images. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. In 13 of 67 (19%) patients, the most radioactive lymph node was negative for metastasis while a less radioactive node contained metastatic disease. Consensus reading by the nuclear medicine physicians determined that in 9 cases, the first lymph node visualized became less intense than another lymph node on later images. Of the 9 cases, 4 were true positive and 5 were false positive when correlated with intraoperative count rate and pathology. Of the cases where the most radioactive node was not positive on histopathology (n = 13), the consensus reading by the nuclear medicine physicians reported 4 of them (31%). Imaging by lymphoscintigram had a sensitivity 31%, specificity 91%, positive predictive value 44%, and negative predictive value 85% for predicting whether the most radioactive lymph node at surgery would be negative for metastasis at pathology. We conclude that in patients with melanoma, lymphoscintigraphy has high specificity and negative predictive value but modest sensitivity and positive predictive value for detecting when the sentinel node will not be the most radioactive lymph node during sentinel lymph node dissection. These findings support that dynamic imaging by lymphoscintigraphy has a role in surgical planning but that the imaging protocol could benefit from further optimization.


Coronary artery magnetic resonance imaging: a patient-tailored approach.
Coronary artery magnetic resonance imaging strategies have tended to focus on the use of a single method performed during either breath-holding or free-breathing for all patients. However, significant variations exist among patients in terms of breath-holding ability and respiratory regularity that make the use of a single technique alone not universally successful. Therefore, it is prudent to make available a number of magnetic resonance imaging methods such that an appropriate respiratory motion reduction strategy can be tailored to suit the patient's respiratory pattern and characteristics. A tailored approach that can draw on different image acquisition techniques for coronary artery imaging is presented. A decision tree is proposed to triage patients into imaging regimes with the greatest probability of success, according to the patient's ability to breath-hold or exhibit steady respiration. Methods include volume free-breathing acquisitions using navigator echoes for respiratory monitoring in the 8- to 10-min scan time range, two-dimensional spiral navigators (2- to 3-min scan time), breath-held multislice and vessel-tracking spirals (16- to 20-second scan time), and real-time imaging approaches incorporating adaptive signal averaging. The development of multiple acquisition strategies substantially improves the opportunities to generate high-quality, diagnostic images of the coronary arteries.


Comparison of recommended and actual mean intakes of fluoride by Canadians.
The findings of two separate 1993 reports, one of the actual intake of fluoride by Canadians and the other on their recommended fluoride intake, are summarized and compared. Recent increases in very mild and mild dental fluorosis suggest that the gap between current fluoride intake and recommended intake is narrowing. The daily swallowing of fluoride dentifrice makes a large contribution to the actual total daily fluoride intake, especially in children seven months to four years of age, the age group most susceptible to fluorosis in the anterior permanent teeth. Because of the available data and methods used in each study, the reported actual and recommended fluoride intakes vary greatly both within and between age groups. It is likely that individual variation in fluoride intake also varies greatly. Comparison of the data in the two reports revealed that, for breast-fed infants and nearly all other age groups without fluoridated water, the ranges of the estimates of actual intake are lower than the recommended ranges. However, for formula-fed infants and all other age groups using fluoridated water, the estimates of actual intake greatly exceed the recommended intake, especially for the seven months to four years age group. Ingestion of fluoride at these levels during tooth development will contribute to dental fluorosis. All of the age groups have fluoride intake estimates below levels at which skeletal signs of fluoride exposure are noticed. Nevertheless, exposure to fluoride should be closely monitored and inappropriate use of discretionary fluorides curtailed.


Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas.
High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol. We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations. Six genes (SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as SCGB3A1 (HIN1) and TLN2 were up-regulated and PTGS1 (COX1) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases. We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas. SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans.


Revisiting the argument from fetal potential.
One of the most famous, and most derided, arguments against the morality of abortion is the argument from potential, which maintains that the fetus' potential to become a person and enjoy the valuable life common to persons, entails that its destruction is prima facie morally impermissible. In this paper, I will revisit and offer a defense of the argument from potential.First, I will criticize the classical arguments proffered against the importance of fetal potential, specifically the arguments put forth by philosophers Peter Singer and David Boonin, by carefully unpacking the claims made in these arguments and illustrating why they are flawed.Secondly, I will maintain that fetal potential is morally relevant when it comes to the morality of abortion, but that it must be accorded a proper place in the argument. This proper place, however, cannot be found until we first answer a very important and complex question: we must first address the issue of personal identity, and when the fetus becomes the type of being who is relevantly identical to a future person. I will illustrate why the question of fetal potential can only be meaningfully addressed after we have first answered the question of personal identity and how it relates to the human fetus.


Idiotypic network connectivity and a possible cause of myasthenia gravis.
Extensive idiotypic connectivity has been discovered between the antibodies composing the immune responses against the acetylcholine receptor (AChR) and alpha-1,3-dextran. The idiotypic connections form an elaborate network linking these disparate antigen systems, and there is an hierarchical organization of the antibodies in this network. The key anti-Ids that interconnect these two responses are more crossreactive, lower-affinity antibodies. Interestingly, 15% of patients with MG, which is caused by autoantibodies against the AChR, have serum antibodies against DEX. Control sera are negative for anti-DEX antibodies. Certain anti-DEX antibodies also bind to anti-AChR antibodies via idiotypic interactions. These findings suggest a model for the initiation of autoimmunity in MG. Antibodies made in response to DEX epitopes on the surface of certain bacteria would elicit the production of anti-Ids. However, some of these anti-Ids would also be autoantibodies against the AChR. Thus, is some circumstances, autoimmunity may develop as a consequence of the normal operation of regulatory idiotypic networks.


CD31 (PECAM-1) is a differentiation antigen lost during human CD4 T-cell maturation into Th1 or Th2 effector cells.
The CD31 antigen (PECAM-1) has been reported to be a stable marker for a human CD4 T-cell subpopulation unable to produce interleukin-4 (IL-4). We show here that CD31 expression is not stable inasmuch as CD4 T-cell lines and clones derived from cell-sorted neonatal CD31+ cells lose CD31 upon repetitive cycles of stimulation and IL-2 expansion. Moreover, various cytokines (IL-1 alpha, IL-4, IL-6, transforming growth factor-beta) fail to reinduce CD31 on CD31- clones. Whereas all CD31+ CD4 T cells rapidly express high levels of the CD45RO antigen and down-regulate the L-selectin antigen after priming, CD31 disappears more slowly because only part of the cells lose CD31 expression upon each cycle of stimulation. Loss of CD31 reflects a functional maturation of CD45RO+ cells since, in a system which favours the development of Th2 effectors, IL-4 is produced by CD31- but not CD31+ effector T cells, whereas interferon-gamma is produced by both types of cells. However, CD31 is not a Th1 marker since it is not expressed on several Th1 antigen-specific clones. We conclude that CD31 is a maturation marker expressed on the great majority of naive CD45RO- CD4 T cells and on a subset of CD45RO+ CD4 T cells that are at an intermediate stage of maturation.


The redox series [Ru(bpy)2(L)]n, n = +3, +2, +1, 0, with L = bipyridine, "click" derived pyridyl-triazole or bis-triazole: a combined structural, electrochemical, spectroelectrochemical and DFT investigation.
The compounds [Ru(bpy)2(L(1))](ClO4)2 (1(ClO4)2), [Ru(bpy)2(L(2))](ClO4)2 (2(ClO4)2), [Ru(bpy)2(L(3))](ClO4)2 (3(ClO4)2), [Ru(bpy)2(L(4))](ClO4)2 (4(ClO4)2), [Ru(bpy)2(L(5))](ClO4)2 (5(ClO4)2), and [Ru(bpy)2(L(6))](ClO4)2 6(ClO4)2 (bpy = 2,2'-bipyridine, L(1) = 1-(4-isopropyl-phenyl)-4-(2-pyridyl)-1,2,3-triazole, L(2) = 1-(4-butoxy-phenyl)-4-(2-pyridyl)-1,2,3-triazole, L(3) = 1-(2-trifluoromethyl-phenyl)-4-(2-pyridyl)-1,2,3-triazole, L(4) = 4,4'-bis-{1-(2,6-diisopropyl-phenyl)}-1,2,3-triazole, L(5) = 4,4'-bis-{(1-phenyl)}-1,2,3-triazole, L(6) = 4,4'-bis-{1-(2-trifluoromethyl-phenyl)}-1,2,3-triazole) were synthesized from [Ru(bpy)2(EtOH)2](ClO4)2 and the corresponding "click"-derived pyridyl-triazole or bis-triazole ligands, and characterized by (1)H-NMR spectroscopy, elemental analysis, mass spectrometry and X-ray crystallography. Structural analysis showed a distorted octahedral coordination environment about the Ru(II) centers, and shorter Ru-N(triazole) bond distances compared to Ru-N(pyridine) distances in complexes of mixed-donor ligands. All the complexes were subjected to cyclic voltammetric studies, and the results were compared to the well-known [Ru(bpy)3](2+) compound. The oxidation and reduction potentials were found to be largely uninfluenced by ligand changes, with all the investigated complexes showing their oxidation and reduction steps at rather similar potentials. A combined UV-vis-NIR and EPR spectroelectrochemical investigation, together with DFT calculations, was used to determine the site of electron transfer in these complexes. These results provided insights into their electronic structures in the various investigated redox states, showed subtle differences in the spectroscopic signatures of these complexes despite their similar electrochemical properties, and provided clues to the unperturbed redox potentials in these complexes with respect to ligand substitutions. The reduced forms of the complexes display structured absorption bands in the NIR region. Additionally, we also present new synthetic routes for the ligands presented here using Cu-abnormal carbene catalysts.


Acute pulmonary embolism in patients with HIV disease.
To determine the incidence, mode of presentation, and outcome of pulmonary embolism (PE) in patients with HIV infection. Retrospective review of clinical case records, imaging department database, and necropsy reports of patients admitted to the specialist HIV/AIDS unit at UCL hospitals from April 1993 to August 1997 in order to identify those with a diagnosis of PE. During the study period there were 3792 admissions of whom 10 (0.26%) had PE. All patients with PE presented with fever, seven were dyspnoeic, and seven had cough: all were thought initially to have respiratory infection. Only five patients had pleural pain. All 10 patients had abnormal baseline chest radiographs. The diagnosis in six was made by computed tomograph (CT) pulmonary angiography, in two was made by ventilation perfusion (V/Q) scanning, in one by both techniques, and in one at necropsy. CT angiography in addition to identifying thrombus also showed concomitant lung parenchymal abnormalities in all but one patient. Nine patients with PE had one or more risk factors for venous thromboembolism as did 34/40 case matched controls (odds ratio = 1.67; 95% confidence interval = 0.18-15.5). All patients diagnosed in life were anticoagulated and five survived. PE was uncommon in this HIV infected population. The diagnosis should be considered in patients with respiratory infection which does not respond to antibiotics. Identifiable risk factors for venous thromboembolism appear to be unhelpful in increasing clinical index of suspicion for PE. As baseline chest radiographs are frequently abnormal, the diagnostic utility of V/Q scanning may be reduced and CT pulmonary angiography is the imaging modality of first choice.


Comparative study of antimicrobial resistance and biofilm formation among Gram-positive uropathogens isolated from community-acquired urinary tract infections and catheter-associated urinary tract infections.
Background: Gram-positive cocci have emerged to be an important cause of urinary tract infection (UTI) both in community-acquired UTI (Com-UTI) and catheter-associated urinary tract infection (CA-UTI). The objective of this study was to investigate the frequency of Gram-positive cocci urinary tract infections, their susceptibility patterns to commonly used antimicrobial agents and the biofilm forming property with respect to catheter-associated UTI and community-acquired UTI. Methods: A total of 1,360 urine samples from indwelling catheter and 10,423 from mid-stream urine were obtained during a 6-month period and processed following standard microbiological guidelines. Biofilm formation was detected using congo red agar (CRA), tube method (TM) and tissue culture plate (TCP) method. Chi-square test and independent sample t-test were employed to calculate the significance. Statistical significance was set at P-value ≤0.05. Results: The infection rate was significantly higher in CA-UTI as compared to Com-UTI (25% vs 18%, p=0.0001). Among 2,216 organisms isolated, 471 were Gram-positive cocci; 401 were obtained from Com-UTI while 70 were from CA-UTI. Enterococcus faecalis was the most common organism isolated from Com-UTI, while Staphylococcus aureus was commonest among CA-UTI. Multi-drug resistance, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci were also significantly higher in CA-UTI as compared to Com-UTI. Biofilm-forming property was significantly higher in CA-UTI than Com-UTI. The sensitivity of congo red agar method and tube method was 79% and 81.9% respectively and specificity was 98.5% each. Antimicrobial resistance was significantly higher in biofilm-formers as compared to non-formers. Conclusion: Gram-positive bacteria are a significant cause of both CA-UTI and Com-UTI with Enterococcus faecalis and Staphylococcus aureus as common pathogen. Biofilm formation and multi-drug resistance is significantly higher in CA-UTI than Com-UTI. Routine surveillance of antimicrobial resistance and biofilm formation is necessary in all cases of UTI to ensure the proper management of patients.


Gatekeepers of the nucleus.
Nuclear pore complexes (NPCs) form the site for entry and exit from the nucleus. A convergence of studies have defined the physical framework for the nuclear transport mechanism. This includes definition of the soluble transport machinery required for protein and RNA movement, x-ray structure analysis of transport factors, definitive compositional analysis of yeast NPCs, and documentation of the relative steady state arrangement of NPC components within the portal. With this information, researchers are now in the exciting position to examine the dynamic interplay between shuttling transport factors and the static pore complex.


Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction.
The generation of properly functioning circuits during brain development requires precise timing of cell migration and differentiation. Disruptions in the developmental plan may lead to neurological and psychiatric disorders. Neocortical circuits rely on inhibitory GABAergic interneurons, the majority of which migrate from subcortical sources. We have shown that the pleiotropic molecule hepatocyte growth factor/scatter factor (HGF/SF) mediates interneuron migration. Mice with a targeted mutation of the gene encoding urokinase plasminogen activator receptor (uPAR), a key component in HGF/SF activation and function, have decreased levels of HGF/SF and a 50% reduction in neocortical GABAergic interneurons at embryonic and perinatal ages. Disruption of interneuron development leads to early lethality in most models. Thus, the long-term consequences of such perturbations are unknown. Mice of the uPAR-/- strain survive until adulthood, and behavior testing demonstrates that they have an increased anxiety state. The uPAR-/- strain also exhibits spontaneous seizure activity and higher susceptibility to pharmacologically induced convulsions. The neocortex of the adult uPAR-/- mouse exhibits a dramatic region- and subtype-specific decrease in GABA-immunoreactive interneurons. Anterior cingulate and parietal cortical areas contain 50% fewer GABAergic interneurons compared with wild-type littermates. However, interneuron numbers in piriform and visual cortical areas do not differ from those of normal mice. Characterization of interneuron subpopulations reveals a near complete loss of the parvalbumin subtype, with other subclasses remaining intact. These data demonstrate that a single gene mutation can selectively alter the development of cortical interneurons in a region- and cell subtype-specific manner, with deficits leading to long-lasting changes in circuit organization and behavior.


Violent interpersonal trauma predicts aggressive thoughts and behaviors towards self and others: findings from the National Comorbidity Survey-Adolescent Supplement.
The purpose of the current study is to examine the relation between adolescent traumatic event exposure and aggression directed towards the self and others. Theoretical perspectives underscore the particularly pernicious effects of violent traumas intentionally perpetrated by others in terms of negative posttraumatic outcomes. However, a careful comparison of trauma type in relation to aggression has not been done with youth. The current project, therefore, examined differences between youth with a history of violent interpersonal trauma (VIT) compared to those with a non-violent trauma type history in terms of aggressive behavior directed towards others as well as aggressive self-directed thoughts (suicidal ideation). The sample was drawn from the National Comorbidity Survey-Replication and consisted of 1928 adolescents (M = 15.4; SD = 1.47 years), each assigned to one of four age- and gender-matched trauma history groups. Consistent with hypotheses, among trauma-exposed youth, those who had experienced or witnessed a VIT (compared to those reporting a non-VIT only) evidenced elevated aggression, even after controlling for a number of theoretically relevant covariates (e.g., gender, age, household income, demographic factors). Results indicate that youth with a history of VIT may be at unique risk for experiencing aggression directed towards others and the self compared to those without this specific trauma history. This is important because trauma type is an easily assessed indicator of potentially elevated risk for these types of deleterious outcomes. Findings are situated in a research agenda aimed at continuing to refine our understanding of the link between interpersonal trauma and aggression.


The flight of macromolecular complexes in a mass spectrometer.
The discovery that conditions can be found such that non-covalent macromolecular complexes can survive the transition from solution to gas phase and remain intact during their flight in a mass spectrometer is an intriguing observation. While the nature of the interaction between the components, either ionic, hydrophobic or van der Waals, undoubtedly has an effect on the stability of these gas phase species, the role of small molecules in conferring additional stability is often overlooked. Here we review historical aspects of the development of mass spectrometry for macromolecular complexes with particular focus on the role of small molecules in stabilizing gas-phase complexes. Moreover, we demonstrate how the dissociation of small molecules from subunits within a macromolecular complex can be used to probe the topological arrangement. Overall, therefore, we show that mass spectrometry used in this way is capable of addressing features of the energy landscape not readily accessed by traditional structural biology approaches.


Association between DRD4 gene polymorphism and personality variation in great tits: a test across four wild populations.
Polymorphisms in the dopamine receptor D4 gene (DRD4) have been related to individual variation in novelty-seeking or exploratory behaviour in a variety of animals, including humans. Recently, the human DRD4 orthologue was sequenced in a wild bird, the great tit (Parus major) and a single nucleotide polymorphism in exon 3 of this gene (SNP830) was shown to be associated with variation in exploratory behaviour of lab-raised individuals originating from a single wild population. Here we test the generality of this finding in a large sample of free-living individuals from four European great tit populations, including the originally sampled population. We demonstrate that the association between SNP830 genotype and exploratory behaviour also exists in free-living birds from the original population. However, in the other three populations we found only limited evidence for an association: in two populations the association appeared absent; while in one there was a nonsignificant tendency. We could not confirm a previously demonstrated interaction with another DRD4 polymorphism, a 15 bp indel in the promoter region (ID15). As yet unknown differences in genetic or environmental background could explain why the same genetic polymorphism (SNP830) has a substantial effect on exploratory behaviour in one population, explaining 4.5-5.8% of the total variance-a large effect for a single gene influencing a complex behavioural trait-but not in three others. The confirmation of an association between SNP830 genotype and personality-related behaviour in a wild bird population warrants further research into potential fitness effects of the polymorphism, while also the population differences in the strength of the association deserve further investigation. Another important future challenge is the identification of additional loci influencing avian personality traits in the wild.


Understanding insomnia through cognitive modelling.
Cognitive models of insomnia have received growing support in recent years and are embraced by the current diagnostic framework. Many people with insomnia report that mental events, such as intrusive thoughts or a racing mind, prevent them from achieving or maintaining sleep. Dysfunctional cognition may play an important role in perpetuating insomnia, with many individuals with psychophysiological insomnia reporting a distorted perception of sleep. Neurocognitive studies have indicated that high-frequency EEG activity associated with cognitive processes is enhanced in patients with insomnia at or around sleep onset, which may distort the individual's judgement about sleep initiation and duration. A subtype of psychophysiological insomnia has been proposed--attention-intention-effort (AIE) syndrome--that takes into consideration the interaction between behavioral and cognitive factors in the development and maintenance of insomnia. A series of studies from the University of Glasgow Sleep Centre using cognitive probe tasks has provided insight into this pathway, particularly with regard to the role of attention bias towards sleep stimuli in mediating insomnia. Further research is required to explore the cortical correlates of attention bias, investigate AIE as a potential causal mechanism of insomnia and examine AIE in other insomnia groups.


Residual economic burden of Streptococcus pneumoniae- and nontypeable Haemophilus influenzae-associated disease following vaccination with PCV-7: a multicountry analysis.
This paper estimates the annual direct medical and caregiver costs of Streptococcus pneumoniae (Sp) and nontypeable Haemophilus influenzae (NTHi)-associated diseases in children younger than 10 years in Canada, Germany, Mexico, and Norway after vaccination with the 7-valent pneumococcal conjugate vaccine (PCV-7). Per-episode direct medical costs for treating Sp- and NTHi-associated diseases were summarised from the literature for three countries, and a Delphi panel was used to estimate resource use and the per-episode costs for Mexico. Per-episode or annual costs were inflated to 2008 local currency and converted to 2008 United States (US) dollars using purchasing power parities. The analysis was for 1 year; therefore, costs were not discounted. Sp- and NTHi-associated diseases resulted in current annual national costs of $179-$260 million ($5.43-$7.89 per capita) in Canada, $290-$435 million ($3.53-$5.29 per capita) in Germany, $277-$432 million ($2.59-$4.05 per capita) in Mexico, and $20-$28 million ($4.35-$6.17 per capita) in Norway. Although acute otitis media (AOM) was associated with the lowest per-case costs, it accounted for between 45% and 88% of the national direct medical costs and between 67% and 96% of caregiver costs for Sp- and NTHi-associated diseases. Sp- and NTHi-associated diseases continue to result in substantial direct medical and caregiver costs despite current PCV-7 vaccination programs.


Changes in various metabolic parameters in blood and milk during experimental Escherichia coli mastitis for primiparous Holstein dairy cows during early lactation.
The objective of this study was to characterize the changes in various metabolic parameters in blood and milk during IMI challenge with Escherichia coli ( E. coli ) for dairy cows during early lactation. Thirty, healthy primiparous Holstein cows were infused (h = 0) with ~20-40 cfu of live E. coli into one front mammary quarter at ~4-6 wk in lactation. Daily feed intake and milk yield were recorded. At -12, 0, 3, 6, 12, 18, 24, 36, 48, 60, 72, 96, 108, 120, 132, 144, 156, 168, 180 and 192 h relative to challenge rectal temperatures were recorded and quarter foremilk was collected for analysis of shedding of E. coli. Composite milk samples were collected at -180, -132, -84, -36, -12, 12, 24, 36, 48, 60, 72, 84, 96, 132 and 180 h relative to challenge (h = 0) and analyzed for lactate dehydrogenase (LDH), somatic cell count, fat, protein, lactose, citrate, beta-hydroxybutyrate (BHBA), free glucose (fglu), and glucose-6-phosphate (G6P). Blood was collected at -12, 0, 3, 6, 12, 18, 24, 36, 60, 72, 84, 132 and 180 h relative to challenge and analyzed for plasma non-esterified fatty acids (NEFA), BHBA and glucose concentration. A generalized linear mixed model was used to determine the effect of IMI challenge on metabolic responses of cows during early lactation. By 12 h, E. coli was recovered from challenged quarters and shedding continued through 72 h. Rectal temperature peaked by 12 h post-challenge and returned to pre-challenge values by 36 h post-IMI challenge. Daily feed intake and milk yield decreased (P <0.05) by 1 and 2 d, respectively, after mastitis challenge. Plasma BHBA decreased (12 h; P <0.05) from 0.96 ± 1.1 at 0 h to 0.57 ± 0.64 mmol/L by 18 h whereas concentration of plasma NEFA (18 h) and glucose (24 h) were significantly greater, 11 and 27%, respectively, after challenge. In milk, fglu, lactose, citrate, fat and protein yield were lower whereas yield of BHBA and G6P were higher after challenge when compared to pre-challenge values. Changes in metabolites in blood and milk were most likely associated with drops in feed intake and milk yield. However, the early rise in plasma NEFA may also signify enhanced adipose tissue lipolysis. Lower concentrations of plasma BHBA may be attributed to an increase transfer into milk after IMI. Decreases in both milk lactose yield and % after challenge may be partly attributed to reduced conversion of fglu to lactose. Rises in G6P yield and concentration in milk after challenge (24 h) may signify increased conversion of fglu to G6P. Results identify changes in various metabolic parameters in blood and milk after IMI challenge with E. coli in dairy cows that may partly explain the partitioning of nutrients and changes in milk components after IMI for cows during early lactation.


Allergen-irritant interaction and the role of corticosteroids.
Studies of exposure to air pollutants, such as ozone and nitrogen dioxide (NO2) +/- sulphur dioxide (SO2), have demonstrated that these agents, either individually or in combination, increase the airway response of both asthmatics and allergic rhinitics to inhaled allergen. Other studies have demonstrated that exposure to these pollutants significantly increased the levels of eosinophil cationic protein (ECP) in the nasal secretions of both asthmatics and allergic rhinitics, suggesting that pollutants may prime eosinophils for subsequent activation by allergen. More recently, our studies have demonstrated that treatment with inhaled corticosteroids, such as fluticasone propionate, significantly attenuated pollution+ allergen-induced release of ECP in allergic rhinitics. Although the mechanisms underlying the potentiating effects of pollutants on allergen-induced changes in the airways of allergic individuals are not fully understood, in vitro studies have suggested that airway epithelial cells may play an important role, since they can synthesize a variety of cytokines and adhesion molecules which influence the activity of eosinophils and other inflammatory cells. Studies of nasal epithelial cells cultured from biopsies of atopic rhinitic and atopic non-rhinitic individuals have shown that they constitutively release significantly greater quantities of pro-inflammatory cytokines than nasal epithelial cells of non-atopic individuals, and that the release of these cytokines is greater from cells of atopic rhinitics during the pollen season. Furthermore, exposure of the cells of rhinitics to ozone led to an even greater release of these cytokines, and this effect was attenuated by treatment with fluticasone propionate and beclomethasone dipropionate.


Natural toxins: risks, regulations and the analytical situation in Europe.
Natural toxins in food and feed are considered important food safety issues of growing concern, in particular mycotoxins, phycotoxins and plant toxins. Most scientific developments have occurred in the past few decades in the area of mycotoxins. Formal health risk assessments have been carried out by the Joint Expert Committee on Food Additives of the World Health Organization and the Food and Agriculture Organization. Limits and regulations for mycotoxins in food and feed have been established in many countries, including practically all European countries. An array of (formally validated) analytical methods and (certified) reference materials have become available. Several European research projects, funded by the European Commission and supported by the European Standardization Committee, have significantly contributed to this development. Quantitative methods of analysis for mycotoxins often make use of immunoaffinity cleanup with liquid chromatographic or gas chromatographic separation techniques in combination with various types of detectors, including mass spectroscopy. For screening purposes (bio)sensor-based techniques are among the promising newcomers. For the phycotoxins the situation is less advanced. Formal risk assessments by authoritative international bodies have not been carried out. Methods of analysis, formally validated according to internationally harmonized protocols, are scarce and animal testing still plays a key role in official methodology. The development of the analytical methodology is partly hampered by the limited availability of certain reliable calibrants and reference materials, although this situation is gradually improving. New regulations in the European Union have increased the pressure to develop and validate chemical methods of analysis. Joint efforts in the European context are now directed towards significantly improving this situation, and techniques such as liquid chromatography-mass spectroscopy offer promise in this respect. Both the working group on biotoxins of the European Standardization Committee and the network of National Reference Laboratories for Marine Biotoxins have taken up responsibilities here. The plant toxins are a category of natural toxins, where the situation is the least developed with respect to regulations, validated methods of analysis and reference materials. Yet, their occurrence in a wide range of consumable plant species demands the attention of the analytical community.


Heart action of the freshwater bivalve Anodonta anatina during activity.
1. Heart action of Anodonta anatina (L.) was investigated by recording the electrocardiogram (ECG), heart impedance, and ventricular and pericardial cavity pressure during different aspects of the normal behaviour. The contribution of mechanical and nervous mechanisms in controlling changes in heart action is discussed. 2. Pressure recordings were generally more reliable than the other methods and it is suggested that pericardial pressure pulses indicate the stroke volume output of the ventricle. 3. During spontaneous periods of prolonged shell closure there was an initial small increase in heart activity followed by a large reduction in both heart rate and systolic pressure, indicating that total heart output was considerably reduced. When the shell reopened, heart rate increased very rapidly with an initial overshoot of the normal level; systolic pressure increased more slowly with no overshoot. 4. These major changes in heart activity appear to be associated with respiratory changes and are controlled largely by the nervous regulatory system, but some minor rhythmic variations in the amplitude of heart beat are probably caused by mechanical factors. 5. Characteristic patterns of change in heart action were recorded during burrowing. These appear to result from haemodynamic changes associated with the muscular movements of the digging cycle. Control of the heart by the nervous regulatory system is apparently of much greater importance in relation to respiratory control than in relation to the haemodynamic functioning of the fluid-muscle system in locomotion.


Domestication of plants in the Americas: insights from Mendelian and molecular genetics.
Plant domestication occurred independently in four different regions of the Americas. In general, different species were domesticated in each area, though a few species were domesticated independently in more than one area. The changes resulting from human selection conform to the familiar domestication syndrome, though different traits making up this syndrome, for example loss of dispersal, are achieved by different routes in crops belonging to different families. Understanding of the genetic control of elements of the domestication syndrome is improving as a result of the development of saturated linkage maps for major crops, identification and mapping of quantitative trait loci, cloning and sequencing of genes or parts of genes, and discoveries of widespread orthologies in genes and linkage groups within and between families. As the modes of action of the genes involved in domestication and the metabolic pathways leading to particular phenotypes become better understood, it should be possible to determine whether similar phenotypes have similar underlying genetic controls, or whether human selection in genetically related but independently domesticated taxa has fixed different mutants with similar phenotypic effects. Such studies will permit more critical analysis of possible examples of multiple domestications and of the origin(s) and spread of distinctive variants within crops. They also offer the possibility of improving existing crops, not only major food staples but also minor crops that are potential export crops for developing countries or alternative crops for marginal areas.


Pheochromocytoma associated with von Hippel-lindau disease in a Pakistani family.
The aim was to study the presentation, disease characteristics, operative outcome, and prognosis in patients with familial Pheochromocytoma associated with von Hippel-Lindau (VHL) disease. There were six patients belonging to two generations of a single family who developed features of VHL over a period of 13 years and were treated at our institute. Patients' characteristics, that is, age, gender, presenting complaints and clinical signs, laboratory and biochemical evaluation, and the presence of associated conditions was gathered from medical records. The preoperative and postoperative radiological imaging and histopathological results were also collected. Out of six cases, five were male, and one was female. The mean age at first presentation was 25 years (16-40). All patients presented with uncontrolled hypertension and were found to have Pheochromocytoma on workup. Three patients had unilateral adrenal tumor, and three had bilateral disease. None of the patients had extra-adrenal Pheochromocytoma. All patients were managed with adrenalectomy and had benign pathology. Two patients subsequently had craniotomy for excision of cerebellar hemangioma, and one patient had bilateral partial nephrectomy at the time of adrenalectomy. There was no peri- post-operative mortality and all patients are being followed by the surgeon(s) and endocrinologist. Pheochromocytoma can be a part of familial conditions including VHL. Other associated features should be suspected, investigated, and treated in these patients that can influence patients' clinical course and prognosis. Family members should also be screened to achieve early diagnosis.


Dicing with chance, life and death in systematic reviews and meta-analyses: D.I.C.E. 3, a simulation study.
To show the effects of chance on meta-analyses, and the potential dangers of being prompted to do a meta-analysis by one favourable trial. In total, 100,000 trials were simulated and combined into 10,000 meta-analyses, using data from the control group of a cancer trial. Each participant record was randomly coded to simulate allocation to 'treatment' or 'control'. Simulated study. De-identified records for 578 patients from the control group of a cancer trial, of whom 147 had died. Time to death from any cause. Of the 100,000 trials, 4897 (4.9%) were statistically significant at 2p < 0.05 and 123 (1.2%) of the 10,000 meta-analyses were significant at 2p < 0.01. The most extreme result was a 20% reduction (99% CI: 0.70-0.91; 2p = 0.00002) in the annual odds of dying in the 'treatment' group. If a meta-analysis contained at least one trial with a statistically significant result (at 2p < 0.05), the likelihood of the meta-analysis being significant (at 2p < 0.01) increased strikingly. For example, among the 473 meta-analyses in which the first trial in a batch of 10 was statistically significant (at 2p < 0.05), 18 (3.8%) favoured treatment at 2p < 0.01. Chance can influence the results of meta-analyses regardless of how well they are conducted. Researchers should not ignore this when they plan a meta-analysis and when they report their results. People reading their reports should also be wary. Caution is particularly important when the results of one or more included studies influenced the decision to do the meta-analysis.


Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?
The discovery of somatic mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) in glioblastomas was remarkable because the enzyme was not previously identified with any known oncogenic pathway. IDH1 is mutated in up to 75% of grade II and grade III diffuse gliomas. Apart from acute myeloid leukaemia, other tumour types do not carry IDH1 mutations. Mutations in a homologous gene, IDH2, have also been identified, although they are much rarer. Although TP53 mutations and 1p/19q codeletions are mutually exclusive in gliomas, in both of these genotypes IDH1 mutations are common. IDH1 and IDH2 mutations are early events in the development of gliomas. Moreover, IDH1 and IDH2 mutations are a major prognostic marker for overall and progression-free survival in grade II-IV gliomas. Mutated IDH1 has an altered catalytic activity that results in the accumulation of 2-hydroxyglutarate. Molecularly, IDH1 and IDH2 mutations are heterozygous, affect only a single codon, and rarely occur together. Because IDH1 does not belong to a traditional oncogenic pathway and is specifically and commonly mutated in gliomas, the altered enzymatic activity of IDH1 may provide a fundamentally new understanding of diffuse glioma.


Effects of adding ezetimibe to fluvastatin on kidney function in patients with hypercholesterolemia: a randomized control trial.
Statins not only reduce low-density lipoprotein (LDL) cholesterol, but also prevent the progression of kidney dysfunction. Ezetimibe, a cholesterol-absorption inhibitor, also lowers LDL cholesterol levels when added to statins; however, the effect of add-on ezetimibe on kidney function has had conflicting results. We conducted an open-labeled, randomized, 12-month trial, comparing the effects of daily therapy with 20 mg fluvastatin either with or without 10 mg ezetimibe in 54 patients with dyslipidemia. The prespecified primary outcome was the percent change from baseline in kidney function, which was defined by the estimated glomerular filtration rate. The secondary outcomes were the changes in surrogate atherosclerotic markers. All analyses were by intention to treat. The primary outcome, the percent change from baseline (±SE) of the estimated glomerular filtration rate, was -5.5±1.9% in the fluvastatin-only group and 6.6±1.9% in the fluvastatin-plus-ezetimibe (combined-therapy) group (p=0.0002). Secondary outcomes, consisting of the cardioankle vascular index, augmentation index, ankle-brachial index, and maximum intima-media thickness of the carotid arteries, did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol was 122±23 mg per deciliter in the fluvastatin group and 111±29 mg per deciliter in the combined-therapy group (a between-group difference of 9.2%, p= 0.036). Side-effect and safety profiles were similar in the two groups. Combined therapy with fluvastatin 20 mg plus ezetimibe 10 mg daily resulted in a significant improvement in changes in the estimated glomerular filtration rate.


An Open-Access, Interactive Decision-Support Tool to Facilitate Guideline-Driven Care for Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is increasing in incidence and is a leading cause of cancer-related mortality worldwide. Adherence to HCC surveillance guidelines and appropriate treatment triage of liver lesions may improve receipt of curative-intent treatment and improved survival. Late-stage HCC diagnosis reflects sub-optimal implementation of effective HCC surveillance, whereas inappropriate treatment triage or linkage to care accounts for the non-receipt of curative-intent in close to half of early-stage HCC in the USA. A free, open-access decision-support tool for liver lesions that incorporates current guideline recommendations in a user-friendly interface could improve appropriate and timely triage of patients to appropriate care. This review provides a summary of gaps and disparities in linkage to HCC care and introduces a free, internet-based, interactive decision-support tool for managing liver lesions. This tool has been developed by the HCC Steering Committee of the Chronic Liver Disease Foundation and is targeted toward clinicians across specialties who may encounter liver lesions during routine care or as part of dedicated HCC surveillance.


Arbitrary birefringent metamaterials for holographic optics at λ = 1.55 μm.
This paper presents an optical element capable of multiplexing two diffraction patterns for two orthogonal linear polarizations, based on the use of non-resonant metamaterial cross elements. The metamaterial cross elements provide unique building blocks for engineering arbitrary birefringence. As a proof-of-concept demonstration, we present the design and experimental characterization of a polarization multiplexed blazed diffraction grating and a polarization multiplexed computer-generated hologram, for the telecommunication wavelength of λ = 1.55 μm. A quantitative study of the polarization multiplexed grating reveals that this approach yields a very large polarization contrast ratio. The results show that metamaterials can form the basis for a versatile and compact platform useful in the design of multi-functional photonic devices.


Surfactant protein levels in severe respiratory syncytial virus infection.
Infection with respiratory syncytial virus (RSV) is a common cause of respiratory disease in infancy. Surfactant phospholipids have been shown to be reduced in severe RSV infection. Reduction in surfactant proteins might also contribute to the pathogenesis of this disease. We investigated daily levels of surfactant proteins in bronchoalveolar lavage (BAL) fluid from 18 ventilated infants with RSV infection (median age 3.1 mo) and in a control group of 16 ventilated surgical patients (median age 0.4 mo). Surfactant proteins were measured by ELISA, total protein by the Lowry method. Surfactant protein A (SP-A) was reduced in BAL fluid from children with RSV infection (median 5.6 micrograms/ml; range 0.6 to 151.9 micrograms/ml) compared with control samples (median 9.0 micrograms/ml; range 0.5 to 139.6 micrograms/ml, p = 0.0368). Surfactant protein B (SP-B) was lower in the RSV group (median 12.0 ng/ml; range 0 to 60. 8 ng/ml) than in control patients (median 118.1 ng/ml; range 0 to 778.2 ng/ml, p < 0.0000). Surfactant protein D (SP-D) was also reduced in the RSV group (median 130.3 ng/ml; range 0 to 1,486.0 ng/ml) versus median 600.4 ng/ml; range 0 to 1,869.0 ng/ml, p < 0. 0000. Total protein levels were higher in the RSV group (median 0.49 mg/ml; range 0.13 to 2.46 mg/ml versus median 0.36 mg/ml; range 0.07 to 1.65 mg/ml, p = 0.0079). The median value of SP-A was significantly lower in the initial sample (2.3 micrograms/ml) than in the final one (6.0 micrograms/ml). However, no significant correlation was found between surfactant protein concentrations and disease severity measured by arterial alveolar oxygen ratio. We conclude that alterations in surfactant protein concentrations are present in severe RSV infection and speculate that these may contribute to the abnormalities of lung function seen in this condition.


Allele-specific silencing of the gain-of-function mutation in Huntington's disease using CRISPR/Cas9.
Dominant gain-of-function mechanisms in Huntington's disease (HD) suggest that selective silencing of mutant HTT produces robust therapeutic benefits. Here, capitalizing on exonic protospacer adjacent motif-altering (PAM-altering) SNP (PAS), we developed an allele-specific CRISPR/Cas9 strategy to permanently inactivate mutant HTT through nonsense-mediated decay (NMD). Comprehensive sequence/haplotype analysis identified SNP-generated NGG PAM sites on exons of common HTT haplotypes in HD subjects, revealing a clinically relevant PAS-based mutant-specific CRISPR/Cas9 strategy. Alternative allele of rs363099 (29th exon) eliminates the NGG PAM site on the most frequent normal HTT haplotype in HD, permitting mutant-specific CRISPR/Cas9 therapeutics in a predicted ~20% of HD subjects with European ancestry. Our rs363099-based CRISPR/Cas9 showed perfect allele specificity and good targeting efficiencies in patient-derived cells. Dramatically reduced mutant HTT mRNA and complete loss of mutant protein suggest that our allele-specific CRISPR/Cas9 strategy inactivates mutant HTT through NMD. In addition, GUIDE-Seq analysis and subsequent validation experiments support high levels of on-target gene specificity. Our data demonstrate a significant target population, complete mutant specificity, decent targeting efficiency in patient-derived cells, and minimal off-target effects on protein-coding genes, proving the concept of PAS-based allele-specific NMD-CRISPR/Cas9 and supporting its therapeutic potential in HD.


Evolving revascularization approaches for myocardial ischemia.
Stable angina pectoris secondary to ischemic heart disease is a common and disabling condition. Medical therapy aims to relieve symptoms, improve exercise capacity, and decrease cardiac events by reducing myocardial oxygen demand or improving coronary blood supply to the ischemic myocardium. If medical treatment is inadequate, invasive revascularization procedures to improve coronary perfusion are considered. Percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery are well-established and widely used myocardial revascularization techniques. Recent advances in PTCA have attempted to address the problem of restenosis, initially through the deployment of bare metal intracoronary stents and, more recently, with drug-eluting stents. Developments in CABG have focused on reducing the invasiveness of the procedure and minimizing the incidence of serious complications. Refinements include the use of mechanical stabilizers, endoscopic harvesting of conduit vessels, robotic telemanipulation systems, and fully automated anastomotic devices. Surgical laser transmyocardial revascularization and therapeutic angiogenesis represent newer approaches to coronary revascularization. Therapeutic angiogenesis aims to deliver an angiogenic growth factor or cytokine to the myocardium to stimulate collateral blood vessel growth throughout the ischemic tissue. The angiogenic factor may be administered as a recombinant protein or as a transgene within a plasmid or gene-transfer vector. Ongoing angiogenic gene therapy clinical trials are evaluating which factors, vectors, and delivery techniques hold the greatest promise for management of patients with chronic stable angina.


Convergence and contingency in production-precipitation relationships in North American and South African C4 grasslands.
Mesic grasslands in North America and South Africa share many structural attributes, but less is known of their functional similarities. We assessed the control of a key ecosystem process, aboveground net primary production (ANPP), by interannual variation in precipitation amount and pattern via analysis of data sets (15- and 24-year periods) from long-term research programs on each continent. Both sites were dominated by C(4) grasses and had similar growing season climates; thus, we expected convergence in precipitation-ANPP relationships. Lack of convergence, however, would support an alternative hypothesis-that differences in evolutionary history and purportedly greater climatic variability in South Africa fundamentally alter the functioning of southern versus northern hemisphere grasslands. Neither mean annual precipitation nor mean ANPP differed between the South African and North American sites (838 vs. 857 mm/year, 423.5 vs. 461.4 g/m(2) respectively) and growing season precipitation-ANPP relationships were similar. Despite overall convergence, there were differences between sites in how the seasonal timing of precipitation affected ANPP. In particular, interannual variability in precipitation that fell during the first half of the growing season strongly affected annual ANPP in South Africa (P < 0.01), but was not related to ANPP in North America (P = 0.098). Both sites were affected similarly by late season precipitation. Divergence in the seasonal course of available soil moisture (chronically low in the winter and early spring in the South African site vs. high in the North American site) is proposed as a key contingent factor explaining differential sensitivity in ANPP to early season precipitation in these two grasslands. These long-term data sets provided no support for greater rainfall, temperature or ANPP variability in the South African versus the North American site. However, greater sensitivity of ANPP to early season precipitation in the South African grassland suggests that future patterns of productivity may be more responsive to seasonal changes in climate compared with the North American site.


CaRuby-Nano: a novel high affinity calcium probe for dual color imaging.
The great demand for long-wavelength and high signal-to-noise Ca(2+) indicators has led us to develop CaRuby-Nano, a new functionalizable red calcium indicator with nanomolar affinity for use in cell biology and neuroscience research. In addition, we generated CaRuby-Nano dextran conjugates and an AM-ester variant for bulk loading of tissue. We tested the new indicator using in vitro and in vivo experiments demonstrating the high sensitivity of CaRuby-Nano as well as its power in dual color imaging experiments.


Evolution of resistance to transgenic crops: interactions between insect movement and field distribution.
The refuge strategy is designed to delay evolution of pest resistance to transgenic crops producing Bacillus thuringiensis Berliner (Bt) toxins. Movement of insects between Bt crops and refuges of non-Bt crops is essential for the refuge strategy because it increases chances that resistant adults mate with susceptible adults from refuges. Conclusions about optimal levels of movement for delaying resistance are not consistent among previous modeling studies. To clarify the effects of movement on resistance evolution, we analyzed simulations of a spatially explicit model based partly on the interaction of pink bollworm, Pectinophora gossypiella (Saunders), with Bt cotton. We examined resistance evolution as a function of insect movement under 12 sets of assumptions about the relative abundance of Bt cotton (50 and 75%), temporal distribution of Bt cotton and refuge fields (fixed, partial rotation, and full rotation), and spatial distribution of fields (random and uniform). The results show that interactions among the relative abundance and distribution of refuges and Bt cotton fields can alter the effects of movement on resistance evolution. The results also suggest that differences in conclusions among previous studies can be explained by differences in assumptions about the relative abundance and distribution of refuges and Bt crop fields. With fixed field locations and all Bt cotton fields adjacent to at least one refuge, resistance evolved slowest with low movement. However, low movement and fixed field locations favored rapid resistance evolution when some Bt crop fields were isolated from refuges. When refuges and Bt cotton fields were rotated to the opposite crop type each year, resistance evolved fastest with low movement. Nonrecessive inheritance of resistance caused rapid resistanceevolution regardless of movement rate. Confirming previous reports, results described here show that resistance can be delayed effectively by fixing field locations and distributing refuges uniformly to ensure that Bt crop fields are not isolated from refuges. However, rotating fields provided better insect control and reduced the need for insecticide sprays.


18 F-FDG avid lesion due to coexistent fibrous dysplasia in a child of embryonal rhabdomyosarcoma: source of false positive FDG-PET.
With increasing use of 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in the current oncological practice, there is a growing body of evidence of false positive scans due to various benign conditions. In this communication we present intensely avid 18 F-FDG uptake in fibrous dysplasia of right tibia in a 12-year-old child suffering from embryonal rhabdomyosarcoma (ERMS) that could have been easily mistaken to be a metastatic focus if not carefully correlated. The patient was a case of ERMS (presenting with left cervical mass with intrathoracic extension) who was treated successfully with chemotherapy and was referred for FDG-PET to evaluate the disease status. His whole body survey was unremarkable except for an intensely avid FDG uptake (SUV max 8.5) in shaft of right tibia. The scan was extended up to foot in view of the fact that a prior bone scan had shown a focal uptake in the similar location. Efforts were undertaken to elucidate the exact etiopathology of the aforementioned 18 F-FDG uptake because the rest of the whole body survey was unremarkable. A plain radiograph (both anteroposterior and lateral views) of the right tibia showed patchy sclerosis involving the middle diaphysis of the right tibia suggesting a fibrous defect. The computed tomography (CT) scan of the same region showed cortical thickening and increased density within the medullary cavity in the shaft of the tibia. A histopathological diagnosis was sought for and the lesion was subsequently proven to be fibrous dysplasia by histopathology of the bone piece obtained from the right tibial lesion by J needle biopsy. The present case is a useful addition to the current body of literature of false positive 18 F-FDG-PET study due to a benign skeletal pathology and underscores the importance of high index of suspicion and careful clinicoradiopathologic correlation, whenever one comes across such an unusual PET finding.


Semantic Predications for Complex Information Needs in Biomedical Literature.
Many complex information needs that arise in biomedical disciplines require exploring multiple documents in order to obtain information. While traditional information retrieval techniques that return a single ranked list of documents are quite common for such tasks, they may not always be adequate. The main issue is that ranked lists typically impose a significant burden on users to filter out irrelevant documents. Additionally, users must intuitively reformulate their search query when relevant documents have not been not highly ranked. Furthermore, even after interesting documents have been selected, very few mechanisms exist that enable document-to-document transitions. In this paper, we demonstrate the utility of assertions extracted from biomedical text (called semantic predications) to facilitate retrieving relevant documents for complex information needs. Our approach offers an alternative to query reformulation by establishing a framework for transitioning from one document to another. We evaluate this novel knowledge-driven approach using precision and recall metrics on the 2006 TREC Genomics Track.


Walnut Consumption, Plasma Metabolomics, and Risk of Type 2 Diabetes and Cardiovascular Disease.
Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases. The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD. The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m2): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training-validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models. A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001). A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk.


PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis.
We report the engineering and characterization of paraoxonase-3 knockout mice (Pon3KO). The mice were generally healthy but exhibited quantitative alterations in bile acid metabolism and a 37% increased body weight compared to the wild-type mice on a high fat diet. PON3 was enriched in the mitochondria-associated membrane fraction of hepatocytes. PON3 deficiency resulted in impaired mitochondrial respiration, increased mitochondrial superoxide levels, and increased hepatic expression of inflammatory genes. PON3 deficiency did not influence atherosclerosis development on an apolipoprotein E null hyperlipidemic background, but it did lead to a significant 60% increase in atherosclerotic lesion size in Pon3KO mice on the C57BL/6J background when fed a cholate-cholesterol diet. On the diet, the Pon3KO had significantly increased plasma intermediate-density lipoprotein/LDL cholesterol and bile acid levels. They also exhibited significantly elevated levels of hepatotoxicity markers in circulation, a 58% increase in gallstone weight, a 40% increase in hepatic cholesterol level, and increased mortality. Furthermore, Pon3KO mice exhibited decreased hepatic bile acid synthesis and decreased bile acid levels in the small intestine compared with wild-type mice. Our study suggests a role for PON3 in the metabolism of lipid and bile acid as well as protection against atherosclerosis, gallstone disease, and obesity.


Assessing the diversity of arbuscular mycorrhizal fungi in semiarid shrublands dominated by Artemisia tridentata ssp. wyomingensis.
Variation in the abiotic environment and host plant preferences can affect the composition of arbuscular mycorrhizal (AMF) assemblages. This study analyzed the AMF taxa present in soil and seedlings of Artemisia tridentata ssp. wyomingensis collected from sagebrush steppe communities in southwestern Idaho, USA. Our aims were to determine the AMF diversity within and among these communities and the extent to which preferential AMF-plant associations develop during seedling establishment. Mycorrhizae were identified using molecular methods following DNA extraction from field and pot culture samples. The extracted DNA was amplified using Glomeromycota specific primers, and identification of AMF was based on phylogenetic analysis of sequences from the large subunit-D2 rDNA region. The phylogenetic analyses revealed seven phylotypes, two within the Claroideoglomeraceae and five within the Glomeraceae. Four phylotypes clustered with known species including Claroideoglomus claroideum, Rhizophagus irregularis, Glomus microaggregatum, and Funneliformis mosseae. The other three phylotypes were similar to several published sequences not included in the phylogenetic analysis, but all of these were from uncultured and unnamed glomeromycetes. Pairwise distance analysis revealed some phylotypes with high genetic variation. The most diverse was the phylotype that included R. irregularis, which contained sequences showing pairwise differences up to 12 %. Most of the diversity in AMF sequences occurred within sites. The smaller genetic differentiation detected among sites was correlated with differences in soil texture. In addition, multiplication in pot cultures led to differentiation of AMF communities. Comparison of sequences obtained from the soil with those from A. tridentata roots revealed no significant differences between the AMF present in these samples. Overall, the sites sampled were dominated by cosmopolitan AMF taxa, and young seedlings of A. tridentata ssp. wyomingensis were colonized in relation to the abundance of these taxa in the soil.


Bacterial exopolysaccharides from extreme marine habitats: production, characterization and biological activities.
Many marine bacteria produce exopolysaccharides (EPS) as a strategy for growth, adhering to solid surfaces, and to survive adverse conditions. There is growing interest in isolating new EPS producing bacteria from marine environments, particularly from extreme marine environments such as deep-sea hydrothermal vents characterized by high pressure and temperature and heavy metal presence. Marine EPS-producing microorganisms have been also isolated from several extreme niches such as the cold marine environments typically of Arctic and Antarctic sea ice, characterized by low temperature and low nutrient concentration, and the hypersaline marine environment found in a wide variety of aquatic and terrestrial ecosystems such as salt lakes and salterns. Most of their EPSs are heteropolysaccharides containing three or four different monosaccharides arranged in groups of 10 or less to form the repeating units. These polymers are often linear with an average molecular weight ranging from 1 x 10(5) to 3 x 10(5) Da. Some EPS are neutral macromolecules, but the majority of them are polyanionic for the presence of uronic acids or ketal-linked pyruvate or inorganic residues such as phosphate or sulfate. EPSs, forming a layer surrounding the cell, provide an effective protection against high or low temperature and salinity, or against possible predators. By examining their structure and chemical-physical characteristics it is possible to gain insight into their commercial application, and they are employed in several industries. Indeed EPSs produced by microorganisms from extreme habitats show biotechnological promise ranging from pharmaceutical industries, for their immunomodulatory and antiviral effects, bone regeneration and cicatrizing capacity, to food-processing industries for their peculiar gelling and thickening properties. Moreover, some EPSs are employed as biosurfactants and in detoxification mechanisms of petrochemical oil-polluted areas. The aim of this paper is to give an overview of current knowledge on EPSs produced by marine bacteria including symbiotic marine EPS-producing bacteria isolated from some marine annelid worms that live in extreme niches.


An oasis in the hospital: the perceived benefits of a cancer support center in a hospital setting offering complementary therapies.
The aim of this study was to explore and describe the experiences of persons attending a cancer support center, providing emotional support to cancer patients through self-selected complementary therapies offered free of charge through qualified volunteer therapists. A grounded theory methodology was used. Sources of data were 16 semistructured interviews with persons attending the center. Interviews were digitally recorded and transcribed verbatim. Analysis was conducted using the constant comparative method. The overarching theme that emerged in this study was the benefits attributed to attendance at the cancer support center. The center was described as an "oasis" in the hospital, and three aspects relating to this were identified: (a) facilitating comfort, (b) increasing personal control, and (c) helping make sense of the cancer experience. A drop-in center offering complementary therapies appeared to enable coping with the diagnosis and treatment of cancer by facilitating comfort and increasing perceptions of personal control. The center also helped some participants to make sense of their experience with cancer. This research has provided a unique insight into the ongoing emotional needs of cancer patients, and directions for further development and research into the provision of holistic care for patients within a hospital setting.


The effect of combined resistance and home-based walking exercise in type 2 diabetes patients.
The aim of this study was to evaluate the effect of combined resistance and home-based walking exercise on glycemic and metabolic control, depression and quality of life in type-2 diabetes patients. This prospective study was conducted at a private hospital in Turkey. Thirty-six type-2 diabetic patients participated in the study. Subjects were randomly distributed in one 8 week exercise intervention or in one control group. Exercise program consisted of resistance training and home-based walking. Before and after the training program, muscular strength, fasting blood glucose, hemoglobin A1C, (HbA1C) and plasma lipid values, quality of life and symptoms of depression of the patients were assessed. Exercise group's baseline HbA1C was significantly higher than the control groups (p< 0.05); other blood parameters were similar between the two groups (p>0.05). At the baseline no significant differences were observed in the depression and four subscales (physical function, physical role, bodily pain, and general health perceptions) of the SF-36 between the exercise and control groups (p>0.05). The exercise group had higher scores of emotional role, vitality and mental health subscales than the control groups after the training programs (p<0.05). Exercise training which included resistance training and home- based walking could be safe, effective and beneficial in diabetic patients.


Using AMANHI-ACT cohorts for external validation of Iowa new-born metabolic profiles based models for postnatal gestational age estimation.
Globally, 15 million infants are born preterm and another 23.2 million infants are born small for gestational age (SGA). Determining burden of preterm and SGA births, is essential for effective planning, modification of health policies and targeting interventions for reducing these outcomes for which accurate estimation of gestational age (GA) is crucial. Early pregnancy ultrasound measurements, last menstrual period and post-natal neonatal examinations have proven to be not feasible or inaccurate. Proposed algorithms for GA estimation in western populations, based on routine new-born screening, though promising, lack validation in developing country settings. We evaluated the hypothesis that models developed in USA, also predicted GA in cohorts of South Asia (575) and Sub-Saharan Africa (736) with same precision. Dried heel prick blood spots collected 24-72 hours after birth from 1311 new-borns, were analysed for standard metabolic screen. Regression algorithm based, GA estimates were computed from metabolic data and compared to first trimester ultrasound validated, GA estimates (gold standard). Overall Algorithm (metabolites + birthweight) estimated GA to within an average deviation of 1.5 weeks. The estimated GA was within the gold standard estimate by 1 and 2 weeks for 70.5% and 90.1% new-borns respectively. Inclusion of birthweight in the metabolites model improved discriminatory ability of this method, and showed promise in identifying preterm births. Receiver operating characteristic (ROC) curve analysis estimated an area under curve of 0.86 (conservative bootstrap 95% confidence interval (CI) = 0.83 to 0.89); P < 0.001) and Youden Index of 0.58 (95% CI = 0.51 to 0.64) with a corresponding sensitivity of 80.7% and specificity of 77.6%. Metabolic gestational age dating offers a novel means for accurate population-level gestational age estimates in LMIC settings and help preterm birth surveillance initiatives. Further research should focus on use of machine learning and newer analytic methods broader than conventional metabolic screen analytes, enabling incorporation of region-specific analytes and cord blood metabolic profiles models predicting gestational age accurately.


Applications and Techniques for Fast Machine Learning in Science.
In this community review report, we discuss applications and techniques for fast machine learning (ML) in science-the concept of integrating powerful ML methods into the real-time experimental data processing loop to accelerate scientific discovery. The material for the report builds on two workshops held by the Fast ML for Science community and covers three main areas: applications for fast ML across a number of scientific domains; techniques for training and implementing performant and resource-efficient ML algorithms; and computing architectures, platforms, and technologies for deploying these algorithms. We also present overlapping challenges across the multiple scientific domains where common solutions can be found. This community report is intended to give plenty of examples and inspiration for scientific discovery through integrated and accelerated ML solutions. This is followed by a high-level overview and organization of technical advances, including an abundance of pointers to source material, which can enable these breakthroughs.


The adult human subventricular zone: partial ependymal coverage and proliferative capacity of cerebrospinal fluid.
Neurogenesis continues throughout adulthood in specialized regions of the brain. One of these regions is the subventricular zone. During brain development, neurogenesis is regulated by a complex interplay of intrinsic and extrinsic cues that control stem-cell survival, renewal and cell lineage specification. Cerebrospinal fluid (CSF) is an integral part of the neurogenic niche in development as it is in direct contact with radial glial cells, and it is important in regulating proliferation and migration. Yet, the effect of CSF on neural stem cells in the subventricular zone of the adult human brain is unknown. We hypothesized a persistent stimulating effect of ventricular CSF on neural stem cells in adulthood, based on the literature, describing bulging accumulations of subventricular cells where CSF is in direct contact with the subventricular zone. Here, we show by immunohistochemistry on post-mortem adult human subventricular zone sections that neural stem cells are in close contact with CSF via protrusions through both intact and incomplete ependymal layers. We are the first to systematically quantify subventricular glial nodules denuded of ependyma and consisting of proliferating neural stem and progenitor cells, and showed that they are present from foetal age until adulthood. Neurosphere, cell motility and differentiation assays as well as analyses of RNA expression were used to assess the effects of CSF of adult humans on primary neural stem cells and a human immortalized neural stem cell line. We show that human ventricular CSF increases proliferation and decreases motility of neural stem cells. Our results also indicate that adult CSF pushes neural stem cells from a relative quiescent to a more active state and promotes neuronal over astrocytic lineage differentiation. Thus, CSF continues to stimulate neural stem cells throughout aging.


Long-term results of electrical stimulation of the lower esophageal sphincter for the treatment of gastroesophageal reflux disease.
In patients with gastroesophageal reflux disease (GERD), temporary electrical stimulation of the lower esophageal sphincter (LES) increases LES pressure without interference with LES relaxation. The aim of the current study was to investigate the safety and efficacy of long term LES electrical stimulation therapy (LES-EST), using a permanently implanted stimulator for the treatment of GERD. Patients with GERD who were at least partially responsive to proton pump inhibitors (PPIs) and who had hiatal hernia of ≤ 3 cm and esophagitis of Los Angeles Grade A, B, or C were included in the study. Stimulation electrodes were placed in the LES and a pulse generator (EndoStim LES Stimulation System; EndoStim BV, The Hague, The Netherlands) was implanted laparoscopically. LES stimulation was delivered at 20 Hz, 215 μs, 3 - 8 mA in multiple 30-minute sessions. Patients were evaluated at follow-up using the GERD Health-Related Quality of Life (HRQL) questionnaire, daily symptom and medication diaries, the SF-12 Health Survey, esophageal pH testing, and high resolution manometry. A total of 24 patients (mean age 53 ± 12 years; 14 men) were implanted and 23 completed the 12-month evaluation. No serious implantation or stimulation-related adverse affects or sensations were reported. Median composite GERD-HRQL score at 12 months was 2.0 (interquartile range [IQR] 0 - 3.0), which was significantly better than baseline scores both on PPI therapy (median 9.0, IQR 6.0 - 10.0; P = 0.002) and off PPIs (median 23.5, IQR 21 - 25.75; P < 0.001). The median percentage of the 24-hour period with esophageal pH < 4.0 at baseline was 10.1 % (IQR 7.7 - 15.5), which was reduced to 3.3 % (1.8 - 6.9) at 12 months (P < 0.001), with 69 % of patients showing either normalization or > 50 % improvement in their distal esophageal pH. At 12 months, 96 % of patients (22/23) were completely off PPI medication. During the long term follow-up of 12 months, LES - EST was safe and effective for the treatment of GERD. There was a significant and sustained improvement in GERD symptoms, reduction in esophageal acid exposure with elimination of daily PPI usage, and no stimulation-related adverse effects.


Spectral Laplace-Beltrami wavelets with applications in medical images.
The spectral graph wavelet transform (SGWT) has recently been developed to compute wavelet transforms of functions defined on non-Euclidean spaces such as graphs. By capitalizing on the established framework of the SGWT, we adopt a fast and efficient computation of a discretized Laplace-Beltrami (LB) operator that allows its extension from arbitrary graphs to differentiable and closed 2-D manifolds (smooth surfaces embedded in the 3-D Euclidean space). This particular class of manifolds are widely used in bioimaging to characterize the morphology of cells, tissues, and organs. They are often discretized into triangular meshes, providing additional geometric information apart from simple nodes and weighted connections in graphs. In comparison with the SGWT, the wavelet bases constructed with the LB operator are spatially localized with a more uniform "spread" with respect to underlying curvature of the surface. In our experiments, we first use synthetic data to show that traditional applications of wavelets in smoothing and edge detectio can be done using the wavelet bases constructed with the LB operator. Second, we show that multi-resolutional capabilities of the proposed framework are applicable in the classification of Alzheimer's patients with normal subjects using hippocampal shapes. Wavelet transforms of the hippocampal shape deformations at finer resolutions registered higher sensitivity (96%) and specificity (90%) than the classification results obtained from the direct usage of hippocampal shape deformations. In addition, the Laplace-Beltrami method requires consistently a smaller number of principal components (to retain a fixed variance) at higher resolution as compared to the binary and weighted graph Laplacians, demonstrating the potential of the wavelet bases in adapting to the geometry of the underlying manifold.


Goitrogenic/antithyroidal potential of green tea extract in relation to catechin in rats.
Catechins are flavonoids found in abundance in green tea, have elicited high interest due to their beneficial effects on health. Though flavonoids have been reported to have an antithyroid effect and also to be goitrogenic there have been no reports about the effect of green tea on rat thyroid. The present study was designed to examine whether high doses of green tea has any harmful effect on thyroid physiology. For this purpose green tea extract was administered orally to male albino rats for 30 days at doses of 1.25 g%, 2.5 g% and 5.0 g%, respectively. Similarly, pure catechin was administered at doses of 25, 50 and 100mg/kg body weight which is equivalent to above doses of green tea extract. Lower body weight gain associated with marked hypertrophy and/or hyperplasia of the follicles was noted in the high dose of green tea and catechin treated groups. Decreased activity of thyroid peroxidase and 5'-deiodinase I and substantially elevated thyroidal Na,K+ATPase activity have been observed. Moreover, serum T3 and T4 levels were found to reduce followed by significant elevation of serum TSH. Taken together, these results suggest that catechin present in green tea extract might behave as antithyroid agent and possibly the consumption of green tea at high dose could alter thyroid function adversely.


Men's and Women's World Championship Marathon Performances and Changes With Fatigue Are Not Explained by Kinematic Differences Between Footstrike Patterns.
World-class marathon runners make initial contact with the rearfoot, midfoot or forefoot. This novel study analyzed kinematic similarities and differences between rearfoot and non-rearfoot strikers within the men's and women's 2017 IAAF World Championship marathons across the last two laps. Twenty-eight men and 28 women, equally divided by footstrike pattern, were recorded at 29.5 and 40 km (laps 3 and 4, respectively) using two high-definition cameras (50 Hz). The videos were digitized to derive spatiotemporal and joint kinematic data, with additional footage (120 Hz) used to identify footstrike patterns. There was no difference in running speed, step length or cadence between rearfoot and non-rearfoot strikers during either lap in both races, and these three key variables decreased in athletes of either footstrike pattern to a similar extent between laps. Men slowed more than women between laps, and overall had greater reductions in step length and cadence. Rearfoot strikers landed with their foot farther in front of the center of mass (by 0.02-0.04 m), with non-rearfoot strikers relying more on flight distance for overall step length. Male rearfoot strikers had more extended knees, dorsiflexed ankles and hyperextended shoulders at initial contact than non-rearfoot strikers, whereas female rearfoot strikers had more flexed hips and extended knees at initial contact. Very few differences were found at midstance and toe-off. Rearfoot and non-rearfoot striking techniques were therefore mostly indistinguishable except at initial contact, and any differences that did occur were very small. The spatiotemporal variables that differed between footstrike patterns were not associated with faster running speeds and, ultimately, neither footstrike pattern prevented reductions in running speeds. The only joint angle measured at a specific gait event to change with fatigue was midswing knee flexion angle in men. Coaches should thus note that encouraging marathon runners to convert from rearfoot to non-rearfoot striking is unlikely to provide any performance benefits, and that training the fatigue resistance of key lower limb muscle-tendon units to avoid decreases in step length and cadence are more useful in preventing reductions in speed during the later stages of the race.


Soda taxes, soft drink consumption, and children's body mass index.
Taxes on sugar-sweetened beverages have been proposed to combat obesity. Using data on state sales taxes for soda and individual-level data on children, we examine whether small taxes are likely to change consumption and weight gain or whether larger tax increases would be needed. We find that existing taxes on soda, which are typically not much higher than 4 percent in grocery stores, do not substantially affect overall levels of soda consumption or obesity rates. We do find, however, that subgroups of at-risk children--children who are already overweight, come from low-income families, or are African American--may be more sensitive than others to soda taxes, especially when soda is available at school. A greater impact of these small taxes could come from the dedication of the revenues they generate to other obesity prevention efforts rather than through their direct effect on consumption.