MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis.
The subthreshold, voltage-gated potassium channel of skeletal muscle is shown to contain MinK-related peptide 2 (MiRP2) and the pore-forming subunit Kv3.4. MiRP2-Kv3.4 channels differ from Kv3.4 channels in unitary conductance, voltage-dependent activation, recovery from inactivation, steady-state open probability, and block by a peptide toxin. Thus, MiRP2-Kv3.4 channels set resting membrane potential (RMP) and do not produce afterhyperpolarization or cumulative inactivation to limit action potential frequency. A missense mutation is identified in the gene for MiRP2 (KCNE3) in two families with periodic paralysis and found to segregate with the disease. Mutant MiRP2-Kv3.4 complexes exhibit reduced current density and diminished capacity to set RMP. Thus, MiRP2 operates with a classical potassium channel subunit to govern skeletal muscle function and pathophysiology.


Ankylosing spondylitis traumatic subaxial cervical fractures - An updated treatment algorithm.
Ankylosing spondylitis (AS) is a rheumatologic disease characterized by ankylosis and ligament ossification of the spine with an elevated risk of vertebrae fractures at the cervical level or cervicothoracic junction. AS related cervical fractures (ASCFs) require early diagnosis and a treatment plan that considers the high risk for additional fractures to avoid neurological complications or death. We present the case of a patient with an ASCF and a review of the literature with key recommendations that shape our algorithm for the proper diagnosis and treatment of ASCFs. We present the case of a 29-year-old male with an ASCF at C5-C6 treated initially with a short segment instrumented arthrodesis that required an additional operation to properly stabilize and protect his spine. Based on our experience with this case and a review of the literature, we discuss three recommendations to improve ASCF management. These include the need for early computed tomography/magnetic resonance image for proper diagnoses, combined surgical approach with long-segment stabilization for maximum stability. Delayed diagnosis or revision surgery, both of which are common in these patients who present with a stiffened and osteoporotic spine, may lead to spinal cord injury or neurologic deficits. Our recommendations based on the most recent evidence can help surgeons better manage these patients and decrease their overall morbidity and mortality.


Oral polio vaccine and human cancer: a reassessment of SV40 as a contaminant based upon legal documents.
To date, the scientific literature and research examining SV40 and cancer-related diseases has been based upon an assumption that SV40 was not present in any poliovirus vaccine administered in the United States and was removed from the killed polio vaccine by 1963. The basis for this presumption has been that the regulations for live oral polio vaccine required that SV40 be removed from the seeds and monovalent pools ultimately produced in the manufacturing process. The Division of Biologic Standards permitted an additional two tissue culture passages--from three to five--in order to allow manufacturers the ability to remove this contaminant from the oral poliovirus vaccines then awaiting licensure. The confirmation of the removal by one drug manufacturer, Lederle, has been made public at an international symposium in January 1997, where its representatives stated that all of Lederle's seeds had been tested and screened to assure that it was free from SV40 virus. However, in litigation involving the Lederle oral polio vaccine, the manufacturer's internal documents failed to reveal such removal in all of the seeds. The absence of confirmatory testing of the seeds, as well as testimony of a Lederle manager, indicate that this claim of removal of SV40 and the testing for SV40 in all the seeds cannot be fully substantiated. These legal documents and testimony indicate that the scientific community should not be content with prior assumptions that SV40 could not have been in the oral polio vaccine. Only further investigation by outside scientific and independent researchers who can review the test results claimed in the January 1997 meeting and who can conduct their own independent evaluations by testing all the seeds and individual mono-valent pools will assure that SV40 has not been present in commercially sold oral poliovirus vaccine manufactured by Lederle.


A Geometrically-Constrained Mathematical Model of Mammary Gland Ductal Elongation Reveals Novel Cellular Dynamics within the Terminal End Bud.
Mathematics is often used to model biological systems. In mammary gland development, mathematical modeling has been limited to acinar and branching morphogenesis and breast cancer, without reference to normal duct formation. We present a model of ductal elongation that exploits the geometrically-constrained shape of the terminal end bud (TEB), the growing tip of the duct, and incorporates morphometrics, region-specific proliferation and apoptosis rates. Iterative model refinement and behavior analysis, compared with biological data, indicated that the traditional metric of nipple to the ductal front distance, or percent fat pad filled to evaluate ductal elongation rate can be misleading, as it disregards branching events that can reduce its magnitude. Further, model driven investigations of the fates of specific TEB cell types confirmed migration of cap cells into the body cell layer, but showed their subsequent preferential elimination by apoptosis, thus minimizing their contribution to the luminal lineage and the mature duct.


The signature of the Cestrum genome suggests an evolutionary response to the loss of (TTTAGGG)n telomeres.
The genus Cestrumin the Solanaceae family is unusual in lacking Arabidopsis-type telomeres (TTTAGGG)n, although short interstitial telomeric sequences (ITSs) occur scattered throughout the genome in both orientations. To isolate candidate telomeric sequences in Cestrum we assumed that some of the ITSs were residues of the original telomeres and that they may still be located in the vicinity of present-day telomeres. Three sequence types associated with ITSs were cloned and characterized; these were termed NA3G, BR23 and A/T-rich minisatellite. These high copy number sequences are dispersed across the genome and clustered at a number of chromosomal loci. Their association with ITSs, which can act as recombination hotspots, might indicate past recombination and chromosomal fusion events, processes that may have contributed to the large size of Cestrum chromosomes. The sequences are frequently arranged as NA3G-ITS-BR23 blocks embedded in an A/T-rich minisatellite array. The A/T-rich minisatellite is of particular interest because the consensus 5'-T(4-5)AGCAG-3' might be a derivative of "typical" eukaryotic telomeric sequence motifs. The sequence is abundant at the end of some chromosomes in C. parqui and is found not only in Cestrum but also in the closely related genera Sessea and Vestia, which also lack Arabidopsis-type telomeric sequences. However, the sequence is absent from the Solanaceae genera investigated that are outside the group, including the closely related genus Streptosolen, which all have the Arabidopsis-type telomere. The data indicate that the A/T rich minisatellite might have evolved in response to the loss of Arabidopsis-type telomeres.


Influence of prophylactic antibiotics on tissue integration versus bacterial colonization on poly(methyl methacrylate).
Biomaterial-associated infections (BAI) remain a major concern in modern health care. BAI is difficult to treat and often results in implant replacement or removal. Pathogens can be introduced on implant surfaces during surgery and compete with host cells attempting to integrate the implant. Here we studied the influence of prophylactically given cephatholin in the competition between highly virulent Staphylococcus aureus and human osteoblast-like cells (U-2 OS, ATCC HTB-94) for a poly(methyl methacrylate) surface in vitro using a peri-operative contamination model. S. aureus was seeded on the acrylic surface in a parallel plate flow chamber prior to adhesion of U-2 OS cells. Next, S. aureus and U-2 OS cells were allowed to grow simultaneously under shear (0.14 1/s) in a modified culture medium containing cephatholin for 8 h, the time period this drug is supposed to be active in situ. Subsequently, the flow was continued with modified culture medium for another 64 h. In the absence of cephatholin, highly virulent S. aureus caused U-2 OS cell death within 18 h. In contrast, the presence of cephatholin for 8 h resulted in survival of U-2 OS cell up to 72 h during simultaneous growth of U-2 OS cells and bacteria. Not all adhering bacteria were killed however, but they showed a delayed growth. These findings are in line with the recalcitrance of biofilms against antibiotic treatment observed clinically, and represent another support for the use of in vitro co-culture models in mimicking the clinical situation.


Time of hospital presentation in patients with acute stroke.
Stroke is a leading cause of death and disability in the United States. Although new treatments are being studied, most must be given early in the course of stroke to be effective. This study was performed to identify factors associated with early hospital arrival in patients with stroke. As part of the National Institute of Neurologic Disorders and Stroke Tissue-Type Plasminogen Activator Pilot Study, information from patients, patients' families, or, most commonly, the medical record was gathered on all patients presenting to the hospital within 24 hours of the onset of stroke. A total of 14 hospitals participated. Three were university hospitals, and 11 were community hospitals with and without university affiliation. The main outcome measure was the time from stroke onset to hospital arrival. Of 2099 patients screened, adequate time data were available in 1159. Thirty-nine percent presented to the hospital 90 minutes or less after symptom onset and 59% within 3 hours. Early hospital arrival after stroke was greatly influenced by the type of first medical contact and, to a lesser degree, by the patient's location at the time of the stroke and the time of the day at which the stroke occurred. Hospital arrival was fastest in patients using 911 as their first medical contact (mean, 155 minutes; median, 84 minutes) vs their personal physician (mean, 379 minutes; median, 270 minutes; P < .0001) or a study hospital (mean, 333 minutes; median, 212 minutes; P < .0001). Time from symptom onset to arrival was longer for patients having the stroke at night compared with patients having a stroke in the morning (P < .05), in the afternoon (P < .01), or in the evening (P < .0001). Time to hospital arrival was significantly longer for patients having the stroke at home than for patients having the stroke at work (P < .01) or in an unknown place (P < .05). Gender, age, race, and presence of brain hemorrhage had no significant effect. As many as 50% of patients with stroke arrive at the hospital within 3 hours of symptom onset. Our data indicate that strategies to increase the use of 911 systems may have a high yield with regard to recruitment into urgent treatment protocols for stroke.


Solvent-dependent structural dynamics of an azido-platinum complex revealed by linear and nonlinear infrared spectroscopy.
The vibrational and anisotropic relaxation dynamics and structural dynamics of a potential anticancer prodrug, trans,trans,trans-[Pt(N3)2(OH)2(py)2], were investigated using time-resolved infrared pump-probe spectroscopy and ultrafast two-dimensional infrared (2D IR) spectroscopy. Herein, two representative bio-friendly solvents, H2O and DMSO, were used, in which the local structural and dynamical variations were monitored using the antisymmetric linear combination of the two N3 stretching vibrational modes as an infrared probe. It was found that the vibrational relaxation process of the N3 antisymmetric stretching (as) mode in H2O is two to three times faster than that in DMSO. The anisotropic relaxation process of the anticancer prodrug was observed to be hindered in DMSO; this indicated a tighter solvent environment around the sample molecule in this solvent. The vibrational frequency time correlation of the N3 antisymmetric stretching mode in H2O decays with a time constant of 1.94 ps, in agreement with the hydrogen bond formation and breaking times of water. In DMSO, the frequency time correlation of the N3 as mode decays on a much longer time scale; this further indicates its sensitivity to the out-layer DMSO structural dynamics, which are relatively static in the experimental time window.


Effect of Solvent Variations in the Alcothermal Synthesis of Template-Free Mesoporous Titania for Dye-Sensitized Solar Cells Applications.
A series of 14 mesoporous titania materials has been synthesized using the simple alcothermal template-free method and various alcohols, such as methanol, propanols and butanols, as solvents. All materials were characterized by both wide and small angle XRD, which exhibited the anatase phase with short-range ordered mesoporous structure that is still forming during post synthetic temperature treatment in most of the investigated materials. Nitrogen adsorption-desorption isotherms confirmed the mesoporous structure with surface area ranging from 241 to 383 m2g- 1 and pore volumes from 0.162 to 0.473 m3g-1, UV-Vis diffuse reflectance showed the redshift of the absorption edge and the bandgap decrease after post synthetic calcination of the materials presented. The TEM, FT-IR, DTA and TG measurements have been made to well characterize the materials synthesized. The mesoporous samples obtained were applied as anode materials for dye-sensitized solar cells and showed good activity in photon-to-current conversion process with efficiency values ranging from 0.54% to 4.6% and fill factors in the 52% to 67% range. The photovoltaic performances were not as high as those obtained for the materials synthesized by us earlier employing ethanol as a solvent. The differences in the electron lifetime, calculated from electrochemical impedance spectroscopy results and varying between 4.3 to 17.5 ms, were found as a main factor determining the efficiency of the investigated photovoltaic cells.


Detection of anabolic steroids in head hair.
We developed a gas chromatography/mass spectrometry method for detection and quantitation of anabolic steroids in head hair. Following alkaline digestion and solid-phase extraction, the MO-TMS derivatives gave a specific fragmentation pattern with EI ionization. For stanozolol, the TMS-HFBA derivative showed several diagnostic ions. For androstanolone, mestanolone (methylandrostanolone), and oxymetholone two chromatographic peaks for cis and trans isomers of derivatives were seen. Recoveries were 35 to 45% for androstanolone, oxymetholone, chlorotestosterone-acetate, dehydromethyltestosterone, dehydrotestosterone, fluoxymesterone, mestanolone, methyltestosterone, and nandrolone; 52% for mesterolone, trenbolone; 65% for bolasterone; 24% for methenolone and 17% for stanozolol. Limits of detection were 0.002 to 0.05 ng/mg and of quantitation were 0.02 to 0.1 ng/mg. Seven white male steroid abusers provided head hair samples (10 to 63 mg) and urine. In the hair samples, methyltestosterone was detected in two (confirmed in urine); nandrolone in two (also confirmed in urine); dehydromethyltestosterone in four (but not found in urine); and clenbuterol in one (but not in urine). Oxymethalone was found in urine in one, but not in the hair. One abuser had high levels of testosterone: 0.15 ng/mg hair, and 1190 ng/mL urine. We conclude that head hair analysis has considerable potential for the detection and monitoring of steroid abuse.


Insulinotropic effect of the non-steroidal compound STX in pancreatic β-cells.
The non-steroidal compound STX modulates the hypothalamic control of core body temperature and energy homeostasis. The aim of this work was to study the potential effects of STX on pancreatic β-cell function. 1-10 nM STX produced an increase in glucose-induced insulin secretion in isolated islets from male mice, whereas it had no effect in islets from female mice. This insulinotropic effect of STX was abolished by the anti-estrogen ICI 182,780. STX increased intracellular calcium entry in both whole islets and isolated β-cells, and closed the K(ATP) channel, suggesting a direct effect on β-cells. When intraperitoneal glucose tolerance test was performed, a single dose of 100 µg/kg body weight STX improved glucose sensitivity in males, yet it had a slight effect on females. In agreement with the effect on isolated islets, 100 µg/kg dose of STX enhanced the plasma insulin increase in response to a glucose load, while it did not in females. Long-term treatment (100 µg/kg, 6 days) of male mice with STX did not alter body weight, fasting glucose, glucose sensitivity or islet insulin content. Ovariectomized females were insensitive to STX (100 µg/kg), after either an acute administration or a 6-day treatment. This long-term treatment was also ineffective in a mouse model of mild diabetes. Therefore, STX appears to have a gender-specific effect on blood glucose homeostasis, which is only manifested after an acute administration. The insulinotropic effect of STX in pancreatic β-cells is mediated by the closure of the K(ATP) channel and the increase in intracellular calcium concentration. The in vivo improvement in glucose tolerance appears to be mostly due to the enhancement of insulin secretion from β-cells.


Post-stroke fatigue and its association with poor functional outcome after stroke in young adults.
Post-stroke fatigue negatively influences short-term functional outcome in older stroke survivors. In young adults, in the midst of their active working and family life, this influence may even be more pronounced. However, there are only few studies on this topic in young patients with stroke. Therefore, we investigated the long-term prevalence of post-stroke fatigue in patients with a young transient ischaemic attack (TIA) or ischaemic stroke and its association with functional outcome. This study is part of a large cohort study among 511 stroke survivors with a first-ever TIA or ischaemic stroke, aged 18-50 years. After a mean follow-up of 9.8 (SD 8.4) years, we assessed the presence of fatigue with the fatigue subscale of the Checklist Individual Strength questionnaire and functional outcome. Prevalence of fatigue between young patients with stroke and 147 stroke-free sex-matched and age-matched controls was compared. OR's for poor functional outcome on modified Rankin Score (mRS>2) and Instrumental Activities of Daily Living (IADL<8) and cognitive performance were calculated using logistic regression analysis. Of the young patients with stroke, 41% experienced symptoms of fatigue, versus 18.4% in controls (p 0.0005). Fatigue was associated with a poor functional outcome, as assessed by the mRS (OR 4.0 (95% CI 1.6 to 9.6), IADL (OR 2.2 (95% CI 1.1 to 4.6), and impairment in speed of information processing (OR 2.2 (95% CI 1.3 to 3.9). Fatigue was very common in young stroke survivors and was associated with a poor functional outcome, even after almost a decade of follow-up.


The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin.
It is unknown whether the true risk of recurrent venous thromboembolism (VTE) is increased in patients with proximal deep vein thrombosis who are treated with continuous intravenous heparin and fail to reach a therapeutic activated partial thromboplastin time (APTT) within 24 to 48 hours of initiation of treatment. To compare the risk of recurrent VTE in patients with early subtherapeutic APTT results and those with APTT results above the lower limit of the therapeutic range, we performed a formal review of the literature. We examined all available studies that provided information on the relation between the risk of recurrent VTE and the APTT response to heparin when initiated as a bolus followed by a continuous intravenous infusion of at least 30 000 U/24 h. Five studies were included in the final analysis. The overall recurrence rate was 6.3% in patients whose APTT results were subtherapeutic for the first 24 to 48 hours and 7% in patients whose APTT results were above the lower limit of the therapeutic range, providing a pooled odds ratio of 0.89 with a 95% confidence interval of 0.2 to 4.0. In patients with VTE who are treated with a bolus of heparin followed by a continuous intravenous infusion of at least 30 000 U/24 h, no convincing evidence shows that the risk of recurrent VTE is critically dependent on achieving a therapeutic APTT result at 24 to 48 hours.


Inattentional blindness on the full-attention trial: Are we throwing out the baby with the bathwater?
When attention is otherwise engaged, observers may experience inattentional blindness, failing to notice objects or events that are presented in plain sight. In an inattentional blindness experiment, an unexpectedstimulus ispresented alongside primary-task stimuli, and its detection is probed. We evaluate a criterion that is commonly used to exclude observers from the data analysis. On the final experimental trial, observers do not perform the primary task, but instead look for anything new. Observers who fail to report the unexpected stimulus on thisfull-attention trialare excluded. On the basis of 4 hypothetical experiments and a review of 128 actual experiments from the literature, we demonstrate some potentially problematic consequences of implementing the full-attention-trial exclusion criterion. Excluded observers may cluster in experimental conditions and the exclusion criterion may lead researchers to understate the pervasiveness of inattentional blindness. It may even render usblindto inattentional blindness on the full-attention trial.


Reward-modulated motor information in identified striatum neurons.
It is widely accepted that dorsal striatum neurons participate in either the direct pathway (expressing dopamine D1 receptors) or the indirect pathway (expressing D2 receptors), controlling voluntary movements in an antagonistically balancing manner. The D1- and D2-expressing neurons are activated and inactivated, respectively, by dopamine released from substantia nigra neurons encoding reward expectation. However, little is known about the functional representation of motor information and its reward modulation in individual striatal neurons constituting the two pathways. In this study, we juxtacellularly recorded the spike activity of single neurons in the dorsolateral striatum of rats performing voluntary forelimb movement in a reward-predictable condition. Some of these neurons were identified morphologically by a combination of juxtacellular visualization and in situ hybridization for D1 mRNA. We found that the striatal neurons exhibited distinct functional activations before and during the forelimb movement, regardless of the expression of D1 mRNA. They were often positively, but rarely negatively, modulated by expecting a reward for the correct motor response. The positive reward modulation was independent of behavioral differences in motor performance. In contrast, regular-spiking and fast-spiking neurons in any layers of the motor cortex displayed only minor and unbiased reward modulation of their functional activation in relation to the execution of forelimb movement. Our results suggest that the direct and indirect pathway neurons cooperatively rather than antagonistically contribute to spatiotemporal control of voluntary movements, and that motor information is subcortically integrated with reward information through dopaminergic and other signals in the skeletomotor loop of the basal ganglia.


p300 modulates nuclear morphology in prostate cancer.
Alterations in nuclear structure distinguish cancer cells from noncancer cells. These nuclear alterations can be translated into quantifiable features by digital image analysis in a process known as quantitative nuclear morphometry. Recently, quantitative nuclear morphometry has been shown to predict metastasis and biochemical recurrence of prostate cancer. However, little is known about the cellular mechanisms underlying these nuclear morphometric changes. Alterations of nuclear matrix proteins are frequently involved in changes of nuclear structure. A number of co-activators interact with these nuclear structure-related proteins, suggesting that they might be involved in quantitative nuclear morphometry changes. We have shown previously that the transcriptional co-activator p300 is involved in prostate cancer progression. However, the ability of a transcriptional regulator like p300 to modulate nuclear morphology has not been described previously. In the present study, we show that p300 expression in prostate cancer biopsy tissue from 95 patients correlates with quantifiable nuclear alterations. Moreover, we show that transfection of p300 into prostate cancer cells in culture induces quantifiable nuclear alterations, such as diameter, perimeter, and absorbance among others, as assessed by digital image analysis. These alterations correlate individually with aggressive features in prostate cancer, such as expression of the proliferation marker Ki-67 and extraprostatic extension of the tumor. Finally, we found that transfection of p300 into prostate cancer cells specifically increases mRNA and protein levels of nuclear matrix peptides lamins A and C, suggesting that these proteins mediate the p300-induced effects. These findings reveal a new insight into the transcriptional and structural regulation of prostate cancer.


Polyuria, polydypsia, and hypertension produced by a six-day intravenous infusion of prostaglandin E1 in the conscious dog.
The effects of a continuous intravenous infusion of prostaglandin E1 (PGE1) on mean arterial pressure (MAP), sodium and water balance, and plasma renin activity (PRA) were examined in 10 conscious dogs maintained on a 70 to 75 mEq/day sodium intake. In a crossover pattern, each dog received 6 days of intravenous PGE1 (0.1 micrograms/kg/min) and 6 days of intravenous diluent. When compared to diluent, intravenous PGE1 resulted in a mild sustained rise in MAP. By Day 6 the intravenous PGE1, MAP had increased from 98 +/- 4 to 112 +/- 5 mm Hg (mean +/- SE) (p less than 0.04). Concurrent with the MAP increase, PRA increased from 0.6 +/- 0.2 to 3.1 +/- 0.7 ng angiotensin I (AI)/ml/hr (p less than 0.03). To assess the role of the renin-angiotensin system in the maintenance of the systemic hypertension. AI converting-enzyme inhibitor was given to four dogs on Day 6 of both intravenous PGE1 and diluent. Only when the dogs were receiving PGE1 did the administration of converting-enzyme inhibitor result in a significant decrease in MAP (-19 +/- 5 mm Hg). In addition to increasing arterial pressure, the chronic infusion of PGE1 also produced changes in salt and water balance. When compared to diluent, PGE1 resulted in a twofold increase in both water intake and urine output, an increase in urinary sodium excretion (from 72 +/- 3 to 84 +/- 6 mEq/day, p less than 0.05, on Day 1), and a decrease in urine osmolality (from 942 +/- 82 to 586 +/- 61 mOsmol/kg H2O/day, p less than 0.05, on Day 1).(ABSTRACT TRUNCATED AT 250 WORDS)


The adaptation to prison by individuals with schizophrenia.
This report documents the adjustment to prison life by individuals with schizophrenia and compares their adaptation with a control group with no known mental illness matched for age, race, sex, most serious crime, and security level. On all outcome variables, number of infractions, number of "lock-ups", days in "lock-up," ability to obtain a job in prison, and ability to obtain release from prison, the group with schizophrenia was inferior to the control group. That inmates with schizophrenia may require special assistance in prison and the need for future investigation are discussed.


A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis.
In order to develop a reproducible, quantifiable means of assessment of the clinical status of patients with idiopathic pulmonary fibrosis (IPF), a composite clinical-radiographic-physiologic (CRP) scoring system was devised, using 7 variables: dyspnea, chest radiograph, spirometry, lung volume, diffusion capacity, resting alveolar-arterial PO2, and exercise O2 saturation. To assess this scoring system, we examined the relationships between CRP scores and histopathologic findings, including a cellular pathology score composed of abnormalities deemed to be potentially reversible, a fibrotic pathology score based on abnormalities felt to be essentially irreversible, and an index of overall pathologic derangement (total pathology score), derived from the sum of the cellular and fibrotic scores. The initial CRP determination at the time of open lung biopsy correlated significantly with the total pathology score (r = 0.61, p less than 0.001). The CRP score determined after 6 months of corticosteroid therapy showed a significant correlation with the fibrotic pathology score present on open lung biopsy (r = 0.76, p less than 0.001). The change in CRP after 6 months of corticosteroid therapy tended to reflect the cellular histopathologic component of the open lung biopsy (r = -0.43, p less than 0.10). Moreover, in none of these relationships did any individual component of the CRP score correlate better with the respective histopathologic index than did the CRP score itself. These data suggest that this CRP score is useful for the estimation of the severity of underlying pathologic derangement and for the longitudinal quantitative assessment of clinical impairment in patients with IPF.


The mouse int-2 gene exhibits basic fibroblast growth factor activity in a basic fibroblast growth factor-responsive cell line.
The int-2 protein is related to basic fibroblast growth factor (bFGF) by amino acid sequence homology. To assess its biological activity, we constructed retroviral vectors containing four variants of mouse int-2 complementary DNA under the transcriptional control of the beta-actin promoter and tested their effects on human SW13 adrenal cortical tumor cells. This cell line specifically requires bFGF, interleukin 1, or transforming growth factor e for anchorage-independent growth in soft agar. Despite encoding a signal sequence that should direct the protein to the secretory pathway, vectors containing unmodified int-2 complementary DNA, or a form optimized for translation initiation at the AUG codon, were incapable of inducing SW13 growth in soft agar. However, SW13 transfectants expressing a construct (pSP1), in which a mouse immunoglobulin signal peptide sequence is linked to the int-2 coding sequences, grew well in soft agar. The concentrated conditioned medium from these pSP1-transfected cells supported anchorage-independent growth of SW13 indicator cells and competed with bFGF for binding to receptors. Western blot analysis with an int-2-specific antiserum detected Mr 30,000-32,000 int-2 products in cell extracts and conditioned medium from pSP1-transfected clones, whereas the conditioned medium from these and other SW13 clones contained only low levels of bFGF as measured in a specific radioimmunoassay. These data suggest that the product of the int-2 gene can functionally replace bFGF in modulating the anchorage-independent growth of SW13 cells.


Identification and characterization of the multidrug resistance gene cfr in a Panton-Valentine leukocidin-positive sequence type 8 methicillin-resistant Staphylococcus aureus IVa (USA300) isolate.
The staphylococcal cfr gene mediates resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A, a phenotype that has been termed PhLOPS(A). The cfr gene has mainly been associated with coagulase-negative staphylococcal isolates from animals, and only a few cfr-positive methicillin-resistant Staphylococcus aureus (MRSA) isolates have been described so far. This study reports the first description of a cfr-positive MRSA isolate (M05/0060) belonging to the pandemic Panton-Valentine leukocidin (PVL)-positive sequence type 8 MRSA IVa/USA300 (ST8-MRSA-IVa/USA300) clone. The cfr gene was detected in M05/0060 using a DNA microarray which was used to screen PVL-positive MRSA isolates for the presence of virulence genes, typing markers, and antimicrobial resistance genes. Antimicrobial susceptibility testing revealed that M05/0060 exhibited the cfr-associated resistance phenotype. Molecular analysis identified the presence of cfr and a second phenicol resistance gene, fexA, on a novel 45-kb conjugative plasmid, which was designated pSCFS7. Within pSCFS7, a DNA segment consisting of cfr, a truncated copy of insertion sequence IS21-558, and a region with homology to the DNA invertase gene bin3 of transposon Tn552 from Bacillus mycoides was integrated into the transposase gene tnpB of the fexA-carrying transposon Tn558. The emergence of a multidrug-resistant cfr-positive variant of ST8-MRSA-IVa/USA300 is alarming and requires ongoing surveillance. Moreover, the identification of a novel conjugative plasmid carrying the cfr gene indicates the ability of cfr to spread to other MRSA strains.


SU-E-T-386: Gamma Analysis of Normalized and Un-Normalized Dose Distributions.
The gamma index method, as currently implemented in all commercial QA software, calls for selection of a normalization point to evaluate agreement between two dose distributions. The implication of this is that there is an infinite number of possible solutions! Which one to pick? A unique and more relevant solution is obtained only if no normalization point is used. The set of test cases suggested by the AAPM TG1 19 were planned using Pinnacle 8.0m and delivered on a Varian 21EX linac for 6 and 18 MV photons. The recommended point and planar dose measurements were obtained using a Pinpoint ion chamber, EDR2 film and MatriXX. The gamma index method using typical 3%, 3 mm criteria with and without a normalization point was used to assess the agreement between calculated and delivered planar dose distributions. The analysis was extended to a set of data for clinically treated patients. The comparison with the TG119 benchmark data showed that all point dose and planar measurements for 6 MV were within the published range. Similar results, although without published data to compare with, were obtained for 18 MV as well. For all complex tests, the percentage of points passing the gamma criteria of 3%, 3 mm was (95.8±1.6)% and (95.6±1.0)% for 6 MV and 18 MV, respectively. Without a normalization point, however, the same gamma analysis fell to (20.7±6.7)% and (13.9±4.0)% for 6 MV and 18 MV, respectively. The clinical data set showed the same trend, with the gamma passing rate declining from (98.9±0.7)% to (33.4±13.1)%. The gamma index method provides a unique answer for gamma passing rate only without normalizing dose distributions to any particular point. The common gamma criteria of 3%, 3 mm, however, is a very poor metric in that case.


Chromium and cobalt ion release following the Durom high carbon content, forged metal-on-metal surface replacement of the hip.
We evaluated the concentrations of chromium and cobalt ions in blood after metal-on-metal surface replacement arthroplasty using a wrought-forged, high carbon content chromium-cobalt alloy implant in 64 patients. At one year, mean whole blood ion levels were 1.61 microg/L (0.4 to 5.5) for chromium and 0.67 microg/L (0.23 to 2.09) for cobalt. The pre-operative ion levels, component size, female gender and the inclination of the acetabular component were inversely proportional to the values of chromium and/or cobalt ions at one year postoperatively. Other factors, such as age and level of activity, did not correlate with the levels of metal ions. We found that the levels of the ions in the serum were 1.39 and 1.37 times higher for chromium and cobalt respectively than those in the whole blood. The levels of metal ions obtained may be specific to the hip resurfacing implant and reflect its manufacturing process.


Phytochemical screening and in vitro antibacterial and anticancer activities of the aqueous extract of Cucumis sativus.
Tumor is a multifactorial sickness and consequently can be viably overwhelmed by a multi-constituently remedial strategy. Herbal extracts shows the example of such stratagem. However, less research have been carried out till date that portray the effect of different extraction techniques on the phyto compounds profile of plant extracts and its effect on anticancer activity. Cucumber (Cucumis sativus L.) is a member of the Cucurbitaceae family like melon, squash and pumpkins. It is a popular vegetable harvest in Indian customary medicine since olden times. It has potential lipid lowering and antioxidant activity and antidiabetic. In the present study, we have evaluated the anticancer prospective of methanolic and acetone extracts of Cucumis sativus (CSME) and (CSAE). Reported results show that (CSME) is rich in bioactive compounds shown anticancer activity with Cell lines of (IC50) with MCF 715.6 ± 1.3 and HeLa 28.2 ± 1. This study on the presence of cytotoxic from the Cucumis sativus L.), which have been further used in herbal formulations study as an anticancer activity. Our conclusion support additional in-depth study of this pharmacologic activity as an malignant tumor agent.


Pleiotropic nuclear defects associated with a conditional allele of the novel nucleoporin Rat9p/Nup85p.
In a screen for mutants defective in nucleocytoplasmic export of mRNA, we have identified a new component of the Saccharomyces cerevisiae nuclear pore complex (NPC). The RAT9/NUP85 (ribonucleic acid trafficking) gene encodes an 84.9-kDa protein that we have localized to NPCs by tagging the RAT9/NUP85 gene with the in vivo molecular marker Green Fluorescent Protein. In cells containing either the rat9-1 allele or a complete deletion of the RAT9/NUP85 gene, poly(A)+ RNA accumulates rapidly in nuclei after a shift from 23 degrees C to 37 degrees C. Under these same conditions, rapid fragmentation of the nucleolus was also observed. At the permissive growth temperature in rat9-1 or RAT9 deletion strains, the nuclear envelope (NE) becomes detached from the main body of the nucleus, forming long thin double sheets of NE. NPCs within these sheets are clustered and some appear to be locked together between opposing sheets of NE such that their nucleoplasmic faces are in contact. The Rat9/Nup85 protein could not be detected in cells carrying a mutation of RAT2/NUP120, suggesting that Rat9p/Nup85p cannot be assembled into NPCs in the absence of Rat2p/Nup120p. In contrast,Rat9/ Nup85 protein was readily incorporated into NPCs in strains carrying mutant alleles of other nucleoporin genes. The possible role of Rat9p/Nup85p in NE integrity and the loss of nucleoporins when another nucleoporin is mutant or absent are discussed.


Peer Rejection and Attention Deficit Hyperactivity Disorder Symptoms: Reciprocal Relations Through Ages 4, 6, and 8.
Attention deficit hyperactivity disorder (ADHD) predicts poor peer relationships. What remains unclear is whether poor peer relationships affect ADHD symptomatology. Hence, reciprocal effects of peer rejection and ADHD symptoms were examined in a community sample of 962 Norwegian children at ages 4, 6, and 8. Results showed that ADHD symptoms at age 4 predicted more peer rejection at age 6, and that peer rejection at age 4 predicted more symptoms at age 6. However, when conducting analyses on ADHD subtypes, hyperactivity-impulsivity and inattentiveness symptoms were adversely affected by peer rejection at ages 6 and 8, whereas peer rejection was unaffected by such symptoms, indicating that the effect of peer rejection on ADHD symptoms was most robust. Mediational relation were also identified.


Biomineralized matrix-assisted osteogenic differentiation of human embryonic stem cells.
The physical and chemical properties of a matrix play an important role in determining various cellular behaviors, including lineage specificity. We demonstrate that the differentiation commitment of human embryonic stem cells (hESCs), both in vitro and in vivo, can be solely achieved through synthetic biomaterials. hESCs were cultured using mineralized synthetic matrices mimicking a calcium phosphate (CaP)-rich bone environment differentiated into osteoblasts in the absence of any osteogenic inducing supplements. When implanted in vivo, these hESC-laden mineralized matrices contributed to ectopic bone tissue formation. In contrast, cells within the corresponding non-mineralized matrices underwent either osteogenic or adipogenic fate depending upon the local cues present in the microenvironment. To our knowledge, this is the first demonstration where synthetic matrices are shown to induce terminal cell fate specification of hESCs exclusively by biomaterial-based cues both in vitro and in vivo. Technologies that utilize tissue specific cell-matrix interactions to control stem cell fate could be a powerful tool in regenerative medicine. Such approaches can be used as a tool to advance our basic understanding and assess the translational potential of stem cells.


Mangiferin in cancer chemoprevention and treatment: pharmacokinetics and molecular targets.
A variety of bioactive food components have been shown to modulate inflammatory responses and to attenuate carcinogenesis. Polyphenols isolated several years ago from various medicinal plants now seem to have a prominent role in the prevention and therapy of a variety of ailments. Mangiferin, a unique, important, and highly investigated polyphenol, has attracted much attention of late for its potential as a chemopreventive and chemotherapeutic agent against various types of cancer. Mangiferin has been shown to target multiple proinflammatory transcription factors, cell- cycle proteins, growth factors, kinases, cytokines, chemokines, adhesion molecules, and inflammatory enzymes. These targets can potentially mediate the chemopreventive and therapeutic effects of mangiferin by inhibiting the initiation, promotion, and metastasis of cancer. This review not only summarizes the diverse molecular targets of mangiferin, but also gives the results of various preclinical studies that have been performed in the last decade with this promising polyphenol.


Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline.
This document seeks to establish guidance for the evaluation and management of women with recurrent urinary tract infections (rUTI) to prevent inappropriate use of antibiotics, decrease the risk of antibiotic resistance, reduce adverse effects of antibiotic use, provide guidance on antibiotic and non-antibiotic strategies for prevention, and improve clinical outcomes and quality of life by reducing recurrence of urinary tract infection (UTI) events. The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. A research librarian conducted searches in Ovid MEDLINE (1946 to January Week 1 2018), Cochrane Central Register of Controlled Trials (through December 2017) and Embase (through January 16, 2018). An update literature search was conducted on September 20, 2018. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low). Such evidence-based statements are provided as Strong, Moderate, or Conditional Recommendations. In instances of insufficient evidence, additional guidance is provided as Clinical Principles and Expert Opinions. Our ability to diagnose, treat, and manage rUTI long-term has evolved due to additional insights into the pathophysiology of rUTI, a new appreciation for the adverse effects of repetitive antimicrobial therapy, rising rates of bacterial antimicrobial resistance (AMR), and better reporting of the natural history and clinical outcomes of acute cystitis and rUTI. As new data continue to emerge in this space, this document will undergo review to ensure continued accuracy.


The effect of virus-blocking Wolbachia on male competitiveness of the dengue vector mosquito, Aedes aegypti.
The bacterial endosymbiont Wolbachia blocks the transmission of dengue virus by its vector mosquito Aedes aegypti, and is currently being evaluated for control of dengue outbreaks. Wolbachia induces cytoplasmic incompatibility (CI) that results in the developmental failure of offspring in the cross between Wolbachia-infected males and uninfected females. This increases the relative success of infected females in the population, thereby enhancing the spread of the beneficial bacterium. However, Wolbachia spread via CI will only be feasible if infected males are sufficiently competitive in obtaining a mate under field conditions. We tested the effect of Wolbachia on the competitiveness of A. aegypti males under semi-field conditions. In a series of experiments we exposed uninfected females to Wolbachia-infected and uninfected males simultaneously. We scored the competitiveness of infected males according to the proportion of females producing non-viable eggs due to incompatibility. We found that infected males were equally successful to uninfected males in securing a mate within experimental tents and semi-field cages. This was true for males infected by the benign wMel Wolbachia strain, but also for males infected by the virulent wMelPop (popcorn) strain. By manipulating male size we found that larger males had a higher success than smaller underfed males in the semi-field cages, regardless of their infection status. The results indicate that Wolbachia infection does not reduce the competitiveness of A. aegypti males. Moreover, the body size effect suggests a potential advantage for lab-reared Wolbachia-males during a field release episode, due to their better nutrition and larger size. This may promote Wolbachia spread via CI in wild mosquito populations and underscores its potential use for disease control.


Characterization of the Castanopsis carlesii Deadwood Mycobiome by Pacbio Sequencing of the Full-Length Fungal Nuclear Ribosomal Internal Transcribed Spacer (ITS).
Short-read next generation sequencing (NGS) platforms can easily and quickly generate thousands to hundreds of thousands of sequences per sample. However, the limited length of these sequences can cause problems during fungal taxonomic identification. Here we validate the use of Pacbio sequencing, a long-read NGS method, for characterizing the fungal community (mycobiome) of Castanopsis carlesii deadwood. We report the successful use of Pacbio sequencing to generate long-read sequences of the full-length (500-780 bp) fungal ITS regions of the C. carlesii mycobiome. Our results show that the studied deadwood mycobiome is taxonomically and functionally diverse, with an average of 85 fungal OTUs representing five functional groups (animal endosymbionts, endophytes, mycoparasites, plant pathogens, and saprotrophs). Based on relative abundance data, Basidiomycota were the most frequently detected phyla (50% of total sequences), followed by unidentified phyla, and Ascomycota. However, based on presence/absence data, the most OTU-rich phyla were Ascomycota (58% of total OTUs, 72 OTUs) followed by Basidiomycota and unidentified phyla. The majority of fungal OTUs were identified as saprotrophs (70% of successfully function-assigned OTUs) followed by plant pathogens. Finally, we used phylogenetic analysis based on the full-length ITS sequences to confirm the species identification of 14/36 OTUs with high bootstrap support (99-100%). Based on the numbers of sequence reads obtained per sample, which ranged from 3,047 to 13,463, we conclude that Pacbio sequencing can be a powerful tool for characterizing moderate- and possibly high-complexity fungal communities.


The health of HIV-exposed children after early weaning.
There are potential health risks associated with the use of early weaning to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-poor settings. Our objective was to examine growth and nutrient inadequacies among a cohort of children weaned early. Children participating in the Breastfeeding Antiretrovirals and Nutrition (BAN) Study in Lilongwe, Malawi, had HIV-infected mothers, were weaned at 6 months and fed LNS until 12 months. 40 HIV-negative, BAN-exited children were compared with 40 HIV-negative, community children matched on age, gender and local health clinic. Nutrient intake was calculated from 24-h dietary recalls collected from BAN-exited children. Anthropometric measurements were collected from BAN-exited and matched community children at 15-16 months, and 2 months later. Longitudinal random effects sex-stratified models were used to evaluate anthropometric differences between the two groups. BAN-exited children consumed adequate energy, protein and carbohydrates but inadequate amounts of fat. The prevalence of inadequate micronutrient intakes were: 46% for vitamin A; 20% for vitamin B6; 69% for folate; 13% for vitamin C; 19% for iron; 23% for zinc. Regarding growth, BAN-exited girls gained weight at a significantly lower rate {0.02 g kg(-1) per day [95% confidence interval (CI): 0.01, 0.03]} than their matched comparison [0.05 g kg(-1) per day (95% CI: 0.03, 0.07)]; BAN girls grew significantly slower [0.73 cm month(-1) (95% CI: 0.40,1.06)] than their matched comparison (1.55 cm month(-1) [95% CI: 0.98, 2.12]). Among this sample of BAN-exited children, early weaning was associated with dietary deficiencies and girls experienced reduced growth velocity. In resource-poor settings, HIV prevention programmes must ensure that breastfeeding stop only once a nutritionally adequate and safe diet without breast milk can be provided.


Staphylococcus aureus V8-protease catalyzed segment exchange reaction of alpha-chain of hemoglobin S: a semisynthetic approach for the preparation of variants of alpha-chain.
The Glu(30)-Arg(31) peptide bond of alpha-chain of hemoglobin is readily and quantitatively hydrolyzed by Staphylococcus Aureus V8-protease at pH 4.0 and 37 degrees C. This region of the alpha-chain represents a 'permissible discontinuity region' of the chain within its tertiary interactions. Protease catalyzed reformation of peptide bonds in such permissible discontinuity regions of fragment complementing systems of proteins appears to be a useful procedure for the preparation of variants of the protein. Therefore, attempts have been now made to 'restitch' the segments alpha 1-30 and alpha 31-141 using V8-protease. The alpha-amino group of alpha 1-30 was selectively dihydroxypropylated (DHP) using [14C]-glyceraldehyde to follow the protease catalyzed reformation of globin. V8-protease catalyzed the condensation of N alpha-DHP-alpha 1-30 and alpha 31-141 to generate N alpha-DHP-alpha 1 141 in the presence of 30% propanol at pH 6.0 and 4 degrees C. The synthetic yield of N alpha-DHP-alpha 1-141 is about 55% in 48 hrs and remained nearly the same even after seven days. Under the same conditions alpha-globin was digested at the Glu(30)-Arg(31) peptide bond to nearly 40%. Thus, the amount of Glu(30)-Arg(31) peptide bond formed in 48 hrs appears to be the result of an equilibrium in the V8-protease catalyzed hydrolytic and synthetic reactions. The reformation of Glu(30)-Arg(31) bond appears to be very selective. V8-protease did not catalyze the peptide bond formation in an equimolar mixture of alpha 31-141 with either alpha 1-23, alpha 1-27, or alpha 28-30 all of which have glutamic acid as the carboxy terminal residue just as in alpha 1-30. The high selectivity in the protease catalyzed formation of Glu(30)-Arg(31) peptide bond suggests that the segment alpha 1-30 of the intact alpha-globin could be exchanged with synthetic analogs of alpha 1-30 using V8-protease without actually isolating the fragment alpha 31-141. Incubation of [14C]-N alpha-DHP-alpha 1-30 with alpha-globin at pH 6.0 and 4 degrees C along with V8-protease in 30% n-propanol indeed resulted in the exchange of the segment alpha 1-30 of alpha-globin with [14C]-N alpha-DHP-alpha 1-30. This V8-protease catalyzed 'segment exchange reaction' should facilitate the preparation of alpha-chains with double mutations from the large number of naturally occurring alpha-chains with single mutation.(ABSTRACT TRUNCATED AT 400 WORDS)


Nighttime intensivist staffing and the timing of death among ICU decedents: a retrospective cohort study.
Intensive care units (ICUs) are increasingly adopting 24-hour intensivist physician staffing. Although nighttime intensivist staffing does not consistently reduce mortality, it may affect other outcomes such as the quality of end-of-life care. We conducted a retrospective cohort study of ICU decedents using the 2009-2010 Acute Physiology and Chronic Health Evaluation clinical information system linked to a survey of ICU staffing practices. We restricted the analysis to ICUs with high-intensity daytime staffing, in which the addition of nighttime staffing does not influence mortality. We used multivariable regression to assess the relationship between nighttime intensivist staffing and two separate outcomes potentially related to the quality of end-of-life care: time from ICU admission to death and death at night. Of 30,456 patients admitted to 27 high-intensity daytime staffed ICUs, 3,553 died in the hospital within 30 days. After adjustment for potential confounders, admission to an ICU with nighttime intensivist staffing was associated with a shorter duration between ICU admission and death (adjusted difference: -2.5 days, 95% CI -3.5 to -1.5, p-value < 0.001) and a decreased odds of nighttime death (adjusted odds ratio: 0.75, 95% CI 0.60 to 0.94, p-value 0.011) compared to admission to an ICU without nighttime intensivist staffing. Among ICU decedents, nighttime intensivist staffing is associated with reduced time between ICU admission and death and reduced odds of nighttime death.


Synovial sarcoma--identification of favorable and unfavorable histologic types: a Scandinavian sarcoma group study of 104 cases.
Synovial sarcoma has traditionally been regarded as a high-grade sarcoma and treated as such. Recently, specific types of poorly differentiated synovial sarcoma have been defined and shown to affect prognosis adversely. We studied 104 primary synovial sarcomas of the extremities and trunk wall without metastasis at diagnosis that were retrieved from the Scandinavian Sarcoma Group Registry (SSG) and the Swedish Cancer Registry from 1986 to 1994. Follow-up was available in all patients, median 6 (3-11) years for the survivors. There were local recurrences in 15% of patients and metastases in 33%. Histologically, the tumors were divided into favorable and unfavorable types. The favorable type had no significant cytologic atypia, and in most instances, no necrosis and a mitotic count of < 10/10 hpf. The unfavorable type included so-called poorly differentiated synovial sarcomas as well as recognizable biphasic and monophasic synovial sarcomas with prominent nuclear atypia, extreme cellularity and nuclear crowding. Designation of a tumor as having favorable vs. unfavorable histology conveyed more prognostic information than any single histologic factor. Kaplan-Meier estimates of metastasis-free survival at 5 years were 83% for patients with histologically favorable tumors and 31% for patients with histologically unfavorable tumors (95% confidence intervals 72-92% and 13-51%, respectively). These findings may influence future treatment protocols for synovial sarcoma.


Recent advances in microfluidic technologies for biochemistry and molecular biologys.
Advances in the fields of proteomics and genomics have necessitated the development of high-throughput screening methods (HTS) for the systematic transformation of large amounts of biological chemical data into an organized database of knowledge. Microfluidic systems are ideally suited for high-throughput biochemical experimentation since they offer high analytical throughput, consume minute quantities of expensive biological reagents, exhibit superior sensitivity and functionality compared to traditional micro-array techniques and can be integrated within complex experimental work flows. A range of basic biochemical and molecular biological operations have been transferred to chip-based microfluidic formats over the last decade, including gene sequencing, emulsion PCR, immunoassays, electrophoresis, cell-based assays, expression cloning and macromolecule blotting. In this review, we highlight some of the recent advances in the application of microfluidics to biochemistry and molecular biology.


A community survey on neighborhood violence, park use, and physical activity among urban youth.
Neighborhoods can be an important feature of the built environment influencing physical activity; however, neighborhood poverty and violence may pose significant barriers for youth physical activity. We conducted a community survey of 107 households with youth 3-12 years of age in select neighborhoods of the city of Newark, New Jersey, a highly impoverished and racially/ethnically segregated city of the United States. The majority of sampled households did not have access to a park, and nearly 60% of youth were not engaged in a team or organized physical activity program. Hearing gunshots and seeing drug deals in the neighborhood were reported by 74% and 56%, respectively, of study participants. In adjusted regression models, a 1-unit increase in self-reported neighborhood safety was associated with perceptions that parks were safe for youth to use (OR = 1.7, CI = 1.3, 2.3) and increased odds of youth using parks (OR = 1.3, CI = 1.0, 1.6). Self-reported neighborhood violence was marginally associated with lower levels of Metabolic Equivalent (MET)-min/week of moderate PA (β = -54.25, P = .05). To ensure national goals of increased physical activity and use of outdoor spaces, addressing the neighborhood contexts under which the most vulnerable of our youth live will be required.


Response of Chile Pepper to Phytophthora capsici in Relation to Soil Salinity.
The response of chile pepper to salinity and infection by Phytophthora capsici was assessed under greenhouse conditions in plants susceptible or resistant to P. capsici. Additionally, the effect of salinity on mycelial growth and production of sporangia and zoospores by P. capsici was evaluated in the laboratory. Salinity treatments consisted of varying levels of electrical conductivity (from 1.8 to 14.4 dS/m) achieved by amending irrigation water or growth media with a mixture of sodium chloride and calcium chloride. In plants susceptible to P. capsici, disease severity increased by approximately 1.3 to 2.7-fold with increasing salinity level, whereas no such effect was observed in plants resistant to P. capsici. Mycelial dry weight increased by 8 to 16%, and radial growth of mycelium was augmented by 5 to 30% with increase in salinity level. Production of sporangia and zoospore formation were reduced by approximately 3 to 85 and 1 to 93%, respectively, under saline conditions. These results indicate that salinity may predispose susceptible chile pepper plants to infection by P. capsici.


Design and laboratory demonstration of an achromatic vector vortex coronagraph.
A vector vortex coronagraph (VVC) is one of promising means for imaging extremely faint objects around bright stars such as exoplanets. We present a design of an achromatic VVC, in which an axially-symmetric half-wave plate (AHP) is placed between crossed polarization filters (circular polarizer and analyzer). The circular polarizer and the analyzer are both composed of a polarizer and a quarter-wave plate (QWP). We demonstrate, via Jones calculus and Fourier analysis, that the achromatic stellar elimination can theoretically be realized by optimal polarization filters, even when chromatic AHP and QWPs are used. We carried out laboratory demonstrations of the designed VVC using a photonic-crystal AHP. As a result, we observed achromatic coronagraphic performance, a light suppression level of 7 × 10(-5), over a wavelength from 543 nm to 633 nm.


Can graphene quantum dots cause DNA damage in cells?
Graphene quantum dots (GQDs) have attracted tremendous attention for biological applications. We report the first study on cytotoxicity and genotoxicity of GQDs to fibroblast cell lines (NIH-3T3 cells). The NIH-3T3 cells treated with GQDs at dosages over 50 μg mL(-1) showed no significant cytotoxicity. However, the GQD-treated NIH-3T3 cells exhibited an increased expression of proteins (p53, Rad 51, and OGG1) related to DNA damage compared with untreated cells, indicating the DNA damage caused by GQDs. The GQD-induced release of reactive oxygen species (ROS) was demonstrated to be responsible for the observed DNA damage. These findings should have important implications for future applications of GQDs in biological systems.


The Impact of the COVID-19 Pandemic on Genitourinary Cancer Care: Re-envisioning the Future.
The coronavirus disease 2019 (COVID-19) pandemic necessitated rapid changes in medical practice. Many of these changes may add value to care, creating opportunities going forward. To provide an evidence-informed, expert-derived review of genitourinary cancer care moving forward following the initial COVID-19 pandemic. A collaborative narrative review was conducted using literature published through May 2020 (PubMed), which comprised three main topics: reduced in-person interactions arguing for increasing virtual and image-based care, optimisation of the delivery of care, and the effect of COVID-19 in health care facilities on decision-making by patients and their families. Patterns of care will evolve following the COVID-19 pandemic. Telemedicine, virtual care, and telemonitoring will increase and could offer broader access to multidisciplinary expertise without increasing costs. Comprehensive and integrative telehealth solutions will be necessary, and should consider patients' mental health and access differences due to socioeconomic status. Investigations and treatments will need to maximise efficiency and minimise health care interactions. Solutions such as one stop clinics, day case surgery, hypofractionated radiotherapy, and oral or less frequent drug dosing will be preferred. The pandemic necessitated a triage of those patients whose treatment should be expedited, delayed, or avoided, and may persist with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in circulation. Patients whose demographic characteristics are at the highest risk of complications from COVID-19 may re-evaluate the benefit of intervention for less aggressive cancers. Clinical research will need to accommodate virtual care and trial participation. Research dissemination and medical education will increasingly utilise virtual platforms, limiting in-person professional engagement; ensure data dissemination; and aim to enhance patient engagement. The COVID-19 pandemic will have lasting effects on the delivery of health care. These changes offer opportunities to improve access, delivery, and the value of care for patients with genitourinary cancers but raise concerns that physicians and health administrators must consider in order to ensure equitable access to care. The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed the care provided to many patients with genitourinary cancers. This has necessitated a transition to telemedicine, changes in threshold or delays in many treatments, and an opportunity to reimagine patient care to maintain safety and improve value moving forward.


[The use of succinates for the correction of metabolic disorders in the penumbra in patients with stroke].
The aim of the study was to determine the quantitative content and correlation between metabolites in the core ischemic zone, the ischemic penumbra and the intact tissue of the opposite hemisphere in the acute stage of ischemic stroke using MR-spectroscopy. We studied 72 patients, including 37 patients (the main group) treated with the antioxidant mexidol (2-ethyl-6-methyl-3-hydroxypiridine succinate) in addition to standard therapy and 35 patients who received standard therapy only. The severity of stroke was assessed using the NIHSS. The Barthel index and Rankin scale were used to evaluate functional outcome in the 30th day, hydrogen MR-spectroscopy was used twice: in the first 24 h from disease onset and in the 5th day. Mexidol used in dose 500 mg intravenously during 14 days reduced significantly the content of lactate (p=0.002) and inositol (p=0.005) in the cells compared to the control group that enhanced the restoration of the balance between aerobic and anaerobic mechanisms of oxidation and positively influenced on the rehabilitation of patients. Positive correlations between the content of lactate in the ischemic penumbra and NIHSS scores (r=0.5786; p=0.049) and the negative correlation between the content of lactate in the ischemic penumbra and the degree of functional restoration assessed by the Barthel index (r= -0.6305; p=0.028) were found. These findings support the evidence for the interaction between the disturbance of glucose metabolism in conditions of hypoxia and the degree of nervous tissue damage.


Lessons learned from metabolomics in cystic fibrosis.
Cystic fibrosis is a mono-genetic multi-system disease; however, respiratory manifestations cause the main morbidity and mortality where chronic bacterial infections lead to bronchiectasis and ultimately respiratory failure. Metabolomics allows a relatively complete snapshot of metabolic processes in a sample using different mass spectrometry methods. Sample types used for discovery of biomarkers or pathomechanisms in cystic fibrosis (CF) have included blood, respiratory secretions, and exhaled breath to date. Metabolomics has shown distinction of CF vs. non-CF for matrices of blood, exhaled breath, and respiratory epithelial cultures, each showing different pathways. Severity of lung disease has been addressed by studies in bronchoalveolar lavage and exhaled breath condensate showing separation by metabolites that the authors of each study related to inflammation; e.g., ethanol, acetone, purines. Lipidomics has been applied to blood and sputum samples showing associations with lung function and Pseudomonas aeruginosa infection status. Finally, studies of bacteria grown in vitro showed differences of bacterial metabolites to be associated with clinical parameters. Metabolomics, in the sense of global metabolomic profiling, is a powerful technique that has allowed discovery of pathways that had not previously been implicated in CF. These may include purines, mitochondrial pathways, and different aspects of glucose metabolism besides the known differences in lipid metabolism in CF. However, targeted studies to validate such potential metabolites and pathways of interest are necessary. Studies evaluating metabolites of bacterial origin are in their early stages. Thus further well-designed studies could be envisioned.


Ratite eggshells from lanzarote, canary islands.
Struthious and aepyornithoid eggshells from Tertiary calcareous sediments on Lanzarote prove the presence, until about 12 million years ago, of large flightless birds. The calcarenite horizon is recognized as an old land surface. Mesozoic sedimentary rocks in the basement of the volcanic islands of Lanzarote and neighboring Fuerteventura indicate that at least part of the Canary Archipelago is underlain by continental crust. Separation of the eastern Canaries from Africa raight have been by rifting, and a land connection might still have existed in the lower Pliocene.


Surprise beyond prediction error.
Surprise drives learning. Various neural "prediction error" signals are believed to underpin surprise-based reinforcement learning. Here, we report a surprise signal that reflects reinforcement learning but is neither un/signed reward prediction error (RPE) nor un/signed state prediction error (SPE). To exclude these alternatives, we measured surprise responses in the absence of RPE and accounted for a host of potential SPE confounds. This new surprise signal was evident in ventral striatum, primary sensory cortex, frontal poles, and amygdala. We interpret these findings via a normative model of surprise.


Novel PEG-coated niosomes based on bola-surfactant as drug carriers for 5-fluorouracil.
Innovative niosomes made up of α,ω-hexadecyl-bis-(1-aza-18-crown-6) (bola), Span 80® and cholesterol (2:5:2 molar ratio) are proposed as suitable delivery systems for the administration of 5-fluorouracil (5-FU), an antitumoral compound largely used in the treatment of breast cancer. The bola-niosomes, after sonication procedure, showed mean sizes of ~200 nm and a loading capacity of ~40% with respect to the amount of 5-FU added during the preparation. Similar findings were achieved with PEG-coated bola-niosomes (bola, Span 80(R), cholesterol, DSPE-mPEG2000, 2:5:2:0.1 molar ratio respectively). 5-FU-loaded PEG-coated and uncoated bola-niosomes were tested on MCF-7 and T47D cells. Both bola-niosome formulations provided an increase in the cytotoxic effect with respect to the free drug. Confocal laser scanning microscopy studies were carried out to evaluate both the extent and the time-dependent bola-niosome-cell interaction. In vivo experiments on MCF-7 xenograft tumor SCID mice models showed a more effective antitumoral activity of the PEGylated niosomal 5-FU at a concentration ten times lower (8 mg/kg) than that of the free solution of the drug (80 mg/kg) after a treatment of 30 days.


Electrophilic radical coupling at the edge of graphene.
We report the selective functionalization of an edge of graphene via the electrografting of 4-nitrobenzene diazonium tetrafluoroborate. The edge - a single line of carbon atoms - forms during the process of cutting a graphene monolayer with an atomically sharp microtome knife. Embedded in a polymeric matrix, the just cut bare graphene edge efficiently transfers electrons to a ferricyanide probe in solution. By monitoring the electron exchange reactions of the edge upon functionalization, we observe an annihilation of the reduction and oxidation peaks of the ferricyanide probe, characteristic of the formation of a nitroaryl passivation layer on the edge of graphene. For the first time, the chemical state of a single line of carbon atoms is influenced and monitored using an electrochemical cell, therefore bypassing the usual requirements of atomic resolution characterization techniques, which often demand very clean graphene samples and vacuum processing.


Ameliorative effects of Compound K and ginsenoside Rh1 on non-alcoholic fatty liver disease in rats.
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease, which has no standard treatment available. Panax notoginseng saponines (PNS) have recently been reported to protect liver against hepatocyte injury induced by ethanol or high fat diet (HFD) in rats. Compound K and ginsenoside Rh1 are the main metabolites of PNS. In this study, we evaluated the effects of CK and Rh1 on NAFLD. Rats fed HFD showed significant elevations in liver function markers, lipids, glucose tolerance, and insulin resistance. Treatment with CK or Rh1 either alone or in combination dramatically ameliorated the liver function impairment induced by HFD. Histologically, CK and Rh1 significantly reversed HFD-induced hepatocyte injury and liver fibrosis. In vitro experiments demonstrated that treatment with CK or Rh1 alone or in combination markedly induced cell apoptosis, and inhibited cell proliferation and activation in HSC-T6 cells. Additionally, CK and Rh1, either alone or in combination, also repressed the expression of fibrotic factors TIMP-1, PC-I, and PC-III. Taken together, our results demonstrate that CK and Rh1 have positive effects on NAFLD via the anti-fibrotic and hepatoprotective activity.


Correlative 3D imaging of whole mammalian cells with light and electron microscopy.
We report methodological advances that extend the current capabilities of ion-abrasion scanning electron microscopy (IA-SEM), also known as focused ion beam scanning electron microscopy, a newly emerging technology for high resolution imaging of large biological specimens in 3D. We establish protocols that enable the routine generation of 3D image stacks of entire plastic-embedded mammalian cells by IA-SEM at resolutions of ∼10-20nm at high contrast and with minimal artifacts from the focused ion beam. We build on these advances by describing a detailed approach for carrying out correlative live confocal microscopy and IA-SEM on the same cells. Finally, we demonstrate that by combining correlative imaging with newly developed tools for automated image processing, small 100nm-sized entities such as HIV-1 or gold beads can be localized in SEM image stacks of whole mammalian cells. We anticipate that these methods will add to the arsenal of tools available for investigating mechanisms underlying host-pathogen interactions, and more generally, the 3D subcellular architecture of mammalian cells and tissues.


The Role of Progesterone and a Novel Progesterone Receptor, Progesterone Receptor Membrane Component 1, in the Inflammatory Response of Fetal Membranes to Ureaplasma parvum Infection.
Ureaplasma parvum (U. parvum) is gaining recognition as an important pathogen for chorioamnionitis and preterm premature rupture of membranes. We aimed to investigate the roles of progesterone (P4) and a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), in the response of fetal membranes to U. parvum. Fetal membrane cells (amnion, chorion and decidua) were isolated and confirmed to be free of Mycoplasmataceae. Cells were treated with U. parvum (5x106 CFU), and adherence was quantified by qPCR. Amnion and chorion cells were transfected with scrambled siRNA or validated PGRMC1 siRNA for 72h. Cells were then treated with U. parvum for 4h with or without pretreatment with P4 (10-7 M) or ethanol for 1h. Interleukin-8 (IL-8), matrix metalloproteinase 9 (MMP9) and cyclooxygenase (COX-2) mRNA expression were quantified by qRT-PCR. Culture medium was harvested and analyzed for IL-8 and prostaglandin (PGE2) secretion by ELISA and MMP9 activity by zymography. U. parvum had a mean adherence of 15.0±0.6%, 16.9± 3.7% and 4.7±0.3% in cultured amnion, chorion and decidua cells, respectively. Exposure to U. parvum elicited significant inflammatory responses including induction of IL-8, COX-2, PGE2 and MMP9. A possible role of PGRMC1 was identified in the inhibition of U. parvum-stimulated COX-2 and MMP9 mRNA expression in chorion cells and MMP9 activity in amnion cells. On the other hand, it might enhance the U. parvum-stimulated IL-8 protein secretion in amnion cells. P4, mediated through PGRMC1, significantly inhibited U. Parvum-induced MMP9 mRNA and COX-2 mRNA expression in chorion cells. P4 appeared to attenuate U. parvum induced IL-8 mRNA expression in chorion cells, but this P4 effect might not mediated through PGRMC1. In summary, U. parvum preferentially adheres to and induces inflammatory responses in chorion and amnion cells. P4 and PGRMC1 appear to differentially modulate the inflammatory responses induced by U. parvum among amnion and chorion cells.


ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways.
It is well established that ErbB1 and ErbB2 can cooperate in mammary epithelial cell transformation. Therefore, to understand how ErbB1/ErbB2 signaling contributes to this process, we used the ErbB kinase inhibitor AG1478in ErbB2-dependent BT-474 and SKBR-3 human breast cancer cells. These cells overexpress ErbB2 and also display moderate levels of ErbB1. Treatment with AG1478 resulted in rapid ErbB2 dephosphorylation, reversible G(1) arrest, and interruption of constitutive mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Consequently, both MAPK-dependent transcription of cyclin D1 and phosphorylation of the cyclin-dependent kinase (Cdk) inhibitor p27 were inhibited. The inhibition of PI3K/Akt resulted in increased activity of glycogen synthase kinase-3beta, which phosphorylated cyclin D1, potentially reducing its steady-state levels. The loss of cyclin D1 reduced the amount of cyclin D1/Cdk4 complexes that can sequester p27 in the cytosol. This plus the reduced phosphorylation of p27 by MAPK enhanced the stability of p27 that associated with nuclear Cdk2 at high stoichiometry and inhibited its kinase activity. Antisense p27 oligonucleotides decreased p27 levels and abrogated the G(1) arrest induced by AG1478. Similarly, infection with an adenovirus encoding inducible cyclin D1 also counteracted the antiproliferative effect of AG1478. These data imply that: (a) modulation of both p27 and cyclin D1 are required for the growth arrest that results from blockade of the ErbB2 kinase; and (b) ErbB2 overexpressing cells use both MAPK and PI3K/Akt to modulate p27 and cyclin D1 and, hence, subvert the G(1)-to-S transition.


HIV, multidrug-resistant TB and depressive symptoms: when three conditions collide.
Management of multidrug-resistant TB (MDR-TB) patients co-infected with human immunodeficiency virus (HIV) is highly challenging. Such patients are subject to long and potentially toxic treatments and may develop a number of different psychiatric illnesses such as anxiety and depressive disorders. A mental health assessment before MDR-TB treatment initiation may assist in early diagnosis and better management of psychiatric illnesses in patients already having two stigmatising and debilitating diseases. To address limited evidence on the baseline psychiatric conditions of HIV-infected MDR-TB patients, we aimed to document the levels of depressive symptoms at baseline, and any alteration following individualized clinical and psychological support during MDR-TB therapy, using the Patient Health Questionnaire-9 (PHQ-9) tool, among HIV-infected patients. This was a retrospective review of the medical records of an adult (aged >15 years) HIV/MDR-TB cohort registered for care during the period of August 2012 through to March 2014. A total of 45 HIV/MDR-TB patients underwent baseline assessment using the PHQ-9 tool, and seven (16%) were found to have depressive symptoms. Of these, four patients had moderate to severe depressive symptoms. Individualized psychological and clinical support was administered to these patients. Reassessments were carried out for all patients after 3 months of follow-up, except one, who died during the period. Among these 44 patients, three with baseline depressive symptoms still had depressive symptoms. However, improvements were observed in all but one after 3 months of follow-up. Psychiatric illnesses, including depressive symptoms, during MDR-TB treatment demand attention. Routine administration of baseline mental health assessments by trained staff has the potential to assist in determining appropriate measures for the management of depressive symptoms during MDR-TB treatment, and help in improving overall treatment outcomes. We recommend regular monitoring of mental health status by trained counsellors or clinical staff, using simple, validated and cost-effective tools.


A new diagnostic test for VLCAD deficiency using immunohistochemistry.
Muscle pathology is often unhelpful in elucidating the specific underlying abnormality in patients with metabolic myopathy with rhabdomyolysis, including very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Biochemical analyses require large amounts of biopsy samples for each enzyme assay. To develop a more efficient diagnostic method for VLCAD deficiency. The authors performed immunohistochemical analysis using an antibody to VLCAD on muscles from 344 patients (226 men and 118 women) without a specific diagnosis who had at least one of the following symptoms: myoglobinuria, high CK level, muscle pain, muscle stiffness, sudden infant death syndrome, and Reye-like syndrome. Immunoreactivity to VLCAD was absent or markedly reduced in 13 patients. Biochemical analyses confirmed that all these patients had low enzymatic activity and reduced amount of protein. They all had the myopathic phenotype. The authors identified homozygous or compound heterozygous mutations in all of them. All recombinant proteins had reduced enzymatic activity except for 128G>A (G43D) and 796C>G (P266A) mutants, indicating that they are neutral polymorphisms. The new screening method for the detection of VLCAD deficiency using an immunohistochemical technique identified 13 new Japanese patients with VLCAD deficiency.


A human subcortical network underlying social avoidance revealed by risky economic choices.
Social interactions have a major impact on well-being. While many individuals actively seek social situations, others avoid them, at great cost to their private and professional life. The neural mechanisms underlying individual differences in social approach or avoidance tendencies are poorly understood. Here we estimated people's subjective value of engaging in a social situation. In each trial, more or less socially anxious participants chose between an interaction with a human partner providing social feedback and a monetary amount. With increasing social anxiety, the subjective value of social engagement decreased; amygdala BOLD response during decision-making and when experiencing social feedback increased; ventral striatum BOLD response to positive social feedback decreased; and connectivity between these regions during decision-making increased. Amygdala response was negatively related to the subjective value of social engagement. These findings suggest a relation between trait social anxiety/social avoidance and activity in a subcortical network during social decision-making.


Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance.
Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB). Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis. Here we propose a novel measure--Codon Deviation Coefficient (CDC)--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance. As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions.


Thermal magnetic resonance: physics considerations and electromagnetic field simulations up to 23.5 Tesla (1GHz).
Glioblastoma multiforme is the most common and most aggressive malign brain tumor. The 5-year survival rate after tumor resection and adjuvant chemoradiation is only 10 %, with almost all recurrences occurring in the initially treated site. Attempts to improve local control using a higher radiation dose were not successful so that alternative additive treatments are urgently needed. Given the strong rationale for hyperthermia as part of a multimodal treatment for patients with glioblastoma, non-invasive radio frequency (RF) hyperthermia might significantly improve treatment results. A non-invasive applicator was constructed utilizing the magnetic resonance (MR) spin excitation frequency for controlled RF hyperthermia and MR imaging in an integrated system, which we refer to as thermal MR. Applicator designs at RF frequencies 300 MHz, 500 MHz and 1GHz were investigated and examined for absolute applicable thermal dose and temperature hotspot size. Electromagnetic field (EMF) and temperature simulations were performed in human voxel models. RF heating experiments were conducted at 300 MHz and 500 MHz to characterize the applicator performance and validate the simulations. The feasibility of thermal MR was demonstrated at 7.0 T. The temperature could be increased by ~11 °C in 3 min in the center of a head sized phantom. Modification of the RF phases allowed steering of a temperature hotspot to a deliberately selected location. RF heating was monitored using the integrated system for MR thermometry and high spatial resolution MRI. EMF and thermal simulations demonstrated that local RF hyperthermia using the integrated system is feasible to reach a maximum temperature in the center of the human brain of 46.8 °C after 3 min of RF heating while surface temperatures stayed below 41 °C. Using higher RF frequencies reduces the size of the temperature hotspot significantly. The opportunities and capabilities of thermal magnetic resonance for RF hyperthermia interventions of intracranial lesions are intriguing. Employing such systems as an alternative additive treatment for glioblastoma multiforme might be able to improve local control by "fighting fire with fire". Interventions are not limited to the human brain and might include temperature driven targeted drug and MR contrast agent delivery and help to understand temperature dependent bio- and physiological processes in-vivo.


Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study.
Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old. To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians. Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used (<1 year for all subjects) and scores for cognitive domains were established. Neuropathologies [cerebral atrophy, ventricular dilation, atherosclerosis, cerebral amyloid angiopathy (CAA), Lewy bodies, hippocampal sclerosis (HS), hippocampal TDP-43 proteinopathy, neuritic plaque (NP) and neurofibrillary tangle (NFT) counts, Braak staging, and National Institute on Aging-Reagan Institute (NIARI) criteria for the neuropathological diagnosis of Alzheimer's disease (AD)] were compared among subjects with different ratings of dementia. Linear regression was applied to evaluate the association between cognitive domain scores and neuropathologies. Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living. AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.


Survey of osteopathic and allopathic residents' attitudes toward osteopathic manipulative treatment.
More than 50% of new osteopathic physicians receive their residency training in programs accredited by the Accreditation Council for Graduate Medical Education (ACGME) rather than in programs approved by the American Osteopathic Association (AOA). To examine the implications of this training pattern for trends in the practice of osteopathic manipulative treatment (OMT), the authors surveyed attitudes toward OMT with questionnaires targeted to osteopathic and allopathic residents in family medicine residency programs. Osteopathic residents in specialties other than family medicine were also surveyed. Differences in views between osteopathic residents in AOA-approved and ACGME-accredited programs--as well as the views of the allopathic residents--were analyzed using chi(2) tests. Fewer osteopathic residents in ACGME-accredited family medicine programs (39.5%) reported frequent use of OMT than did osteopathic residents in AOA-approved family medicine programs (67.9%). This difference appears to result more from experiences during residency training than from expectations formed before residency training. Ninety percent of the allopathic residents who responded to the survey said they believed that OMT is effective for treating somatic dysfunction. Moreover, 70.9% of allopathic physicians indicated they had at least some interest in learning OMT. To the authors' knowledge, this study was the first to quantify a change in attitude of allopathic residents toward a more positive view of osteopathic medicine.


The styrene metabolite, phenylglyoxylic acid, induces striatal-motor toxicity in the rat: influence of dose escalation/reduction over time.
Exposure to the industrial solvent, styrene, induces locomotor and cognitive dysfunction in rats, and parkinsonian-like manifestations in man. The antipsychotic, haloperidol (HP), well known to induce striatal toxicity in man and animals, and styrene share a common metabolic pathway yielding p-fluoro phenylglyoxylic acid and phenylglyoxylic acid (PGA), respectively. Using an exposure period of 30 days and the vacous chewing movement (VCM) model as an expression of striatal-motor toxicity, we found that incremental PGA dosing (220-400 mg/kg) significantly increased VCMs up to day 25, but decreased to control levels shortly after reaching maximum dose. However, a diminishing dose of PGA (400-200 mg/kg) did not evoke an immediate worsening of VCMs but precipitated a significant increase in VCMs following dosage reduction to 200 mg/kg on day 22. PGA exposure, therefore, compromises striatal-motor function that is especially sensitive to changes in exposure dose. Longer alternating dose exposure studies are needed to establish whether motor dysfunction is progressive in severity or longevity. These findings are of significance for the environmental toxicology of styrene in the chemical industry.


Kinetics of antibody responses to Plasmodium falciparum-infected erythrocyte variant surface antigens.
The kinetics of antibody responses to the Plasmodium falciparum malaria parasite-induced erythrocyte surface antigens (PIESAs) in 26 Kenyan children were examined by use of flow cytometry and agglutination assays. Although 19 of the 26 children mounted a primary antibody response to PIESAs within 2 weeks of experiencing an acute episode and maintained high antibody levels for at least 12 weeks, the remaining 7 children had responses that were weak and brief. Resistance to reparasitization was decreased in the children with short-lived responses. Isotype profiles of responses in 11 of the children studied suggest that they may have failed to switch to IgG after the initial IgM response. These data suggest that children vary widely in their ability to respond to PIESAs and that, in some individuals or with certain PIESA variants, short-lived antibody responses are induced that may be associated with poor antibody class switching.


Distribution of methanogenic potential in fractions of turf grass used as inoculum for the start-up of thermophilic anaerobic digestion.
This study aims to investigate thermophilic methanogens in turf used as an inoculum. Results showed that Methanoculleus sp. regarded as hydrogenotrophic and Methanosarcina sp. regarded as acetoclastic methanogens were present in turf tested. However, active acetoclastic methanogens were present in turf soil only. The current study showed that thermophilic methanogens were present in various turf grass species: Stenotaphrum secundatum, Cynodon dactylon, and Zoysia japonica. Severe treatments of grass leaves under oxic conditions, including blending, drying and pulverizing did not affect the thermophilic hydrogenotrophic methanogenic activity of the grass. A dried and pulverized grass extract could be generated that can serve as a readily storable methanogenic inoculum for thermophilic anaerobic digestion. The methanogens could also be physically extracted into an aqueous suspension, suitable as an inoculum. The possible contribution of the presence of methanogens on grass plants to global greenhouse emissions is briefly discussed.


Optimizing early upper gastrointestinal cancer detection at endoscopy.
Survival rates for upper gastrointestinal cancers are poor and oesophageal cancer incidence is increasing. Upper gastrointestinal cancer is also often missed during examinations; a predicament that has not yet been sufficiently addressed. Improvements in the detection of premalignant lesions, early oesophageal and gastric cancers will enable organ-preserving endoscopic therapy, potentially reducing the number of advanced upper gastrointestinal cancers and resulting in improved prognosis. Japan is a world leader in high-quality diagnostic upper gastrointestinal endoscopy and the clinical routine in this country differs substantially from Western practice. In this Perspectives article, we review lessons learnt from Japanese gastroscopy technique, training and screening for risk stratification. We suggest a key performance indicator for upper gastrointestinal endoscopy with a minimum total procedure time of 8 min, and examine how quality assurance concepts in bowel cancer screening in the UK could be applied to upper gastrointestinal endoscopy and improve clinical practice.


Immunological analysis and pathological examination of gnotobiotic mice monoassociated with Mycoplasma pneumoniae.
Although mycoplasmal pneumonia has been generally considered to be a disease with good prognosis, a pathogenic host immune response has been associated with its occurrence. In the present study, the pathogenic significance of the immune response was examined using germ-free mice either infected intranasally with Mycoplasma pneumoniae or inoculated with M. pneumoniae antigens (soluble antigen and partially purified antigen). In gnotobiotic mice monoassociated with M. pneumoniae, 10(4) c.f.u. M. pneumoniae per lung were isolated 2-28 days after infection. Inflammatory changes with infiltration of lymphocytes were histopathologically detected in the perivascular area at 2 and 7 days after infection. In the mice intranasally inoculated with soluble antigen or partially purified antigens (F6 and F10 antigens), infiltration of neutrophils and lymphocytes was histopathologically detected at 2 days after inoculation. Severe pneumonia with tissue destruction was observed in the mice inoculated with F6 antigen. A gamma interferon (IFN-gamma) dominant response in endogenous cytokine expression was observed in all the treated mice. These results indicate that inflammatory changes in the lung tissue were prolonged in gnotobiotic mice monoassociated with M. pneumoniae compared with mice inoculated with M. pneumoniae antigen. In addition, it was shown that IFN-gamma plays an important role in the pathogenesis of pneumonia in mice either infected with M. pneumoniae or inoculated with its antigen. In particular, the F6 antigen has been considered to be an important virulence factor in terms of induction of tissue injury causing infiltration of lymphocytes and neutrophils in the lung, suggesting a close interaction between the immune response and the occurrence of M. pneumoniae pneumonia.


Enhancing the Bactericidal Efficacy of Nanostructured Multifunctional Surface Using an Ultrathin Metal Coating.
Insects and plants exhibit bactericidal behavior through nanostructures, which leads to physical contact killing that does not require antibiotics or chemicals. Also, certain metallic ions (e.g., Ag+ and Cu2+) are well-known to kill bacteria by disrupting their cellular functionalities. The aim of this study is to explore the improvement in bactericidal activity by combining extreme physical structure with surface chemistry. We have fabricated tall (8-9 μm high) nanostructures on silicon surfaces (NSS) having sharp tips (35-110 nm) using a single-step, maskless deep reactive ion etching technique inspired by dragonfly wing. Bactericidal efficacy of the nanostructured surfaces coated with a thin layer of silver (NSS_Ag) or copper (NSS_Cu) was measured quantitatively using standard viability plate-count method and flow cytometry. NSS_Cu surfaces kill bacteria very efficiently (killing 97% within 30 min) when compared to the uncoated NSS. This can be attributed to the addition of a surface chemistry to the nanostructures. The antibacterial activity of NSS_Cu is further indicated by the morphological differences of the dying/dead bacteria observed in the SEM images. The nanostructured surfaces demonstrate excellent superhydrophobic behavior, even with an ultrathin layer of metal (Ag/Cu) coating. The nanostructured surfaces exhibit static contact angle greater than 150° and contact hysteresis less than 10°. Moreover, reflectance is found to be <1% (for NSS_Cu < 0.5%) for all the nanostructured surfaces in the wavelength range 250-800 nm. The results obtained suggest that the fabricated nanostructured surfaces are multifunctional and can be used in various practical applications.