Bevacizumab for recurrent glioblastoma multiforme: a meta-analysis.
The FDA's approval of bevacizumab for recurrent glioblastoma on May 9, 2009, was based on the significant response rate and clinical benefits seen from randomized phase II studies. Large-scale phase III data are unavailable. In an effort to determine benchmark efficacy parameters for bevacizumab and analyze its dose--response effect, the authors performed a meta-analysis of 15 studies published from 2005 to 2009, involving 548 patients with a median age of 53 years (range, 5-74 years), that used bevacizumab to treat recurrent glioblastoma. Median overall survival was 9.3 months (95% CI, 7.9-10.6 months). The respective 6-month progression-free and 6-month overall survival rates were 45% (95% CI, 34%-57%) and 76% (95% CI, 69%-84%), respectively. Median time to tumor progression was 6.1 months (95% CI, 4.2-8.1 months). The response analysis yielded a 6% complete response (95% CI, 2%-9%), 49% partial response (95% CI, 37%-61%), and 29% stable disease (95% CI, 20%-38%). No difference was seen in bevacizumab dose--response benefit between 5 mg/kg and 10 to 15 mg/kg. The efficacy benchmarks from this meta-analysis did not differ from those of the recently published randomized phase II studies. The lack of a dose--response effect would require confirmation in a prospectively conducted clinical trial.


Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity.
Amyloid-β (Aβ) peptides are the main components of the plaques found in the brains of patients with Alzheimer's disease. However, Aβ peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aβ peptides. Recently, anti-infective properties of Aβ peptides have been reported. Here, we investigated the interaction of Aβ peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aβ1-42, Aβ2-42, and Aβ3p-42 but not the non-amyloidogenic peptides Aβ1-40 and Aβ2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aβ peptide variants ending at position 42 (Aβx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aβx-40. Furthermore, Aβx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aβ1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aβ1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aβx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.


[Septal nuclei in the regulation of vago-sensitive neurons activity of the solitary nucleus in cats].
The descending influences of the septal nuclei (lateral nucleus--LSN and bed nucleus stria terminalis--BNST) on activity of viscero-sensory neurons of the nucleus of tractus solitarius (NTS) identified by stimulation of cervical part of the n. vagus were investigated in the cat anaesthetised by chloraloze-nembutal combination. It was found that out of 70 units recorded in the NTS area 50 were identified as those of primary and secondary input vagal neurons. Influence of single, paired and frequency stimulation on the septal structures was studied on these neurons. It was revealed that 30% (15 un) reacted by phase-specific response to the single stimulation of the septal nuclei. The latent period of initial excitation was in the range 5-25 ms. During the paired stimulation these neurons were not able to react to the second stimulus for the equal 10-300 ms. It was revealed that 34% (17 un) of the identified vagal neurons reacted by a tonic change of their spontaneous activity. The increase of frequency stimulation to 20 Hz evoked different changes of the rhythmical activity of the vagal neurons (increase, diminishing or inhibition). The study of interaction between central and peripheral signals in the solitary neurons induced blocking influence of descending septal discharge on the vagal test response. It is possible that the septal downward impulses reach the vago-sensitive solitary neurons indirectly through other structures of the limbic brain (amygdala, hypothalamus) and participate in modulation of the spontaneous activity of these neurons.


An RME1-independent pathway for sporulation control in Saccharomyces cerevisiae acts through IME1 transcript accumulation.
The RES1-1 mutation was isolated on the basis of its ability to allow MATa/MAT alpha diploid Saccharomyces cerevisiae cells to express a late sporulation-regulated gene, SPR3, in the presence of excess copies of RME1. RME1 is a repressor of meiosis that is normally expressed in cells that lack the a1/alpha 2 repressor encoded by MAT. The RES1-1 mutation also supports sporulation in mat-insufficient diploids. This phenotype does not result from a failure to express RME1 and is not due to activation of the silent copies of mating type information. RES1-1 activates sporulation by allowing IME1 accumulation in all cell types, irrespective of the presence of the MAT products. IME1 is still responsive to RME1 in RES1-1 cells, since double mutants (rme1 RES1-1) that are deficient at MAT can sporulate better than either single mutant. RES1-1 is not an allele of IME1.


Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action.
In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-γ+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCRαβ- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCRαβ- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.


Chromium(III) complexation to natural organic matter: mechanisms and modeling.
Chromium is a common soil contaminant, and it often exists as chromium(III). However, limited information exists on the coordination chemistry and stability of chromium(III) complexes with natural organic matter (NOM). Here, the complexation of chromium(III) to mor layer material and to Suwannee River Fulvic Acid (SRFA) was investigated using EXAFS spectroscopy and batch experiments. The EXAFS results showed a predominance of monomeric chromium(III)-NOM complexes at low pH (<5), in which only Cr···C and Cr-O-C interactions were observed in the second coordination shell. At pH > 5 there were polynuclear chromium(III)-NOM complexes with Cr···Cr interactions at 2.98 Å and for SRFA also at 3.57 Å, indicating the presence of dimers (soil) and tetramers (SRFA). The complexation of chromium(III) to NOM was intermediate between that of iron(III) and aluminum(III). Chromium(III) complexation was slow at pH < 4: three months or longer were required to reach equilibrium. The results were used to constrain chromium-NOM complexation in the Stockholm Humic Model (SHM): a monomeric complex dominated at pH < 5, whereas a dimeric complex dominated at higher pH. The optimized constant for the monomeric chromium(III) complex was in between those of the iron(III) and aluminum(III) NOM complexes. Our study suggests that chromium(III)-NOM complexes are important for chromium speciation in many environments.


[The direct composite crown].
The direct composite crown is a restoration replacing the original toothcrown in form and function. It can be an alternative for indirect gold or porcelain restorations if the oral health condition is not stable, if indirect restorations require a high biological price or if financial resources are limited. The longterm durability of these restorations is still unknown. As a direct composite crown can be considered as minimally invasive and can be easily replaced by an indirect restoration if needed, there are hardly any contra-indications for its use.


A 25-kD inhibitor of actin polymerization is a low molecular mass heat shock protein.
The 25-kD inhibitor of actin polymerization (25-kD IAP), isolated from turkey smooth muscle (Miron, T., M. Wilchek, and B. Geiger, 1988. Eur. J. Biochem. 178:543-553), is shown here to be a low molecular mass heat shock protein (HSP). Direct sequence analysis of the purified protein, as well as cloning and sequencing of the respective cDNA, disclosed a high degree of homology (67% identity, 80% similarity) to the human 27-kD HSP. Southern blot of chicken genomic DNA disclosed one band, suggesting the presence of a single gene, and Northern blot analysis revealed abundant transcript of approximately 1 kb in gizzard and heart tissues and lower amounts in total 18-d chick embryo RNA and in cultured fibroblasts. Exposure of the latter cells to 45 degrees C resulted in over 15-fold increase in the apparent level of the 25-kD IAP protein, confirming that its expression is regulated by heat shock. Immunofluorescent microscopic localization indicated that after heat treatment, the levels of the 25-kD IAP were markedly increased and the protein was apparently associated with cytoplasmic granules. Heat shock also had a transient, yet prominent, effect on the microfilament system in cultured fibroblasts: stress fibers disintegrated within 10-15 min after incubation at 45 degrees C, yet upon further incubation at the elevated temperature, conspicuous actin bundles were apparently reformed.


Antimicrobial safety and tolerability: differences and dilemmas.
The adverse drug reactions associated with antimicrobials have become a topic of major importance and concern in the last few years. Antimicrobial toxicity may take many forms, varying from mild, transient phenomena to dramatic, life-threatening events such as seizures or cardiac arrhythmias. We review the toxicity of antimicrobials in general and of the fluoroquinolones in particular and attempt to explain the adverse events by use of structure-adverse event relationships where possible. There are currently 5 main mechanisms that can be invoked to explain antimicrobial toxicity: direct effects, hypersensitivity, changes in microbial flora, drug interactions, and microbial lysis. The adverse drug reactions seen with fluoroquinolones are explained on the basis of these 5 mechanisms. The various organ systems affected by the fluoroquinolones are considered; then individual members of the fluoroquinolone class are reviewed. The unexpected and dramatic problems encountered with temafloxacin and trovafloxacin are discussed as well.


Paratubal cyst complicated by tubo-ovarian torsion: computed tomography features.
Paratubal cysts complicated by tubo-ovarian torsion are an uncommon cause of acute right iliac fossa pain in children and very rarely diagnosed accurately preoperatively. We report a constellation of diagnostic CT features in a 12-year-old pubertal girl.


Incorrect aseptic techniques in medicine preparation and recommendations for safer practices: a systematic review.
Many patient deaths have been reported because of administration of contaminated intravenous medicines due to incorrect aseptic techniques. Our aim was to review the literature for (1) incorrect practices in aseptic drug preparation and administration and (2) recommendations for safer practices in hospitals. A systematic literature search was conducted in PubMed covering 2007-2015. Studies were included if they concerned aseptic medicine preparation and administration in hospitals by different healthcare professionals, assessed incorrect practices and made recommendations for safer aseptic preparation and administration. 26 studies were included of which 19 were original articles. 12 of the studies concerned description of incorrect practices that led to contamination. The studies reported 11 incorrect practices that increased the risk of contamination of parenteral medicines. The most reported incorrect practices were multiple use of phials and syringes (2/12 studies) and lack of overall disinfection during the aseptic preparation and administration (3/12 studies). 22 practices were recommended to avoid contamination, which were classified into six categories: equipment and medicines (7); disinfection (6); working environment (3); storing (3); catheter care (2) and quality of prepared medicines (1). The results indicate that pharmacists prepared syringes with less contamination than nurses because of the pharmacist's aseptic skills and environmental aspects in pharmacy units. The review discusses many appropriate and enhanced practices in aseptic drug preparation and administration. As the change for the better in contamination rates of administered medicines seems to be challenging to achieve in hospitals, better and possibly international procedures for safe parenteral practices need to be developed.


Multiple infection of apple trees by distinct strains of 'Candidatus Phytoplasma mali' and its pathological relevance.
Forty-eight apple trees infected by 'Candidatus Phytoplasma mali' were examined using single-strand conformation polymorphism (SSCP) and sequence analysis of a variable hflB gene fragment and the immunodominant membrane protein-encoding imp gene. SSCP analysis of polymerase chain reaction-amplified hflB gene fragments revealed diverse profiles, differing in number and position of the bands. The 'Ca. P. mali' content of a single infected apple tree was termed an accession. Cloning of fragments from accessions that yielded fewer bands resulted in clone populations showing uniform or moderately polymorphic SSCP patterns and largely homogenous nucleotide sequences. In contrast, inserts from accessions yielding more bands were heterogeneous and formed two to four distinct groups of profiles. DNA fragments from such accessions were diverse and clustered distantly when subjected to phylogenetic analysis, mostly as two homogenous groups plus one or a few other sequences. Similar results were obtained upon imp gene examination. The collective data indicate that accessions exhibiting more complex patterns were composed of two or three distinct 'Ca. P. mali' strains. There is evidence that multiple infections are of pathological relevance due to strain interactions leading to shifts in the populations. In triply infected trees of one accession, no specific symptoms were induced by the presence of two of the strains. The rare appearance of pronounced symptoms was associated with a separate strain that possessed a unique SSCP profile and a unique hflB sequence. The two mild strains from this apple accession also induced only mild symptoms on periwinkle and tobacco and occurred specifically in one of these plants.


Proline analogues inhibit human skin fibroblast growth and collagen production in culture.
Several structural analogues of proline have been shown to be incorporated into proteins in place of proline. As a consequence, the proliferation of cells in culture and the extracellular deposition of collagen in animal systems are reduced. In this study, the effects of two proline analogues, cis-4-hydroxy-L-proline and L-azetidine-2-carboxylic acid, on the growth parameters and procollagen production by cultured normal human skin fibroblasts were examined. The results indicated that incubation of the cells with the analogues reduced the rate of fibroblast proliferation and lowered the plating efficiency. Further experiments demonstrated that fibroblasts in the presence of L-azetidine-2-carboxylic acid synthesized procollagen polypeptides which were not in a triple-helical conformation, as judged by limited pepsin proteolysis. Also, a significantly increased fraction of the newly synthesized collagenous peptides was in a dialyzable form, suggesting increased degradation of the nonhelical chains. The rate of translation of collagenous polypeptides and the preprocollagen messenger RNA activity in the cells were not affected by the analogues. The proline analogues thus appear to inhibit the production of procollagen on the posttranslational level by preventing the polypeptides from folding into a stable triple-helical conformation. The nonhelical polypeptides are then readily susceptible to proteolysis leading to reduced deposition of extracellular collagen fibers. Similar experiments were also performed with fibroblasts cultured from patients with active progressive systemic sclerosis. Quantitatively and qualitatively comparable inhibition of procollagen production by L-azetidine-2-carboxylic acid was noted with scleroderma cells as with control fibroblast cultures. The results suggest, therefore, that proline analogues may, in the future, prove useful in limiting excessive collagen deposition in scleroderma and other forms of dermal fibrosis.


Numerical and behavioral effects within a pulse-driven system: consequences for shared prey.
Some of the clearest examples of the ramifying effects of resource pulses exist in deciduous forests dominated by mast-producing trees, such as oaks, beech, and hornbeam. Seed production in these forests represents only the first of several pulsed events. Secondary pulses emerge as mast-consuming small rodents numerically respond to seed production and tertiary pulses emerge as generalist predators numerically respond to rodents. Raptors may also respond behaviorally (i.e., diet shifts) to subsequent crashes in small rodents following the crash phase in seed production. In oak-dominated forest in the Hudson Valley, New York, these various pulse and crash phases act synergistically, although not simultaneously, to influence thrush population dynamics through predation on nests, juveniles, and adults. As a consequence, factors limiting population growth rate and their age-specific action vary as a function of past acorn production. We highlight these interactions based on our eight-year study of thrush demography, acorn production, and small mammal abundance coupled with information on regional adult thrush population trends from the Breeding Bird Survey. We use these data sets to demonstrate the sequence of primary to tertiary pulses and how they influence breeding thrush populations. To extend our discussion beyond masting phenomena in the eastern United States, we briefly review the literature of alternative avian prey within pulsed systems to show (1) numerical and behavioral responses by generalist predators are ubiquitous in pulsed systems, and this contributes to (2) variability in reproduction and survivorship of avian prey linked to the underlying dynamics of the pulse. We conclude by exploring the broad consequences of cascading resource pulses for alternative prey based upon the indirect interaction of apparent competition among shared prey and the nature of temporal variability on populations.


Pet feeding habits and the microbiological contamination of dog food bowls: effect of feed type, cleaning method and bowl material.
Safe pet feeding practices and food bowl hygiene measures are important for minimising the risk of microbiological contaminations in the domestic environment. This study compares the practices reported by dog and cat caregivers, and investigates whether cleaning method, feed type or bowl material affects the microbiological contamination of dog food bowls. Data from 351 dog caregivers and 186 cat caregivers were collected via an online survey. The majority of dogs (70.7%) were fed twice daily, whereas cats (43%) were mostly fed ad libitum. The most common material for dog food bowls was metal (67.1%) versus plastic (38.1%) and metal (37.6%) for cats. Dog food bowls were most frequently cleaned after each meal (35.7%); whereas for cats, 21.5% were cleaned after each meal, 22.7% once a day and 19.3% 2-3 times a week. Total mesophilic aerobic bacteria counts (TMABc), Enterobacteriaceae counts and pathogenic bacteria (Salmonella spp., Campylobacter spp., Verotoxigenic E. coli [VTEC]) were assessed for 96 dog food bowls. TMABc were higher in metal vs. plastic bowls (p < 0.001) and in those used for wet food vs. dry food (p = 0.0397). Enterobacteriaceae counts were higher in bowls washed by hand vs. dishwasher (p = 0.0515), whereas no differences were found between hand washing vs. dry wiping. Salmonella spp., Campylobacter spp. or E. coli VTEC contaminations were not detected. The surveyed Italian dog and cat caregivers reported different habits concerning feeding frequency, food bowl material and cleaning frequency. Wet food and metal bowls were associated with higher levels of microbiological contamination of dog food bowls. Furthermore, in relation to wet washing methods, contaminations were likely to be greater following hand washing than they were following the use of a dishwasher. Practical guidelines for safe feeding practices and hygiene measures are needed to minimise the risk of microbiological contaminations in domestic environments.


[The effect of different curing methods on the rate of base resin shrinkage]
OBJECTIVE:On the base of resin characters,the relation between the fit of deture base and curing ways was discussed.METHODS:Four resins and three processing techniques were evaluated in this study to measure the polymerization shrinkage and discuss the effect of different curing methods on base resin shrinkage. The processing techniques were conventional hot water curing method,microwave curing and microwave compression curing method. RESULTS:(1)The processing of hot water curing is long, though the linear shrinkage is the smallest.The shrinkage of each resin differs.It aslo shows great deformability. (2)Microwave curing is faster. Studies indicate that it is easy to produce porosity in the interior of the resin by mononer releasing quickly,and greater shrinkage was observed in polymerization than conventional hot water. (3)Microwave compresion curing method is cleaner and faster too. There's little difference among the resins and this system can produce a more homogeneous deture base and reduce porosity. But it has the greatest shrinkage. CONCLUSION:All of the data revealed that different curing methods have great influence on the shrinkage of base resin composites.


Origin and scope of long-range stabilizing interactions and associated SOMO-HOMO conversion in distonic radical anions.
High-level quantum-chemical methods have been used to study the scope and physical origin of the significant long-range stabilizing interactions between nonmutually conjugated anion and radical moieties in SOMO-HOMO converted distonic radical anions. In such species, deprotonation of the acid fragment can stabilize the remote radical by tens of kilojoules, or, analogously, formation of a stable radical (by abstraction or homolytic cleavage reactions) increases the acidity of a remote acid by several pKa units. This stabilization can be broadly classified as a new type of polar effect that originates in Coloumbic interactions but, in contrast to standard polar effects, persists in radicals with no charge-separated (i.e., dipole) resonance contributors, is nondirectional, and hence of extremely broad scope. The stabilization upon deprotonation is largest when a highly delocalized radical is combined with an initially less stable anion (i.e., the conjugate base of a weaker acid), and is negligible for highly localized radicals and/or stable anions. The effect is largest in the gas phase and low-polarity solvents but is quenched in water, where the anion is sufficiently stabilized. These simple rules can be employed to design various switchable compounds able to reversibly release radicals in response to pH for use in, for example, organic synthesis or nitroxide-mediated polymerization. Moreover, given its wide chemical scope, this effect is likely to influence the protonation state of many biological substrates under radical attack and may contribute to enzyme catalysis.


Inflammation markers are modulated by responses to diets differing in postprandial insulin responses in individuals with the metabolic syndrome.
Inflammation may be a mechanism by which high postprandial insulin and glucose responses increase the risk of type 2 diabetes mellitus. We hypothesized that dietary carbohydrates characterized by different postprandial insulin responses may differentially modify cytokine concentrations in plasma and gene expression in subcutaneous adipose tissue. Individuals (n = 47) with the metabolic syndrome were randomly assigned to a 12-wk diet with oat and wheat bread and potato (high postprandial insulin response) or rye bread and pasta (low postprandial insulin response). Postprandial glucose and insulin responses to the oat and wheat bread meal and to the rye bread meal were determined in 19 individuals before intervention. During the 12-wk diet, the change in the gene expression of interleukin (IL)-10 receptor alpha and tumor necrosis factor-alpha in subcutaneous adipose tissue differed between the groups (P = 0.002 and P = 0.083, respectively). Moreover, the change in fasting plasma concentrations of IL-1beta and IL-6 differed between the groups (P = 0.020 and P = 0.055, respectively). In the postprandial challenge, the insulin response to the rye bread meal was lower than that to the oat and wheat bread meal (P < 0.001), whereas there were no differences in the mean blood glucose response. In contrast, plasma glucose concentrations decreased more below fasting concentrations 2.5-3 h after the oat and wheat bread meal than after the rye bread meal. A late postprandial rebound of free fatty acids was detected after the oat and wheat bread meal (P = 0.048). Long-term intake of cereal foods with differing postprandial insulin responses may be a factor that modulates the inflammatory status in individuals with the metabolic syndrome.


Comparative evaluation of alkylphenolic compounds on estrogenic activity in vitro and in vivo.
This study was undertaken to compare the sensitivity of screening test methods and to investigate the structure-activity relationships of the estrogenic activity of alkylphenolic compounds (APs) using in vitro and in vivo assays. Two in vitro systems, MCF-7 cell proliferation (E-screen assay) and competitive binding assay to estrogen receptor (ER), were selected to evaluate the estrogenic effects. Uterotrophic assay and Calbindin-D9K (CaBP9K) mRNA expression were also examined in ovariectomized Sprague-Dawley female rats. A series of APs with various alkyl groups were examined, namely, 4-propylphenol, 4-butylphenol, 4-t-butylphenol, 4-pentylphenol, 4-nonylphenol, 4-octylphenol, 4-t-octylphenol, and 4-phenylphenol, and 17beta-estradiol (E2) was used as a positive control. In the E-screen assay, E2 was found to induce maximum proliferation of MCF-7 cells at 1 nM. Among the APs, 4-t-octylphenol and 4-nonylphenol were found to be considerably more potent than any other compound and estrogenic effects were detectable at 1 and 10 microM, respectively. 4-t-Octylphenol and 4-nonylphenol inhibited the binding of E2 to the ER of MCF-7 cells in a competitive ER binding assay. The uterotrophic effects to APs (10, 50, 200, and 400 mg/kg/d) were compared to E2 (1 microg/kg) in ovariectomized rats after treatment for 3 d. 4-Nonylphenol, 4-t-octylphenol, and 4-phenylphenol produced dose-dependent increases in the uterine weights of ovariectomized rats. In the CaBP-9K mRNA expression test, CaBP-9K mRNA levels were detected in the uteri of ovariectomized rats treated with 4-pentylphenol (400 mg/kg), 4-nonylphenol, 4-phenylphenol (200 and 400 mg/kg), and 4-t-octylphenol (50 mg/kg and above), respectively. In the dot blot assay, CaBP-9K mRNA levels were significantly increased in rats exposed to 4-t-octylphenol (200 and 400 mg/kg), 4-pentylphenol, 4-nonylphenol, and 4-phenylphenol (400 mg/kg), respectively. Among the APs, compounds with bulky alkyl groups or higher carbon numbers possessed higher estrogenic capacity. In addition, the pattern of CaBP-9K expression correlated with that of the 3-d uterotrophic assay. Therefore, our results suggest that the CaBP-9K gene might be used as a potential biomarker for the screening of endocrine disruptors.


Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.


Somatosensory versus cerebellar contributions to proprioceptive changes associated with motor skill learning: A theta burst stimulation study.
It is well established that proprioception (position sense) is important for motor control, yet its role in motor learning and associated plasticity is not well understood. We previously demonstrated that motor skill learning is associated with enhanced proprioception and changes in sensorimotor neurophysiology. However, the neural substrates mediating these effects are unclear. To determine whether suppressing activity in the cerebellum and somatosensory cortex (S1) affects proprioceptive changes associated with motor skill learning. 54 healthy young adults practiced a skill involving visually-guided 2D reaching movements through an irregular-shaped track using a robotic manipulandum with their right hand. Proprioception was measured using a passive two-alternative choice task before and after motor practice. Continuous theta burst stimulation (cTBS) was delivered over S1 or the cerebellum (CB) at the end of training for two consecutive days. We compared group differences (S1, CB, Sham) in proprioception and motor skill, quantified by a speed-accuracy function, measured on a third consecutive day (retention). As shown previously, the Sham group demonstrated enhanced proprioceptive sensitivity after training and at retention. The S1 group had impaired proprioceptive function at retention through online changes during practice, whereas the CB group demonstrated offline decrements in proprioceptive function. All groups demonstrated motor skill learning. However, the magnitude of learning differed between the CB and Sham groups, consistent with a role for the cerebellum in motor learning. Overall, these findings suggest that the cerebellum and S1 are important for distinct aspects of proprioceptive changes during skill learning.


R-cadherin is a Pax6-regulated, growth-promoting cue for pioneer axons.
The transcription factor Pax6 has been implicated in two processes that may be related in brain development: establishment of regional cell adhesion properties and axon guidance. In Pax6 mutant mouse embryos, forebrain pioneer axons make pathfinding errors. These errors occur in a region of the ventral thalamus in which the expression of the cell adhesion molecule R-cadherin (Cdh4) is lost in Pax6 mutants. In vitro, an R-cadherin substrate promoted pioneer axon outgrowth. Furthermore, pioneer axon outgrowth was rescued in vivo by selective replacement of R-cadherin by electroporation into cultured Pax6 mutant embryos. Thus, these studies implicate Pax6 as an early brain patterning gene that establishes regional adhesive codes to guide pioneer axons.


Amaurosis following blood loss.
Complete and permanent amaurosis following blood loss is exceptional and occurs in elderly persons with previous circulatory disturbances. We present a case of unilateral amaurosis in an 18-year-old boy following gastric hemorrhage. To the best of our knowledge this is the first documented case of permanent amaurosis following blood loss in a young person.


Anatomy of smooth muscle cells in nonmalignant and malignant human prostate tissue.
Differently graded areas of human prostate adenocarcinoma were examined after Masson's trichrome staining or immunohistochemistry for smooth muscle alpha-actin, type IV collagen and laminin. In addition, the ultrastructure of the prostatic smooth muscle cells (SMC) during glandular proliferation and epithelial invasion in selected tumors was studied. The SMC formed a thick layer below the epithelial structures in unaffected areas and were closely associated with each other in homotypic interactions. As the tumor grade increased, the SMC gradually lost interactions with each other and became atrophic. With the growth of the epithelial compartment, the SMC initially segregated to the tumor periphery and the intercellular spaces increased. In high grade tumors, the epithelial cancer cells invaded the spaces between the SMC. Immunohistochemical analysis of the basal membrane revealed increased disruption of the usually thick basal membrane, which became thinner and faintly stained with each of the antibodies used. We conclude that most SMC become atrophic following epithelial invasion in human tumors and that degradation of the basal membrane is an important factor in this process. At the ultrastructural level, different SMC phenotypes occur in prostatic tissues during epithelial invasion. Interconversion between these phenotypes is suggested and a probable relationship among them is proposed.


Specific GFP-binding artificial proteins (αRep): a new tool for in vitro to live cell applications.
A family of artificial proteins, named αRep, based on a natural family of helical repeat was previously designed. αRep members are efficiently expressed, folded and extremely stable proteins. A large αRep library was constructed creating proteins with a randomized interaction surface. In the present study, we show that the αRep library is an efficient source of tailor-made specific proteins with direct applications in biochemistry and cell biology. From this library, we selected by phage display αRep binders with nanomolar dissociation constants against the GFP. The structures of two independent αRep binders in complex with the GFP target were solved by X-ray crystallography revealing two totally different binding modes. The affinity of the selected αReps for GFP proved sufficient for practically useful applications such as pull-down experiments. αReps are disulfide free proteins and are efficiently and functionally expressed in eukaryotic cells: GFP-specific αReps are clearly sequestrated by their cognate target protein addressed to various cell compartments. These results suggest that αRep proteins with tailor-made specificity can be selected and used in living cells to track, modulate or interfere with intracellular processes.


Metabolic Engineering of Saccharomyces cerevisiae for Rosmarinic Acid Production.
Rosmarinic acid is a hydroxycinnamic acid ester commonly found in the Boraginaceae and Lamiaceae plant families. It exhibits various biological activities, including antioxidant, anti-inflammatory, antibacterial, antiallergic, and antiviral properties. Rosmarinic acid is used as a food and cosmetic ingredient, and several pharmaceutical applications have been suggested as well. Rosmarinic acid is currently produced by extraction from plants or chemical synthesis; however, due to limited availability of the plant sources and the complexity of the chemical synthesis method, there is an increasing interest in producing this compound by microbial fermentation. In this study, we aimed to produce rosmarinic acid by engineered baker's yeast Saccharomyces cerevisiae. Multiple biosynthetic pathway variants, carrying only plant genes or a combination of plant and Escherichia coli genes, were implemented using a full factorial design of experiment. Through analysis of variances, the effect of each enzyme variant (factors), together with possible interactions between these factors, was assessed. The best pathway variant produced 2.95 ± 0.08 mg/L rosmarinic acid in mineral medium with glucose as the sole carbon source. Increasing the copy number of rosmarinic acid biosynthetic genes increased the titer to 5.93 ± 0.06 mg/L. The study shows the feasibility of producing rosmarinic acid by yeast fermentation.


Water-Based Exercise in Patients With Nonspecific Chronic Low-Back Pain: A Systematic Review With Meta-Analysis.
Babiloni-Lopez, C, Fritz, N, Ramirez-Campillo, R, and Colado, JC. Water-based exercise in patients with nonspecific chronic low-back pain: a systematic review with meta-analysis. J Strength Cond Res 38(1): 206-219, 2024-This study aimed to systematically review and synthesize evidence (i.e., active [land-based training] and nonactive controls [e.g., receiving usual care]) regarding the effects of water-based training on patients with nonspecific chronic low-back pain (NSCLBP). Web of Science (WOS), PubMed (MEDLINE), EMBASE, EBSCO (SPORTDiscus; CINAHL), and PEDro were searched, with no date restrictions, until October 2021. The included studies satisfied the following criteria: (a) NSCLBP (≥12 weeks) patients, (b) water-based intervention, (c) control group (land-based trained; nonactive group), and (d) outcomes related to pain, disability, quality of life, or flexibility. The main outcome analyzed in the meta-analysis was pain intensity. Secondary outcomes included disability, body mass index, and flexibility. The random-effects model was used, and effect size (ES) values are presented with 95% confidence intervals (CIs). The impact of heterogeneity was assessed (I2 statistic), with values of <25%, 25-75%, and >75% representing low, moderate, and high levels, respectively. Alpha was set at p < 0.05. In conclusion, 15 studies (n = 524) were meta-analyzed. After intervention, pain intensity was reduced compared with nonactive controls (ES = -3.61; p < 0.001) and a similar reduction was noted when compared with land-based trained group (ES = -0.14; p = 0.359). Greater decrease in disability (ES = 2.15; p < 0.001) and greater increase in sit-and-reach (i.e., flexibility; ES = -2.44; p < 0.001) were noted after intervention compared with the nonactive group. In conclusion, water-based exercise therapy reduces pain intensity, disability, and increases flexibility in NSCLBP compared with nonactive subjects and was equally effective compared with land-based exercise to reduce pain. Favorable effects may be expected at ≤8 weeks. However, due to several methodological issues (e.g., high heterogeneity), for the improvement of most outcomes, we are unable to provide other than a weak recommendation in favor of intervention compared with control treatment.


Molecular characterization of Escherichia coli isolated from cheese and biocontrol of Shiga toxigenic E. coli with essential oils.
The current research was carried out to study the incidence of Escherichia coli (E. coli) in Egyptian cheese (Kariesh and Ras) and molecular characterization of certain E. coli virulence genes (stx1, stx2, eaeA, hlyA and fimH) using multiplex PCR technique. Biocontrol of E. coli with essential oils (clove and thyme oil) was also studied. A total of 150 random samples of Kariesh and Ras cheese (75 each) were collected from various areas in Governorate of Menoufia. According to our results, the frequency of E. coli isolated from Kariesh and Ras cheese was 16% and 5.3%, respectively. Serological identification classified the E. coli strains into two groups, enterohemorrhagic E. coli (EHEC) serogroup (O26: H11, O91: H21, O111: H2 and O103: H2). While the enterotoxigenic E. coli (ETEC) serogroup were detected as O125: H21 which is the most prevalent strain. O171: H2, O86 and O119: H6 belonging to enteropathogenic E. coli (EPEC). The most prevalent gene detected in E. coli strains was stx1 (87.5%) followed by stx2 (86%), fimH (75%), hlyA (50%) and eaeA (25%) genes. Concerning the antimicrobial activity with essential oils, thyme oil (1%) is considered as the bactericidal effect against E. coli (ATCC35150) with improved the sensory evaluation than clove oil (1%). In conclusion, Kariesh and Ras cheese are extremely tainted with pathogenic E. coli strains, which represent a strong hazard on the human health.


Adverse effects of female obesity and interaction with race on reproductive potential.
Across the reproductive spectrum, obesity is associated with greater risks for adverse health outcomes, including higher rates of infertility, subfertility, early pregnancy loss, fetal deaths and stillbirths, congenital anomalies, and pregnancy complications. The excess reproductive morbidity associated with obesity may increase with longer duration, making the current trends among children and young adults particularly critical in terms of their future reproductive potential. Obese women have a lower chance of pregnancy following in vitro fertilization (IVF), require higher dosages of gonadotropins, and have reduced rates of implantation, clinical intrauterine gestation, and live birth rates and increased rates of pregnancy loss, as well as greater risks for prematurity and preeclampsia even when stratified by plurality. Racial and ethnic differences by overweight and obesity in IVF outcomes have been reported. Compared with normal-weight women, failure to achieve a clinical intrauterine gestation is significantly more likely among obese women overall, normal-weight and obese Asian women, normal-weight Hispanic women, and overweight and obese Black women. Among women who do conceive, compared with normal-weight women, failure to achieve a live birth is significantly more likely among overweight and obese women overall, and among overweight and obese Asian women, overweight and obese Hispanic women, and normal-weight and obese Black women. Although weight loss should theoretically be the first line of therapy for obese women, other lifestyle factors, such as regular physical exercise, elimination of tobacco use and alcohol consumption, and stress management, may be of more immediate benefit in achieving conception.


A review on mass spectrometry-based quantitative proteomics: Targeted and data independent acquisition.
Mass spectrometry (MS) based proteomics have achieved a near-complete proteome coverage in humans and in several other organisms, producing a wealth of information stored in databases and bioinformatics resources. Recent implementation of selected/multiple reaction monitoring (SRM/MRM) technology in targeted proteomics introduced the possibility of quantitatively follow-up specific protein targets in a hypothesis-driven experiment. In contrast to immunoaffinity-based workflows typically used in biological and clinical research for protein quantification, SRM/MRM is characterized by high selectivity, large capacity for multiplexing (approx. 200 proteins per analysis) and rapid, cost-effective transition from assay development to deployment. The concept of SRM/MRM utilizes triple quadrupole (QqQ) mass analyzer to provide inherent reproducibility, unparalleled sensitivity and selectivity to efficiently differentiate isoforms, post-translational modifications and mutated forms of proteins. SRM-like targeted acquisitions such as parallel reaction monitoring (PRM) are pioneered on high resolution/accurate mass (HR/AM) platforms based on the quadrupole-orbitrap (Q-orbitrap) mass spectrometer. The expansion of HR/AM also caused development in data independent acquisition (DIA). This review presents a step-by-step tutorial on development of SRM/MRM protein assay intended for researchers without prior experience in proteomics. We discus practical aspects of SRM-based quantitative proteomics workflow, summarize milestones in basic biological and medical research as well as recent trends and emerging techniques.


Structure of delta1-CoZn(7.8), an example of a phason pinning-unpinning transformation?
The novel structure of the delta1 phase in the cobalt-zinc system was determined by single-crystal X-ray diffraction. The structure features fused double icosahedra linked by edge- and face-sharing. The delta1-CoZn(7.8) structure is incommensurately modulated along the columnar b direction. The extent of the linear pentagonal antiprismatic intergrowth is limited to a maximum of two overlapping icosahedra because of geometric demands and radii relations. Even this limited fusion of icosahedra leads to strain that is believed to be the origin of the structural modulation. The compound was synthesized using a centrifugation-aided filtration method which yielded single crystals grown on cobalt pieces in a zinc-rich melt. The (3 + 1)-dimensional superspace group is F2/m(0beta0)s0 and the modulation wavevector was determined to q = 0.234b*. The partial amorphization of the sample when subjected to mechanical grinding is an indication of a metastable structure. The incommensurability of the structure may be seen as an ordered pinning of phasons.


Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl)phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl)benzenesulfonanilide (16c) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)]. These compounds are more active than vancomycin [MIC=2.0microg/mL (MRSA), 125microg/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria.


Novel form of long-term synaptic depression in rat hippocampus induced by activation of alpha 1 adrenergic receptors.
Neurons located in the locus coeruleus project to hippocampus and provide noradrenergic innervation necessary for hippocampal-dependent learning and memory. The mechanisms underlying the function of norepinephrine (NE) in memory processing are unknown but likely reside in the ability of NE to modulate the efficacy of glutamate synaptic transmission via activation of G-protein-coupled adrenergic receptors. Here we show that application of NE to rat hippocampal slices in vitro induces a long-term depression (LTD) of synaptic transmission at excitatory CA3-CA1 synapses that persists for >/=40 min after agonist washout. This LTD, which we refer to as NE LTD, is mediated by activation of alpha1 adrenergic receptors because the alpha1 agonist methoxamine can induce LTD at the same magnitude as that induced with the nonselective adrenergic agonist NE. Furthermore, NE LTD induced by either NE or methoxamine is blocked with the alpha1 receptor antagonist, prazosin, but is unaffected by antagonists of alpha2 and beta receptors. This plasticity persists in the presence of the GABA(A) receptor antagonist bicuculline, indicating that adrenergic modulation of GABA(A) receptor-mediated transmission does not underlie NE LTD. Induction of NE LTD requires presynaptic activity during agonist application and postsynaptic activation of N-methyl-d-aspartate receptors, fulfilling Hebbian criteria of coincident pre- and postsynaptic activity. The expression of NE LTD is likely to be postsynaptic because paired-pulse facilitation ratios during NE LTD expression are not different from baseline, similar to LTD induced by low-frequency stimulation. Thus we report the identification and characterization of a novel Hebbian form of LTD in hippocampus that is induced after activation of alpha1 adrenergic receptors. This plasticity may be a mechanism by which the adrenergic system participates in normal cognitive function.


No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation.
Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged > or =60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.


An integrated study of acute effects of valproic acid in the liver using metabonomics, proteomics, and transcriptomics platforms.
An integrated omics approach was undertaken in order to elucidate a systems biology level understanding of the acute hepatotoxcity of valproic acid (VPA). Metabonomics, proteomics and gene expression microarray platforms were employed in this systems biology study. CD-1 female pregnant mice were injected subcutaneously with 600 mg/kg VPA or vehicle control. Urine, serum, and liver tissue were collected at 6, 12, and 24 h after dosing. Principal component analysis (PCA) of the metabonomics data showed clustering of the dosed groups away from the controls for the urine samples. Looser clustering was seen in the other sample sets investigated. However, VPA administration resulted in altered glucose concentrations in urine samples at 12 and 24 h and in aqueous liver tissue extracts at 12 h after VPA administration. Proteomics studies identified two proteins, glycogen phosphorylase and amylo-1,6-glucosidase, which were increased in dosed animals relative to control. Both of these proteins are involved in converting glycogen to glucose. Examination of the expression of 20,000 liver genes did not reveal significantly altered expression at 6, 12, or 24 h after VPA exposure. The combined studies indicated a perturbation in the glycogenolysis pathway following administration of VPA.


Disclosure of membership in the lesbian, gay, bisexual, and transgender community by individuals with communication impairments: a preliminary web-based survey.
The purpose of this preliminary investigation was to examine potential barriers to seeking services for communication impairments perceived by lesbian, gay, bisexual, and transgender (LGBT) people. Specifically, this clinical survey investigated (a) the rate and importance of disclosure of membership in the LGBT community by people with communication impairments to their clinicians and (b) the perception of bias of audiologists and speech-language pathologists against LGBT individuals with communication impairments. A total of 192 people identifying as LGBT with a communication impairment responded to a web-based survey. The survey contained questions about the respondents' demographic information, living situation, and experiences with clinical services for communication impairments. In addition, the survey contained open-ended comment sections. There were differences in the responses of LGBT people with speech-language impairments and those with hearing impairments. The majority of respondents did not disclose their membership in the LGBT community, although they felt it was important. Most respondents reported perceiving bias toward a heterosexual orientation from their clinicians. Exploration of issues important to the LGBT community contributes to the growing emphasis on diversity and cultural competency in communication sciences and disorders. Specific clinical recommendations and directions for future research are discussed.


A ToxR-dependent role for the putative phosphoporin VCA1008 in bile salt resistance in Vibrio cholerae El Tor N16961.
The putative phosphoporin encoded by vca1008 of Vibrio cholerae O1 is expressed in vivo during infection and is essential for the intestinal colonization of infant mice. In vitro, its expression is induced under inorganic phosphate (P(i)) limitation in a PhoB/R-dependent manner. In this work we demonstrated that VCA1008 has a strain-specific role in the physiology and pathogenicity of V. cholerae O1. Disruption of vca1008 led to a growth defect, an inability to colonize and a high susceptibility to sodium deoxycholate (DOC; the major bile compound) in the El Tor biotype strain N16961, but did not affect the classical strain O395 in the same way. Furthermore, vca1008 promoter activity was higher in N16961 cells grown under a low P(i) supply in the presence of DOC than in the absence of the detergent. In the P(i)-limited cells, vca1008 was positively regulated by PhoB, but when DOC was added to the medium, it negatively affected the PhoB-mediated activation of the gene, and enhanced vca1008 expression in a ToxR-dependent manner. These findings reveal for the first time a complex strain-specific interplay between ToxR and PhoB/R systems to control porin genes, as well as the influence of DOC on the expression of PhoB- and ToxR-regulated genes and pathogenesis in pandemic strains of V. cholerae.


Optic neuritis in the era of biomarkers.
The Optic Neuritis Treatment Trial, a landmark study completed in 1991, stratified the risk of multiple sclerosis in patients with optic neuritis. Since that time, unique biomarkers for optic neuritis have been found. The antibody against aquaporin-4 (AQP4)-immunoglobulin G (IgG) discovered in 2004 was found to be both the pathologic cause and a reliable biomarker for neuromyelitis optica spectrum disorders. This finding enabled an expanded definition of the phenotype of neuromyelitis optica spectrum disorder and improved treatment of the disease. Subsequently, myelin oligodendrocyte glycoprotein (MOG) IgG was recognized to be a marker for MOG-IgG-associated disorder, a central demyelinating disease characterized by recurrent optic neuritis, prominent disk edema, and perineural optic nerve enhancement on magnetic resonance imaging. Most multiple sclerosis disease-modifying agents are ineffective for AQP4-IgG-positive neuromyelitis optica spectrum disorder and MOG-IgG-associated disorder. Because there are crucial differences in treatment and prognosis between multiple sclerosis, AQP4-IgG-positive neuromyelitis optica spectrum disorder, and MOG-IgG-associated disorder, ophthalmologists should be aware of these new biomarkers of optic neuritis and incorporate their testing in all patients with atypical optic neuritis.


Gastrojejunocolic fistula following surgery for peptic ulcer.
This article aims to emphasize that gastrojejunocolic fistula following peptic ulcer surgery, though uncommon in the post vagotomy era, still continues to occur. We stress the changing trends in its epidemiology, aetiopathogenesis and treatment. The case records of 12 patients with gastrojejunocolic fistula (seen over a 15 year period) were reviewed. Details regarding clinical presentation, investigations and treatment were analyzed and the results compared with previous published series. All the 12 patients in this study had a short loop posterior retrocolic gastrojejunostomy as part of the primary peptic ulcer surgery. Diarrhoea and profound weight loss was present in all of them. Incompleteness of vagotomy was proved in all the six patients investigated for the same. The fistula was demonstrated in all of them on barium enema, while it was seen on upper GI endoscopy in 4. Eight patients were treated by a one stage resection and repair of fistula. A three stage procedure was performed in two.


A questionnaire-based study of sleep-wake patterns and sleep quality in a TMJ and orofacial pain clinic.
To determine the relationships among sleep quality, perceived pain, and psychological distress among patients with TMJ and orofacial pain. The authors examined 3276 patients with temporomandibular disorder (TMD) who visited the Orofacial Pain Clinic at Yonsei University College of Dentistry. The authors conducted a survey using the sleep-quality questionnaire and classified TMD patients into two groups based on Diagnostic Criteria for TMD. For statistical analysis, the authors calculated the correlations between pain intensity as measured using a numeric rating scale (NRS) and various factors. The statistical analysis revealed correlations between pain intensity on the NRS and some of the factors in the sleep questionnaire. The pain intensity increased with age and for lower sleep efficiency (both p < 0.05). These results imply that clinicians treating patients with orofacial pain should examine their sleep-wake patterns and sleep quality.


Excess diagnosis of non-Hodgkin's lymphoma during spring in the USA.
A seasonal peak in hematologic malignancies may support hypotheses of infection-related precipitating events. Moderately increased incidence rates have been observed during the spring for leukemias and Hodgkin's disease but few studies have been conducted of non-Hodgkin's lymphoma (NHL). Our study consisted of 77,173 NHL patients in the Surveillance, Epidemiology, and End Results database diagnosed during 1973 - 99. Chi-square analyses showed excess observed-vs.-expected diagnoses during March, April, and June (P < 0.0001). B-cell origin subtype, but not T-cell/NK, was diagnosed more frequently in March. Controlling for age, sex, geographical location, and diagnosis year, multivariate Poisson regression revealed peaks in both March and April (P < 0.0001). Excluding cases in December, due to consistent troughs, regression uncovered greater-than-expected incidence during spring months for patients aged 20 - 39 years and 40 - 64 years (P = 0.043, P = 0.0001) but not among patients >or= 65 years. Future studies are needed to discern if a spring peak is due to diagnostic bias or other uncontrolled factors.


Typhoid and Paratyphoid Cost of Illness in Pakistan: Patient and Health Facility Costs From the Surveillance for Enteric Fever in Asia Project II.
The objective of this study was to estimate the cost of illness from enteric fever (typhoid and paratyphoid) at selected sites in Pakistan. We implemented a cost-of-illness study in 4 hospitals as part of the Surveillance for Enteric Fever in Asia Project (SEAP) II in Pakistan. From the patient and caregiver perspective, we collected direct medical, nonmedical, and indirect costs per case of enteric fever incurred since illness onset by phone after enrollment and 6 weeks later. From the health care provider perspective, we collected data on quantities and prices of resources used at 3 of the hospitals, to estimate the direct medical economic costs to treat a case of enteric fever. We collected costs in Pakistani rupees and converted them into 2018 US dollars. We multiplied the unit cost per procedure by the frequency of procedures in the surveillance case cohort to calculate the average cost per case. We collected patient and caregiver information for 1029 patients with blood culture-confirmed enteric fever or with a nontraumatic terminal ileal perforation, with a median cost of illness per case of US $196.37 (IQR, US $72.89-496.40). The median direct medical and nonmedical costs represented 8.2% of the annual labor income. From the health care provider perspective, the estimated average direct medical cost per case was US $50.88 at Hospital A, US $52.24 at Hospital B, and US $11.73 at Hospital C. Enteric fever can impose a considerable economic burden in Pakistan. These new estimates of the cost of illness of enteric fever can improve evaluation and modeling of the costs and benefits of enteric fever prevention and control measures, including typhoid conjugate vaccines.


Phoma-like fungi on soybeans.
Numerous coelomycetous fungi classified in Ascochyta, Phoma and Phyllosticta, and lately established and/or re-classified genera and species, namely Boeremia and Peyronellaea have been recorded from spots on leaves and pods of soybeans. These rarely observed pathogens are cosmopolitan, ubiquitous species on diseased and dead plant materials, and define frequently as weak or opportunistic parasites. Based on the Genealogical Concordance Phylogenetic Species Recognition, the authors summarize the re-evaluation of the taxonomic status of Phoma sojicola (syn. Ascochyta sojicola) and Phyllosticta sojicola. Inspite of the former delimitation of Ph. sojicola based on small differences in morphological features, it has proved to be identical to Peyronellaea pinodella (syn. Phoma pinodella). Similarly, it was also confirmed that Ph. sojicola was identical to Boeremia exigua var. exigua (syn. Phoma exigua var. exigua). The authors and co-workers contributed to the identification of Phoma-like fungi by combined conventional and molecular methods. Protein-encoding genes (TEF1 and β-tubulin) were successfully applied within the Phoma genus to infer phylogenetic relationships.


Substance use disorder treatment and technology access among people who use drugs in rural areas of the United States: A cross-sectional survey.
To evaluate how technology access affected substance use disorder (SUD) treatment prior to COVID-19 for people who use drugs in rural areas. The Rural Opioid Initiative (January 2018-March 2020) was a cross-sectional study of people with prior 30-day injection drug or nonprescribed opioid use from rural areas of 10 states. Using multivariable mixed-effect regression models, we examined associations between participant technology access and SUD treatment. Of 3,026 participants, 71% used heroin and 76% used methamphetamine. Thirty-five percent had no cell phone and 10% had no prior 30-day internet use. Having both a cell phone and the internet was associated with increased days of medication for opioid use disorder (MOUD) use (aIRR 1.29 [95% CI 1.11-1.52]) and a higher likelihood of SUD counseling in the prior 30 days (aOR 1.28 [95% CI 1.05-1.57]). Lack of cell phone was associated with decreased days of MOUD (aIRR 0.77 [95% CI 0.66-0.91]) and a lower likelihood of prior 30-day SUD counseling (aOR 0.77 [95% CI 0.62-0.94]). Expanding US rural SUD treatment engagement via telemedicine may require increased cell phone and mobile network access.


Perinatal androgens and adult behavior vary with nestling social system in siblicidal boobies.
Exposure to androgens early in development, while activating adaptive aggressive behavior, may also exert long-lasting effects on non-target components of phenotype. Here we compare these organizational effects of perinatal androgens in closely related Nazca (Sula granti) and blue-footed (S. nebouxii) boobies that differ in neonatal social system. The older of two Nazca booby hatchlings unconditionally attacks and ejects the younger from the nest within days of hatching, while blue-footed booby neonates lack lethal aggression. Both Nazca booby chicks facultatively upregulate testosterone (T) during fights, motivating the prediction that baseline androgen levels differ between obligately siblicidal and other species. We show that obligately siblicidal Nazca boobies hatch with higher circulating androgen levels than do facultatively siblicidal blue-footed boobies, providing comparative evidence of the role of androgens in sociality. Although androgens confer a short-term benefit of increased aggression to Nazca booby neonates, exposure to elevated androgen levels during this sensitive period in development can also induce long-term organizational effects on behavior or morphology. Adult Nazca boobies show evidence of organizational effects of early androgen exposure in aberrant adult behavior: they visit unattended non-familial chicks in the colony and direct mixtures of aggression, affiliative, and sexual behavior toward them. In a longitudinal analysis, we found that the most active Non-parental Adult Visitors (NAVs) were those with a history of siblicidal behavior as a neonate, suggesting that the tendency to show social interest in chicks is programmed, in part, by the high perinatal androgens associated with obligate siblicide. Data from closely related blue-footed boobies provide comparative support for this interpretation. Lacking obligate siblicide, they hatch with a corresponding low androgen level, and blue-footed booby adults show a much lower frequency of NAV behavior and a lower probability of behaving aggressively during NAV interactions. This species difference in adult social behavior appears to have roots in both pleiotropic and experiential effects of nestling social system. Our results indicate that Nazca boobies experience life-long consequences of androgenic preparation for an early battle to the death.


Hypertension screening in the follow-up of premature infants.
Results of hypertension screening using the Doppler technique in a group of premature infants following discharge from an intensive care nursery are reported. Systolic blood pressure (BP) was measured at follow-up in 79/99 premature infants who were cared for in the special care nursery over a 9-month period. The mean BP was 99.3 +/- 2.0 (SEM) mm Hg at a mean age of 14.7 +/- 1.3 weeks; mean age corrected for 40 weeks of gestation was 7.4 +/- 1.3 weeks. Seven infants (8.9%) with BP greater than 113 on three separate occasions were identified as hypertensive. Three of these hypertensive infants were found to have a specific etiology requiring treatment: neuroblastoma, coarctation of the aorta, and unilateral ureteropelvic junction obstruction. No difference was found between the hypertensive and normotensive infants for a variety of perinatal and neonatal factors, including the presence or duration of an umbilical arterial catheter. These data suggest that the premature infant may be at risk for the development of hypertension. In the future, neonatal follow-up programs may find hypertension screening a useful part of their evaluation.


Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID.
Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help.


Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry.
Vasculogenic mimicry (VM) describes the unique ability of highly aggressive melanoma tumor cells to express endothelial cell-associated genes (such as EphA2 and VE-cadherin) and form vasculogenic-like networks when cultured on a three-dimensional matrix. VM has been described in several types of aggressive tumors, including melanoma, prostate, breast, and ovarian carcinomas. However, the molecular underpinnings of this phenomenon remain somewhat elusive. In this study, we examined key molecular mechanisms underlying VM in aggressive human cutaneous and uveal melanoma. The data reveal that phosphoinositide 3-kinase (PI3K) is an important regulator of VM, specifically affecting membrane type 1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) activity, critical in the formation of vasculogenic-like networks. Using specific inhibitors of PI3K, melanoma VM was abrogated coincident with decreased MMP-2 and MT1-MMP activity. Furthermore, inhibition of PI3K blocked the cleavage of laminin 5 gamma 2 chain, resulting in decreased levels of the gamma 2' and gamma 2x promigratory fragments. Collectively, these results indicate that PI3K is an important regulator of melanoma VM directly affecting the cooperative interactions of MMP-2, MT1-MMP, and laminin 5 gamma 2 chain and, thus, the remodeling of the tumor cell microenvironment. PI3K may represent an excellent target for therapeutic intervention of a novel signaling cascade underlying VM.


How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study.
Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT-2i CVOTs of a general T2D population. T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) by the total T2D population. In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV-preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE-TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2-, 3- and 4-fold higher compared to the CANVAS (34%), EMPA-REG OUTCOME (21%) and VERTIS-CV (17%) trials, respectively. In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE-TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries.


Prevalence of and risk factors for quinolone-resistant Neisseria gonorrhoeae infection in Ontario.
Quinolone-resistant Neisseria gonorrhoeae has swiftly emerged in Canada. We sought to determine its prevalence in the province of Ontario and to investigate risk factors for quinolone-resistant N. gonorrhoeae infection in a Canadian setting. We used records from the Public Health Laboratory of the Ontario Agency for Health Protection and Promotion in Toronto, Ontario, and the National Microbiology Laboratory in Winnipeg, Manitoba, to generate epidemic curves for N. gonorrhoeae infection. We extracted limited demographic data from 2006 quinolone-resistant N. gonorrhoeae isolates and from a random sample of quinolone-susceptible isolates. We also extracted minimum inhibitory concentrations for commonly tested antibiotics. Between 2002 and 2006, the number of N. gonorrhoeae infections detected by culture decreased by 26% and the number of cases detected by nucleic acid amplification testing increased 6-fold. The proportion of N. gonorrhoeae isolates with resistance to quinolones increased from 4% to 28% over the same period. Analysis of 695 quinolone-resistant N. gonorrhoeae isolates and 688 quinolone-susceptible control isolates from 2006 showed a higher proportion of men (odds ratio [OR] 3.1, 95% confidence interval [CI] 2.3-4.1) and patients over 30 years of age (OR 3.1, 95% CI 2.4-3.8) in the quinolone-resistant group. The proportion of men who have sex with men appeared to be relatively similar in both groups (OR 1.4, 95% CI 1.1-1.8). Quinolone-resistant strains were more resistant to penicillin (p < 0.001), tetracycline (p < 0.001) and erythromycin (p < 0.001). All isolates were susceptible to cefixime, ceftriaxone, azithromycin and spectinomycin. During 2006 in Ontario, 28% of N. gonorrhoeae isolates were resistant to quinolones. Infections in heterosexual men appear to have contributed significantly to the quinolone resistance rate. Medical practitioners should be aware of the widespread prevalence of quinolone-resistant N. gonorrhoeae and avoid quinolone use for empiric therapy.


Effectiveness of inhaled corticosteroids in chronic obstructive pulmonary disease: immortal time bias in observational studies.
Recent large-scale cohort studies that reported an important reduction in mortality and chronic obstructive pulmonary disease (COPD) morbidity with inhaled corticosteroids may be biased. We used a population-based cohort of Saskatchewan residents 55 years of age or over, first hospitalized for COPD during 1990 to 1997, to study this potential bias. These 979 subjects were followed for a year from discharge until their first readmission for COPD or death (389 subjects). Inhaled corticosteroid exposure was measured as any dispensing within 90 days after discharge. Cox's proportional hazards model was used to compare the time-fixed analysis employed in the recent studies with the alternative time-dependent analysis. The time-fixed adjusted rate ratio was 0.69 (95% CI: 0.55-0.86) for inhaled corticosteroid use within 90 days, whereas the time-dependent rate ratio was 1.00 (95% CI: 0.79-1.26). With the time-fixed analysis, the rate ratios were affected by the length of the exposure period, decreasing from 0.98 for a 15-day exposure period to 0.51 for 365 days, but remained stable between 1.06 and 0.94 with the time-dependent analysis. Inhaled corticosteroid use after hospitalization for COPD was not found to reduce mortality and morbidity. Although observational studies can be valuable, the recent reports of reductions in mortality and morbidity with inhaled corticosteroids are biased by their inappropriate allocation of exposure and analysis of immortal time.


Transient Co-Expression of Bioactive Murine Interferon-Gamma and HBsAg in Tobacco and Lettuce Leaves.
The synchronous expression of antigen and adjuvant proteins in plant hosts presents an intriguing potential for vaccine production and the enhancement of appropriate immune responses. In this study, we examined the expression of bioactive murine interferon-gamma (mIFN-γ) along with HBsAg in tobacco and lettuce leaves aimed to further perform the analysis of immune responses in the mouse model. Monocistronic and bicistronic cassettes, carrying genes encoding mIFN-γ and HBsAg in various orders, were constructed. These cassettes were placed under the control of the 35S CaMV promoter and included the 5' leader sequence of Tobacco Ech Virus (TEV). Through Agrobacterium infiltration, the cassettes were transferred into plant leaves. The concentration of mIFN-γ in different constructs and HBsAg was tested by ELISA. Murine IFN-γ was characterized through Western blotting, and its bioactivity was evaluated by assessing the up-regulation of MHC class II in macrophages derived from mouse bone marrow. Extracts of agroinfiltrated leaves contained recombinant mIFN-γ and HBsAg proteins at about 14 unit/mg and 50 ng/mg of soluble protein, respectively. Subsequently, mIFN-γ was purified from the plant extract and its ability to up-regulate MHC class II in mouse bone marrow-derived macrophages was confirmed by immunofluorescence. The co-expression of recombinant HBsAg and mIFN-γ using TEV 5' leader-based cassettes in tobacco and lettuce leaves produced both proteins with active mIFN-γ in different concentrations. The attractive utility and feasibility of using plant transient co-expression systems aimed to co-delivery of vaccine antigen and appropriate cytokine to elicit immune response for different applications.


Management of inherited thrombophilia in pregnancy.
Adverse pregnancy outcomes, such as pregnancy loss and pre-eclampsia, are associated with thrombotic mechanisms and thrombophilia. Antithrombotic interventions, particularly low-molecular-weight heparin, have been investigated in women identified by previous pregnancy outcome; however, the results have been inconsistent. This may reflect heterogeneity of both the study groups and the disease processes resulting in inadequate stratification to guide antithrombotic interventions. Furthermore, the variation in gestation at initiation of low-molecular-weight heparin treatment might be important. Despite limited evidence of efficacy, low-molecular-weight heparin is often used in an attempt to prevent these complications, owing to the lack of other effective treatments and its perceived safety in pregnancy. Research is required to better understand the disease processes, identify possible biomarkers and thereby more homogeneous groups for targeted treatment.


A rare novel deletion of the tyrosine hydroxylase gene in Parkinson disease.
Tyrosine hydroxylase (TH) enzyme is a rate limiting enzyme in dopamine biosynthesis. Missense mutation in both alleles of the TH gene is known to cause dopamine-related phenotypes, including dystonia and infantile Parkinsonism. However, it is not clear if single allele mutation in TH modifies the susceptibility to the adult form of Parkinson disease (PD). We reported a novel deletion of entire TH gene in an adult with PD. The deletion was first identified by copy number variation (CNV) analysis in a genome-wide association study using Illumina Infinium BeadChips. After screening 635 cases and 642 controls, the deletion was found in one PD case but not in any control. The deletion was confirmed by multiple quantitative PCR (qPCR) assays. There is no additional exonic single nucleotide variant in the one copy of TH gene of the patient. The patient has an age-at-onset of 54 years, no evidence for dystonia, and was responsive to L-DOPA. This case supports the importance of the TH gene in PD pathogenesis and raises more attention to rare variants in candidate genes being a risk factor for Parkinson disease.


Alcohol use and cannabis use trajectories and sexual/gender minority disparities in young adulthood.
Sexual and gender minority (SGM) young people may use alcohol or cannabis (A/C) at higher rates that non-SGM peers, but little is known about whether SGM young adults experience poorer health, psychosocial, and other outcomes at similar levels of A/C use. We used longitudinal survey data from a community cohort recruited from California middle schools in 2008 (average age 11.5) and followed across 12 waves through 2020. Participants reported on past-month A/C use at each wave. Individuals also reported SGM status as well as outcomes in multiple domains in Wave 12. Sequelae of change models tested differences in intercept and slope for A/C use trajectories from Waves 1-12 across SGM groups, and simultaneously examined differences in outcomes by SGM status adjusting separately for A/C trajectories. SGM (n = 445) and non-SGM (n = 2,089) groups did not differ on baseline probability of A/C use. SGM individuals showed steeper increases in probability of cannabis but not alcohol use over time. Adjusting for trajectories of A/C use, SGM individuals had significant disparities relative to non-SGM peers with respect to: Employment and economic stability, criminal justice involvement, social functioning, subjective physical health, behavioral health, and perceived unmet mental health treatment need. At the same levels of A/C use from middle school through young adulthood, SGM individuals show disparities in multiple domains compared to non-SGM peers. Targeted efforts to reduce substance use in conjunction with other structural disadvantages experienced by SGM youths are needed to address the emergence of disparities in young adulthood. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Bacterial culture of septic synovial structures of horses: does a positive bacterial culture influence prognosis?
The influence of synovial fluid culture on short- and long-term prognosis of cases with septic synovitis requires study. Horses with a positive bacterial culture from septic synovial fluid are less likely to survive or return to successful athletic function than those with a negative bacterial culture from septic synovial fluid. Records of mature horses presented to 2 equine referral hospitals for investigation of suspected septic synovitis were examined. Horses (n=206) were included in the study if synovial fluid was submitted for full laboratory examination, including bacterial culture. A diagnosis of septic synovitis was based on a nucleated cell count>30x10(9) cells/l or>90% neutrophils and other clinical, cytological and bacteriological parameters. Long-term follow-up was obtained by telephone questionnaire. Univariate analysis, using the Fisher's exact test, was used for all outcomes. Fourteen (20.9%) of 67 horses with a positive bacterial culture from synovial fluid were subjected to euthanasia because of persistent synovial sepsis compared to 2 (1.44%) of 139 with negative bacterial cultures (P<0.001). Overall survival and successful long-term return to function in horses with a positive bacterial culture was 50% (24/48 horses) compared to 70.5% (74/105) in culture negative horses (P=0.01). In horses that survived to be discharged, successful long-term return to function was not significantly different between culture positive and culture negative groups. Growth of Staphylococcus aureus from synovial fluid did not affect short-term survival to discharge from the hospital compared to other positive bacterial culture; however, successful long-term return to function was only 30.4% (4/13) in horses from which S. aureus was cultured compared to 73.9% (17/23) of horses in which other bacteria were cultured (P=0.015). CONCLUSIONS AND POTENTIAL CLINICAL RELEVANCE: Horses with a positive bacterial culture from a septic synovitis have a poorer prognosis for survival to discharge from hospital and overall long-term return to function than horses that yielded no bacterial growth. When S. aureus was cultured, the long-term prognosis was poorer.


Selfish DNA: a sexually-transmitted nuclear parasite.
A quantitative population genetics model for the evolution of transposable genetic elements is developed. This model shows that "selfish" DNA sequences do not have to be selectively neutral at the organismic level; indeed, such DNA can produce major deleterious effects in the host organism and still spread through the population. The model can be used to explain the evolution of introns within eukaryotic genes; this explanation does not invoke a long-term evolutionary advantage for introns, nor does it depend on the hypothesis that eukaryotic gene structure may be an evolutionary relic. Transposable genes that carried information specifying sexual reproduction in the host organism would favor their own spread. Consequently, it is tempting to speculate that some of the genes controlling sex were originally selected as transposable elements.


Graphics and statistics for cardiology: designing effective tables for presentation and publication.
Research is of little use if its results are not effectively communicated. Data visualised in tables (and graphs) are key components in any scientific report, but their design leaves much to be desired. This article focuses on table design, following two general principles: clear vision and clear understanding. Clear vision is achieved by maximising the signal to noise ratio. In a table, the signal is the data in the form of numbers, and the noise is the support structure necessary to interpret the numbers. Clear understanding is achieved when the story in the data is told effectively, through organisation of the data and use of text. These principles are illustrated by original and improved tables from recent publications. Two special cases are discussed separately: tables produced by the pharmaceutical industry (in clinical study reports and reports to data safety monitoring boards), and study flow diagrams as proposed by the Consolidated Standards of Reporting Trials and Preferred Reporting Items for Systematic Reviews and Meta-Analyses initiatives.


Global hydrogen reservoirs in basement and basins.
Hydrogen is known to occur in the groundwaters of some ancient cratons. Where associated gases have been dated, their age extends up to a billion years, and the hydrogen is assumed also to be very old. These observations are interpreted to represent the radiolysis of water and hydration reactions and migration of hydrogen into fracture systems. A hitherto untested implication is that the overwhelming bulk of the ancient low-permeability basement, which is not adjacent to cross-cutting fractures, constitutes a reservoir for hydrogen. New data obtained from cold crushing to liberate volatiles from fluid inclusions confirm that granites and gneiss of Archean and Palaeoproterozoic (>1600 Ma) age typically contain an order of magnitude greater hydrogen in their entrained fluid than very young (<200 Ma) granites. Sedimentary rocks containing clasts of old basement also include a greater proportion of hydrogen than the young granites. The data support the case for a global reservoir of hydrogen in both the ancient basement and in the extensive derived sediments. These reservoirs are susceptible to the release of hydrogen through a variety of mechanisms, including deformation, attrition to reduce grain size and diagenetic alteration, thereby contributing to the hydrogen required by chemolithoautotrophs in the deep biosphere.


Plasmodium falciparum malaria in children at a tertiary teaching hospital: ABO blood group is a risk factor.
ABO blood group antigens are formed by terminal glycosylation of glycoproteins and glycolipid chains present on cell surfaces. Glycosylation modulates all kinds of cell-to-cell interactions and this may be relevant in malaria pathophysiology, in which adhesion has been increasingly implicated in disease severity. This study was done to determine the association between ABO phenotypes and the severity of P. falciparum malaria in children. One hundred and twenty one children were assessed at the Department of Child Health, KBTH from May to August 2008. ABO blood groups were determined by agglutination. The haemoglobin measurement was done with the haematology analyzer, Sysmex KX-21N. Malaria parasites were enumerated and the presence of malaria pigment noted. Identification of P. falciparum was done. Statistical tests used were odds ratio and chi square at a significance level of p<0.05. 24.3% of the 121 children had severe falciparum malaria, and their mean haemoglobin was 4.49 g/dl (SD ± 1.69). No significant association was found between the ABO phenotypes and malaria infection (p > 0.05). Blood group A was associated with more severe malaria as compared to the blood group O individuals (Odds ratio = 0.79, p > 0.05); blood group AB (Odds ratio = 0.14, p > 0.05) and also there was a significant difference in severity of malaria between blood group O and blood group B (Odds ratio = 1.28, p > 0.05). Non-O blood group children are more prone to severe malaria caused by P. falciparum malaria than the group O, despite the lack of significant association between ABO blood groups and falciparum malaria.


Acne vulgaris.
Acne vulgaris affects over 80% of teenagers, and persists beyond the age of 25 years in 3% of men and 12% of women. Typical lesions of acne include comedones, inflammatory papules, and pustules. Nodules and cysts occur in more severe acne and can cause scarring and psychological distress. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of topical and oral treatments in people with acne vulgaris? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: topical treatments (adapalene, azelaic acid, benzoyl peroxide, clindamycin, erythromycin [alone or plus zinc]; isotretinoin, tetracycline, tretinoin); and oral treatments (doxycycline, isotretinoin, lymecycline, minocycline, oxytetracycline, tetracycline).


Oligonucleotide mixture analysis via electrospray and ion/ion reactions in a quadrupole ion trap.
Electrospray ionization combined with ion/ion reactions in a quadrupole ion trap can be used for the direct analysis of oligonucleotide mixtures. Elements to the success of this approach include factors related to ionization, ion/ion reactions, and mass analysis. This paper deals with issues regarding the ion polarity combination, viz., positive oligonucleotides/negative charge-transfer agent versus negative oligonucleotides/positive charge-transfer agent. Anions derived from perfluorocarbons appear to be directly applicable to mixtures of positive ions derived from electrospray of oligonucleotides, in direct analogy with positive protein ions. Conditions for forming positive oligonucleotide ions devoid of adducts were more difficult to establish than for forming relatively clean negative oligonucleotide ions. A new approach for manipulating negative ion charge states in the ion trap is described and is based on use of the electric field of the positive charge-transfer agent for storage of high-mass negative ions formed during the ion/ion reaction period. Oxygen cations are shown to be acceptable for charge-state manipulation of mixed-base oligomers but induce fragmentation in polyadenylate homopolymers. Protonated isobutylene (C4H9+), on the other hand, is shown to induce significantly less fragmentation of polyadenylate homopolymers.


The psychotic phenomenon in probable Alzheimer's disease: a positron emission tomography study.
Positron emission tomography was used to examine the mechanisms of the psychotic phenomenon in Alzheimer's disease (AD). Data from 2 patients with delusions and 2 with hallucinations were compared with those of 5 AD patients without psychosis. The patients with paranoid delusions had diminished relative regional cerebral blood flow (rel-CBF) in the left dorsolateral prefrontal and left medial temporal cortices. The patients with visual hallucinations showed diminished rel-CBF in the right parietal, left medial temporal, and left dorsolateral prefrontal cortices. These findings support the hypothesis that a frontal-temporal abnormality is associated with paranoid delusions in AD. By contrast, visual hallucinations are associated with parietal as well as frontal and temporal lobe dysfunction. In these patients, a left prefrontal-temporal cortex dysfunction appears to be a common denominator for the development of the psychotic phenomenon in AD.


Immunohistochemical Evaluation of Mast Cells in Leukoplakia and Oral Squamous Cell Carcinoma.
More than 90% of oral cancers are squamous cell carcinomas with oral leukoplakia being the most common potentially malignant disorder. Among the cell types in the stroma, mast cells play an important role in tumourigenesis through various mechanisms. The present study was aimed at comparing the mast cell count among normal oral mucosa, leukoplakia and Oral squamous cell carcinoma (OSSC) and to evaluate the possible role of mast cells in carcinogenesis. Mast cell count was assessed immunohistochemically using anti-mast cell tryptase amongst 20 cases of leukoplakia and OSSC each and 10 normal gingival samples. Overall comparison was done using Kruskal Wallis test and intergroup comparison was done using Mann-Whitney U test. The results of the present study showed an increase in mast cell count from normal oral mucosa (Mean: 7.73) to leukoplakia (Mean: 15.11) to squamous cell carcinoma (Mean: 22.73). Comparison of mean number of mast cells amongst three groups (p-value: 0.001) and intergroup comparisons showed statistical significance. Mast cells favour malignant transformation and can be used as indicators of disease progression.