title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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CD36 selection of 3D7 Plasmodium falciparum associated with severe childhood malaria results in reduced VAR4 expression. | A subset of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1(SM)) is involved in the cytoadherence of P. falciparum-infected red blood cells (iRBC) contributing to the pathogenesis of severe disease among young children in malaria endemic areas. The PfEMP1(SM) are encoded by group A var genes that are composed of a more constrained range of amino acid sequences than groups B and C var genes encoding PfEMP1(UM) associated with uncomplicated malaria. Also, unlike var genes from groups B and C, those from group A do not have sequences consistent with CD36 binding--a major cytoadhesion phenotype of P. falciparum isolates. A 3D7 PfEMP1(SM) sub-line (3D7(SM)) expressing VAR4 (PFD1235w/MAL8P1.207) was selected for binding to CD36. The protein expression of this parasite line was monitored by surface staining of iRBC using VAR4-specific antibodies. The serological phenotype of the 3D7(SM) parasites was determined by flow cytometry using malaria semi-immune and immune plasma and transcription of the 59 var genes in 3D7 were analysed by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using var-specific primers. A selection-induced increased adhesion of 3D7(SM) iRBC to CD36 resulted in a reduced var4 transcription and VAR4 surface expression. VAR4 is not involved in CD36 adhesion. The current findings are consistent with the notion that CD36 adhesion is not associated with particular virulent parasite phenotypes, such as those believed to be exhibited by VAR4 expressing parasites. | 18,844,973 |
Pre-operative diagnosis of an unusual complication of abdominal aortic aneurysm on multidetector computed tomography: a case report. | Spontaneous fistulation of an abdominal aortic aneurysm (AAA) into the inferior vena cava (IVC) is an unusual and infrequently encountered complication in clinical practice. In the majority of cases, it is a diagnosis made on the operating table, during surgical repair of AAA. We report a patient with an aortocaval fistula diagnosed preoperatively on multidetector computed tomography (MDCT). Preoperative diagnosis of this rare complication is important as it allows appropriate anaesthetic and surgical planning thereby reducing morbidity and mortality. | 18,845,001 |
Potential of an alternative prey to disrupt predation of the generalist predator, Orius insidiosus, on the pest aphid, Aphis glycines, via short-term indirect interactions. | Generalist insect predators can significantly impact the dynamics of pest populations; and, using alternative prey, they can rapidly establish in disturbed agroecosystems. However, indirect interactions between prey can occur, leading to either increased or decreased predation on focal prey. The present paper demonstrates how alternative prey can disrupt predation by the hemipteran Orius insidiosus on the soybean aphid Aphis glycines via short-term indirect interactions. We used laboratory microcosms to measure the impact of the predator on the population growth of the aphid in the presence of alternative prey, soybean thrips Neohydatothrips variabilis, and we characterized the foraging behaviour of the predator to assess prey preference. We showed that O. insidiosus predation on aphids was reduced in the presence of thrips and that this positive impact on aphids increased as thrips density increased. Results from the behavioural experiment support the hypothesis of a prey preference toward thrips. When prey-pest ratio is aphid-biased, short-term apparent commensalism between prey occurs in favour of the most abundant prey (aphids) with no switching behaviour appearing in O. insidiosus. These results demonstrate that potential indirect interactions should be taken into account when considering O. insidiosus as a biocontrol agent against the soybean aphid. | 18,845,007 |
Lamotrigine-associated rash: to rechallenge or not to rechallenge? | The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area. | 18,845,017 |
Sex ratio at birth and family composition in sub-saharan Africa: inter-couple variations. | In this study, sex ratios at birth (male/female births) were found to vary according to family composition. Using Demographic and Health Survey (DHS) maternity histories from sub-Saharan Africa, the study shows that the sex ratio at birth increases with the number of previous male births and decreases with the number of previous female births. For families with only males, the sex ratio increases from 1.046 for the first birth to 1.083 for the 8th birth. For families with only females, the sex ratio decreases from 1.046 for the first birth to 0.942 for the 8th birth. The differences were highly significant when tested with a linear logistic model (p=0.018 for males; p=1.85 x 10(-11) for females). The effect was not symmetrical, and was found to be significantly stronger for females. These effects could be reproduced assuming a strong heterogeneity between couples. The distribution of sex ratios was fitted with an asymmetrical log-gamma function, which revealed a wide range of variation in the sex ratio between 0.50 and 1.30, and a peak around 1.14. The results and their implications are discussed in the light of former findings in France and in the United States of America. | 18,845,027 |
Our patients do not need endocarditis prophylaxis for genitourinary tract procedures: insights from the 2007 American Heart Association guidelines. | The 2007 American Heart Association guidelines for the prevention of infective endocarditis have dramatically reduced both the types of eligible procedures and the types of eligible cardiac lesions that require prophylaxis. Antibiotic prophylaxis to prevent infective endocarditis is not indicated for any patient undergoing obstetric and/or gynaecological procedures, not even for patients with underlying cardiac lesions with the highest risk of developing complications from endocarditis. This sharp departure from previously published guidelines relies on the recognition that endocarditis is more likely to develop from "randomly occurring" bacteremia (e.g., from brushing teeth) than from invasive procedures and that antibiotic prophylaxis has not been proven to be effective. A short discussion on enterococcal infections associated to obstetric and gynaecological procedures and therapeutic implications is presented. | 18,845,049 |
Functional overloading facilitates the regeneration of injured soleus muscles in mice. | The effect of functional overloading on the regenerating process of injured skeletal muscle was investigated in 10-week-old male mice (C57BL/6J). Functional overloading on soleus of both hindlimbs was performed by cutting the distal tendons of plantaris and gastrocnemius muscles for 2 weeks before cardiotoxin (CTX) injection as the preconditioning and also during 10 weeks of recovery. To activate the necrosis-regeneration cycle, 0.1 ml of 10-microM CTX was injected into soleus muscle. The mean values of absolute muscle weight and the percentage of Pax7-positive nuclei in soleus were increased by the preconditioning. These values, as well as total muscle protein content, in the group with CTX injection plus overloading were larger than in the group with CTX injection alone. Fibers with central nucleus were noted in the group with CTX injection with or without overloading. The rate of disappearance of fibers having central nucleus during recovery was stimulated by overloading. Histological analyses revealed that the regeneration of injured soleus muscle with overloading proceeded more rapidly than the muscle without overloading. These results, in combination with previous lines of evidence, strongly suggest that functional overloading may facilitate the regeneration of injured skeletal muscles. | 18,845,057 |
Are all seborrheic keratoses benign? Review of the typical lesion and its variants. | Seborrheic keratosis (SK) is one of the more common benign epidermal neoplasms seen in adult and middle-aged patients. As little is written in the literature about the variants of SK, this article aims to categorize and discuss the different subtypes and their important associations. An in-depth literature search using OVID Medline and PubMed was conducted to classify the various subtypes of SK. Clinical variants were photographed and used to help document the subtypes. The pathology is described for each. Six subtypes of SK were identified: dermatosis papulosa nigra, stucco keratosis, inverted follicular keratosis, large cell acanthoma, lichenoid keratosis, and flat seborrheic keratosis. Although the etiology and pathogenesis of SKs are still largely debatable, several underlying mechanisms and contributing factors have been identified. All subtypes represent benign lesions, and treatment is usually done for cosmetic reasons. Several of the subtypes may act as cutaneous markers for internal malignancy and should be monitored closely for any atypical changes. Although all subtypes of SK are benign, their association with other malignant lesions and ability to serve as cutaneous markers of internal malignancy emphasize the importance of correctly identifying all variants. | 18,845,088 |
Cutaneous granulomas with predominantly CD8(+) lymphocytic infiltrate in a child with severe combined immunodeficiency. | Combined immunodeficiency disorders comprise a heterogeneous group of diseases characterized by both humoral and cell-mediated immunodeficiency. Cutaneous granulomas manifestations in children with combined immunodeficiency are rare. We report the case of a 6-year-old boy who presented with disseminated cutaneous granulomas and a history of multiple infections. Laboratory evaluation revealed severe combined immunodeficiency, and deoxyribonucleic acid (DNA) analysis confirmed mutations on a gene of chromosome 19 that encodes an enzyme called Janus kinase 3 (Jak-3). Immunohistochemistry revealed expression of CD8(+) in the perivascular lymphocytic infiltrate Disseminated granulomatous lesions in children with a history of frequent infections should prompt the clinician to initiate detailed immunocompetence evaluation as they might prove to be the first manifestation of immunologic impairment. | 18,845,095 |
Occupational allergic contact dermatitis from epoxy resin in a golf club repairman. | A golfer presented with facial and hand eczema. He had exacerbations of his hand eczema prior to golf tournaments. Being an authorized golf club repairman, he had been working with a two-part glue containing an epoxy resin (ER) based on diglycidyl ether of bisphenol A (DGEBA) and the hardener diethylenetriamine (DETA) for approximately 4 years before he developed any skin problems. He was patch-tested with the standard, which contains an ER based on DGEBA (DGEBA-R), epoxy (containing DETA), and rubber glove series and had positive reactions to DGEBA-R only. Other work materials (a latex glove, a golf glove made of leather, and part of the handle of his own golf club "as is" and in a methyl tert-butyl ether extract) were tested, with negative results. Allergic contact dermatitis from ER affects the skin by direct contact; the dermatitis is usually localized to the hands and forearms. If the face and eyelids are involved, the dermatitis may be due to exposure to airborne hardeners or reactive diluents, exposure to airborne dust from residual monomers, or ectopic allergic reactions. Our repairman had sandpapered an old glued surface, which may have led to possible airborne dust formation, thus explaining the facial eczema. Therefore, a worker with contact allergy to ER may continue working provided the skin is protected from contamination. | 18,845,108 |
Preliminary investigation to determine the cytotoxicity of various cryoprotectants on southern African abalone (Haliotis midae) embryos. | Cryopreservation could provide stock quantities of embryos for transgenic research. This study aimed to determine the least toxic cryoprotective agent for Haliotis midae embryos. They were exposed for 30min to concentrations varying from 5% to 20% of the following cryopreservatives: methanol (MET), polyethylene glycol (PEG), dimethyl sulfoxide (ME(2)SO) and glycerol (GLY). In contrast to cryopreservation studies done in other molluscs, PEG showed the least toxicity to H. midae embryos in concentrations ranging from 5% to 15%. MET was also less toxic than ME(2)SO and GLY at correlating concentrations. GLY showed the most toxic effects with most embryos dead or abnormal at concentrations above 15%. | 18,845,135 |
DNA methyltransferase 1o functions during preimplantation development to preclude a profound level of epigenetic variation. | Most mouse embryos developing in the absence of the oocyte-derived DNA methyltransferase 1o (DNMT1o-deficient embryos) have significant delays in development and a wide range of anatomical abnormalities. To understand the timing and molecular basis of such variation, we studied pre- and post-implantation DNA methylation as a gauge of epigenetic variation among these embryos. DNMT1o-deficient embryos showed extensive differences in the levels of methylation in differentially methylated domains (DMDs) of imprinted genes at the 8-cell stage. Because of independent assortment of the methylated and unmethylated chromatids created by the loss of DNMT1o, the deficient embryos were found to be mosaics of cells with different, but stable epigenotypes (DNA methylation patterns). Our results suggest that loss of DNMT1o in just one cell cycle is responsible for the extensive variation in the epigenotypes in both embryos and their associated extraembryonic tissues. Thus, the maternal-effect DNMT1o protein is uniquely poised during development to normally ensure uniform parental methylation patterns at DMDs. | 18,845,137 |
Intracellular trafficking of Notch receptors and ligands. | The Notch pathway represents a highly conserved signaling network, which regulates the formation and maintenance of various organ systems along development and during adulthood. Direct cell-cell contacts between ligand- and receptor-expressing cells underlie activation of the Notch pathway. Notch signaling requires endocytosis in both signal emitting and receiving cells. Recent findings on the roles of a number of modulators show that they act either on the maintenance of an active receptor at the membrane, or on the production of active ligand, or on signal transduction after activation. | 18,845,146 |
Structure of the cyclomodulin Cif from pathogenic Escherichia coli. | Bacterial pathogens have evolved a sophisticated arsenal of virulence factors to modulate host cell biology. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) use a type III protein secretion system (T3SS) to inject microbial proteins into host cells. The T3SS effector cycle inhibiting factor (Cif) produced by EPEC and EHEC is able to block host eukaryotic cell-cycle progression. We present here a crystal structure of Cif, revealing it to be a divergent member of the superfamily of enzymes including cysteine proteases and acetyltransferases that share a common catalytic triad. Mutation of these conserved active site residues abolishes the ability of Cif to block cell-cycle progression. Finally, we demonstrate that irreversible cysteine protease inhibitors do not abolish the Cif cytopathic effect, suggesting that another enzymatic activity may underlie the biological activity of this virulence factor. | 18,845,161 |
Modeling distributions of flying insects: effective attraction radius of pheromone in two and three dimensions. | The effective attraction radius (EAR) of an attractive pheromone-baited trap was defined as the radius of a passive "sticky" sphere that would intercept the same number of flying insects as the attractant. The EAR for a particular attractant and insect species in nature is easily determined by a catch ratio on attractive and passive (unbaited) traps, and the interception area of the passive trap. The spherical EAR can be transformed into a circular EAR(c) that is convenient to use in two-dimensional encounter rate models of mass trapping and mating disruption with semiochemicals to control insects. The EAR(c) equation requires an estimate of the effective thickness of the layer where the insect flies in search of mates and food/habitat. The standard deviation (SD) of flight height of several insect species was determined from their catches on traps of increasing heights reported in the literature. The thickness of the effective flight layer (F(L)) was assumed to be SD x square root of 2pi, because the probability area equal to the height of the normal distribution,1/(SD x square root of 2pi), times the F(L) is equal to the area under the normal curve. To test this assumption, 2000 simulated insects were allowed to fly in a three-dimensional correlated random walk in a 10-m thick layer where an algorithm caused them to redistribute according to a normal distribution with specified SD and mean at the midpoint of this layer. Under the same conditions, a spherical EAR was placed at the center of the 10-m layer and intercepted flying insects distributed normally for a set period. The number caught was equivalent to that caught in another simulation with a uniform flight density in a narrower layer equal to F(L), thus verifying the equation to calculate F(L). The EAR and F(L) were used to obtain a smaller EAR(c) for use in a two-dimensional model that caught an equivalent number of insects as that with EAR in three dimensions. This verifies that the F(L) estimation equation and EAR to EAR(c) conversion methods are appropriate. | 18,845,163 |
Thermodynamics and folding pathway of tetraloop receptor-mediated RNA helical packing. | Little is known about the thermodynamic forces that drive the folding pathways of higher-order RNA structure. In this study, we employ calorimetric [isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC)] and spectroscopic (NMR and UV) methods to characterize the thermodynamics of the GAAA tetraloop-receptor interaction, utilizing a previously described bivalent construct. ITC studies indicate that the bivalent interaction is enthalpy driven and highly stable, with a binding constant (K(obs)) of 5.5x10(6) M(-1) and enthalpy (DeltaH(obs)(o)) of -33.8 kcal/mol at 45 degrees C in 20 mM KCl and 2 mM MgCl(2). Thus, we derive the DeltaH(obs)(o) for a single tetraloop-receptor interaction to be -16.9 kcal/mol at these conditions. UV absorbance data indicate that an increase in base stacking quality contributes to the enthalpy of complex formation. These highly favorable thermodynamics are consistent with the known critical role for the tetraloop-receptor motif in the folding of large RNAs. Additionally, a significant heat capacity change (DeltaC(p,obs)(o)) of -0.24 kcal mol(-1) K(-1) was determined by ITC. DSC and UV-monitored thermal denaturation experiments indicate that the bivalent tetraloop-receptor construct follows a minimally five-state unfolding pathway and suggest the observed DeltaC(p,obs)(o) for the interaction results from a temperature-dependent unbound receptor RNA structure. | 18,845,162 |
Fragrance material review on 1,7,7-trimethylbicyclo[4.4.0]dec-3-yl acetate. | A toxicologic and dermatologic review of 1,7,7-trimethylbicyclo[4.4.0]dec-3-yl acetate when used as a fragrance ingredient is presented. | 18,845,203 |
Fragrance material review on amylcyclohexyl acetate. | A toxicologic and dermatologic review of amylcyclohexyl acetate when used as a fragrance ingredient is presented. | 18,845,222 |
Cytoprotective effect of arjunolic acid in response to sodium fluoride mediated oxidative stress and cell death via necrotic pathway. | The present study was conducted to investigate the role of arjunolic acid (AA) against sodium fluoride (NaF)-induced cytotoxicity and necrotic cell death in murine hepatocytes. Dose-dependent studies suggest that incubation of hepatocytes with NaF (100mM) for 1h significantly decreased the cell viability as well as intracellular antioxidant power. Besides, NaF administration increased the activities of the membrane leakage enzymes and accumulation of intracellular reactive oxygen species; decreased the activities of the antioxidant enzymes, the glutathione (GSH) and total thiol contents; and elevated the level of oxidised glutathione (GSSG), lipid peroxidation end products as well as protein carbonyl content. In addition to the oxidative impairments, fluoride exposure caused hepatic cell death mainly via the necrotic pathway as supported by the flowcytometric and DNA fragmentation analyses. Incubation with AA (100 microg/ml) both prior to and in combination with NaF almost normalized the altered activities of antioxidant indexes. AA treatment enhanced the cellular antioxidant capability and protected hepatocytes against NaF-induced cytotoxicity and necrotic death. The cytoprotective activity of AA was found to be comparable to that of a known antioxidant, vitamin C. Combining, data suggest that AA plays a protective role against NaF-induced cellular damage and prevents hepatocytes from necrotic death. | 18,845,235 |
The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. | Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis. | 18,845,241 |
Acetylcholine activity in selective striatal regions supports behavioral flexibility. | Daily living often requires individuals to flexibly respond to new circumstances. There is considerable evidence that the striatum is part of a larger neural network that supports flexible adaptations. Cholinergic interneurons are situated to strongly influence striatal output patterns which may enable flexible adaptations. The present experiments investigated whether acetylcholine actions in different striatal regions support behavioral flexibility by measuring acetylcholine efflux during place reversal learning. Acetylcholine efflux selectively increased in the dorsomedial striatum, but not dorsolateral or ventromedial striatum during place reversal learning. In order to modulate the M2-class of autoreceptors, administration of oxotremorine sesquifumurate (100 nM) into the dorsomedial striatum, concomitantly impaired reversal learning and an increase in acetylcholine output. These effects were reversed by the m(2) muscarinic receptor antagonist, AF-DX-116 (20 nM). The effects of oxotremorine sesquifumurate and AF-DX-116 on acetylcholine efflux were selective to behaviorally-induced changes as neither treatment affected acetylcholine output in a resting condition. In contrast to reversal learning, acetylcholine efflux in the dorsomedial striatum did not change during place acquisition. The results reveal an essential role for cholinergic activity and define its locus of control to the dorsomedial striatum in cognitive flexibility. | 18,845,266 |
Habituation in songbirds. | Songbirds respond to initial playback of a recorded conspecific song in numerous ways, from changes in gene expression in the brain to changes in overt physical activity. When the same song is presented repeatedly, responses have been observed to habituate at multiple levels: molecular, cellular and organismal. Core criteria of habituation have been established at each level, although in no case have all the formal parameters been rigorously measured. At the level of overt behavior, classical field studies showed that territorial birds respond to the song of a potential challenger with a variety of behaviors, and many (but not all) of these behaviors decline with repeated stimulus presentation. More recent laboratory studies have defined analogous responses to song presentation in the zebra finch (Taeniopygia guttata), the dominant species in current molecular and neurobiological research and one that does not use song for territorial defense. Studies in the zebra finch have also demonstrated activation followed by habituation of responses measured at both electrophysiological and molecular (gene expression and signal transduction) levels. In all cases, habituation is specific for a very particular stimulus--an individual song presented in a particular context. There are strong correlations between habituation measurements made at these different levels, but some dissociations have also been observed, implying that molecular, electrophysiological and behavioral habituations are not equivalent manifestations of a single core process. | 18,845,267 |
Abdominal hysterectomy with or without angle stitch: correlation with subsequent vaginal vault prolapse. | The objective of the study was to assess whether cardinal-uterosacral ligament lateral vaginal cuff angle stitches at the time of total hysterectomy may assist in preventing subsequent apical vault prolapse. Total hysterectomies without cuff angle stitches were performed in 7 unembalmed cadavers. Successive hanging weights of 1, 2, 3, and 4 kg were loaded against the vaginal cuff and distances moved were recorded. The same process was repeated after tying bilateral angle stitches. Average distances pulled with 1, 2, 3, and 4 kg of traction against the cuff without angle stitches were 14.6 +/- 1.4, 19.1 +/- 1.7, 23.1 +/- 2.3, and 27.6 +/- 2.0 mm, respectively. After completing angle sutures, these distances were 13.1 +/-1.1, 17.3 +/- 1.5, 20.9 +/- 1.9, and 25.1 +/- 2.6 mm, respectively (P = .026). Methodical incorporation of the cardinal-uterosacral ligaments into the vaginal cuff margins at time of total abdominal hysterectomy may help minimize subsequent apical vault prolapse. | 18,845,281 |
Continuing improvement of chronic pelvic pain in women after short-term Mensendieck somatocognitive therapy: results of a 1-year follow-up study. | Chronic pelvic pain is a common source of disability among women in the western world. Here we report that 3 months of Mensendieck somatocognitive intervention in chronic pelvic pain patients was followed by continued improvements of outcomes at 1-year follow-up in a randomized, controlled study design. Forty women with chronic pelvic pain unexplained by pelvic pathology were randomly assigned to 2 groups: (1) standard gynecologic treatment and (2) gynecologic treatment plus somatocognitive therapy aimed at reducing physical pain by changing posture, movement, and respiration patterns. A standardized Mensendieck test (SMT) of motor function (assessing posture, movement, gait, sitting posture, and respiration), a self-rating questionnaire assessing psychologic distress and general well-being (GHQ-30) and a visual analog score of pain (VAS) were obtained before, after 90 days of treatment and 1 year after inclusion. Patients treated by standard gynecologic treatment/supervision did not improve significantly at 1-year follow-up in any of the test modalities. By contrast, those who in addition received somatocognitive therapy had improved scores for all motor functions and pain, as well as GHQ-30 scores for coping, and anxiety-insomnia-distress. Mensendieck somatocognitive therapy combined with standard gynecologic care improves psychologic distress, pain experience, and motor functions of women with chronic pelvic pain better than gynecologic treatment alone. The effect lasted and even further improvement occurred 9 months after treatment. | 18,845,283 |
Prospective study of cardiorespiratory fitness and depressive symptoms in women and men. | Most studies of the relationship between cardiorespiratory fitness (CRF) and depression have been limited to cross-sectional designs. The objective of this study was to follow individuals over time to examine whether those with higher levels of CRF have lower risk of developing depressive symptoms. Participants were 11,258 men and 3085 women enrolled in the Aerobics Center Longitudinal Study in Dallas, TX. All participants completed a maximal treadmill exercise test at baseline (1970-1995) and a follow-up health survey in 1990 and/or 1995. Individuals with a history of a mental disorder, cardiovascular disease, or cancer were excluded. CRF was quantified by exercise test duration, and categorized into age and sex-stratified groups as low (lowest 20%), moderate (middle 40%), or high (upper 40%). Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). Those who scored 16 or more on the CES-D were considered to have depressive symptoms. After an average of 12 years of follow-up, 282 women and 740 men reported depressive symptoms. After adjusting for age, baseline examination year, and survey response year, the odds of reporting depressive symptoms were 31% lower for men with moderate CRF (odds ratio, OR 0.69; 95% confidence interval, CI 0.56-0.85) and 51% lower for men with high CRF (OR 0.49, CI 0.39-0.60), compared to men with low CRF. Corresponding ORs for women were 0.56 (CI 0.40-0.80) and 0.46 (CI 0.32-0.65). Higher CRF is associated with lower risk of incident depressive symptoms independent of other clinical risk predictors. | 18,845,305 |
Mechanistic studies on PseB of pseudaminic acid biosynthesis: a UDP-N-acetylglucosamine 5-inverting 4,6-dehydratase. | UDP-N-acetylglucosamine 5-inverting 4,6-dehydratase (PseB) is a unique sugar nucleotide dehydratase that inverts the C-5'' stereocentre during conversion of UDP-N-acetylglucosamine to UDP-2-acetamido-2,6-dideoxy-beta-l-arabino-hexos-4-ulose. PseB catalyzes the first step in the biosynthesis of pseudaminic acid, which is found as a post-translational modification on the flagellin of Campylobacter jejuni and Helicobacter pylori. PseB is proposed to use its tightly bound NADP+ to oxidize UDP-GlcNAc at C-4'', enabling dehydration. The alpha,beta unsaturated ketone intermediate is then reduced by delivery of the hydride to C-6'' and a proton to C-5''. Consistent with this, PseB from C. jejuni has been found to incorporate deuterium into the C-5'' position of product during catalysis in D2O. Likewise, PseB catalyzes solvent isotope exchange into the H-5'' position of product, and eliminates HF from the alternate substrate, UDP-6-deoxy-6-fluoro-GlcNAc. Mutants of the putative catalytic residues aspartate 126, lysine 127 and tyrosine 135 have severely compromised dehydratase, solvent isotope exchange, and HF elimination activities. | 18,845,311 |
Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity. | The transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes through an oxidative stress process. Here, we have analyzed the role of different NADPH oxidase isoforms in the intracellular signalling induced by TGF-beta in hepatocytes, to later explore whether this mechanism is altered in liver tumor cells. Primary cultures of rat and human hepatocytes, HepG2 and Hep3B cells were used in in vitro studies to analyze the TGF-beta response. TGF-beta-induced apoptosis in rat hepatocytes does not require Rac-dependent NADPH oxidases. TGF-beta upregulates the Rac-independent Nox4, which correlates with its pro-apoptotic activity. Regulation of Nox4 occurs at the transcriptional level and is counteracted by intracellular survival signals. siRNA targeted knock-down of Nox4 attenuates NADPH oxidase activity, caspase activation and cell death in rat hepatocytes. NOX4 upregulation by TGF-beta is also observed in human hepatocytes, coincident with apoptosis. In human hepatocellular carcinoma (HCC) cell lines, NOX4 upregulation by TGF-beta is only observed in cells that are sensitive to its cytotoxic effect, such as Hep3B cells. siRNA targeted knock-down of NOX4 in these cells impairs TGF-beta-induced apoptosis. Upregulation of NOX4 by TGF-beta is required for its pro-apoptotic activity in hepatocytes. Impairment of this TGF-beta-induced response might confer apoptosis resistance in HCC cells. | 18,845,355 |
Type 3 metallothioneins respond to water deficit in leaf and in the cambial zone of white poplar (Populus alba). | The involvement of metallothioneins (MTs) in response to plant water stress and recovery was assessed by analyzing gene expression in leaves and in the cambial zone of white poplar. One-year-old plants were submitted to two different watering regimes: irrigation was withheld for 9d and then resumed until day 17, or soil moisture was maintained to field capacity by irrigation during the experiment. Changes in leaves and stem water relations, gas exchange and CO(2) assimilation were recorded. The expression profiles of MT genes were analyzed in developing leaves and the cambial zone at maximum stress levels and after recovery and compared with the watered controls. Whole-plant water relations were significantly affected by water deprivation, though a complete recovery of plant water status was reached after resumption of watering. Withholding irrigation resulted in a significant decrease of leaf turgor potential and relative water content without a significant increase of the osmotic potential at full turgor. Similarly, stem water content decreased, leading to a marked increase of stem shrinkage, confirming that mild water stress affected primarily tissue water status. Following water depletion, the transcript analysis of MT genes revealed increased expression of type 3a and 3b MT genes in cambial tissues, and particularly in leaves. After water resumption, transcription decreased, suggesting that the changes in gene expression were related to water deficit. The results indicate that in leaves and, for the first time, in the cambial zone, type 3 MTs respond in a specific manner to changes in water status. These results are consistent with the regulatory cis-elements present in the 5' flanking region of type 3 MT genes. | 18,845,361 |
The fast track back to registered nurses employment. | The registered nurse (RN) workforce continues to decline. One method to attract experienced RNs into the workforce is through RN refresher courses. To determine if our RN refresher program is successful in returning RNs to the workforce, we sought to measure the: characteristics of RNs who participate in our program; relationship among participants' employment and demographics; effect of high fidelity human simulation (HFHS) on participants' learning, and; program's ability to meet participants' preparation for employment. Seventy-three participants were surveyed to measure their demographics and employment; they ranked the HFHS experience and program experience on their learning and employment. Thirty-four (47%) surveys were returned. Thirty-three participants (97%) were female (mean age=50.44 years, SD=6.2). Their mean years of RN licensure was 24.93 years (SD=8.8), and their mean time out of nursing practice was 13.30 years (SD=8.0). Twenty-six (76.5%) were employed, with 20 (60.6%) employed as RNs at acute care facilities. Employed participants were licensed for less years than non-employed participants (p=0.047). Employed participants ranked their HFHS experience highly (p=0.04) and the program highly (p=0.04) on benefiting their current employment. Our refresher program appears to be successful in helping RNs re-enter the nursing workforce. | 18,845,364 |
Risk of hemodialysis graft thrombosis: analysis of monthly flow surveillance. | During clinical application of flow surveillance of hemodialysis grafts, the risk of thrombosis is assessed month after month, rather than after one or several measurements, as has been done in published studies. Adequate assessment of risk should consider the many measurements obtained over time. Prospective cohort diagnostic test study. 176 patients with hemodialysis grafts from 2 university-affiliated dialysis units during a 6-year period. Monthly measurement of graft blood flow or change in flow. Graft thrombosis. We used logistic regression analysis to compute the risk of thrombosis and used receiver operating characteristic (ROC) curves to assess the accuracy in predicting thrombosis within 1 month. Newer grafts were most likely to thrombose, whereas older grafts were unlikely to thrombose even at low flows or large decreases in flow. Areas under the ROC curves were 0.698 for flow and 0.713 for change in flow measured over 2 months. Flow predicted thrombosis with a sensitivity of 53% at a specificity of 79%, and change in flow had a sensitivity of 58% at a specificity of 75%. More than half the thromboses lacked a change in flow measurement, usually because thrombosis occurred before a change could be measured. Thus, the effective predictive accuracy of change in flow was much less than the ROC curves indicated because the curves do not consider missing measurements. Performance characteristics of index tests may vary across patient populations. Flow and change in flow are inaccurate predictors of thrombosis. Many thromboses are not predicted, and intervention based on surveillance likely yields many unnecessary procedures. Thus, this study does not support routine application of surveillance to prevent thrombosis. | 18,845,369 |
Motor and language deficits before and after surgical resection of mesial frontal tumour. | The goal of the present study was to better characterize pre- and immediately post-surgical motor and language deficits resulting from the surgery of tumours located in the medial part of the frontal lobe. Seven patients treated by surgical resection of low-grade gliomas affecting the medial part of the frontal lobe were studied with neuropsychological tasks investigating motor and language abilities before surgery and at three time points after surgery (first, third and seventh day after surgery). The tasks were constructed in a way that allowed the structured comparison between language and motor functions, and controlled the level of external constraint of the production. The main results of this study are: (1) globally the patients were impaired in both language and motor production the day after surgery; (2) the performance improved faster for tasks with strongly constrained production; (3) the verbal and semantic fluency were very sensitive and appropriate tasks for examination of the deficits resulting from the resection; and (4) performances were back to normal seven days after the surgery for most of the tasks. These results confirm that surgery of low-grade gliomas affecting the prefrontal midline areas affects only transiently motor and language functions as tested in this study. They also suggest that verbal and semantic fluency were the most severely affected tests postoperatively. On the basis of these results, the surgical resection of the low-grade gliomas of the prefrontal midline seems a valuable treatment alternative. | 18,845,388 |
[Emergence of vancomycin-dependent enterococci following glycopeptide therapy: case report and review]. | Outbreaks of vancomycin-resistant enterococci have been increasingly reported in France over the last three years. We report here, the emergence of a vancomycin-dependent enterococci isolate following glycopeptide therapy. An Enterococcus faecium isolate that required vancomycin for growth was cultured from the stools of a liver transplant recipient who was colonised with vancomycin-resistant enterococci and who received vancomycin treatment for methicillin-resistant Staphylococcus aureus infection. The resistant isolate and the dependent isolate were typed by pulsed-field gel electrophoresis. The sequence of the ddl gene coding for the D-Ala: D-Ala ligase was analysed. The dependent isolate was primary cultured onto a vancomycin-containing screening medium and could not be subcultured in the absence of vancomycin. Both the resistant and dependent isolates harboured the vanA gene and they had the same DNA restriction pattern after pulsed-field gel electrophoresis. Dependence on vancomycin was associated with a 1-bp deletion in the D-Ala: D-Ala ligase gene leading to an early stop odon. Cultures onto vancomycin-containing media are warranted for clinical specimens from patients, who are known to carry vancomycin-resistant enterococci and receive vancomycin therapy. | 18,845,404 |
Psychotropic medication use for challenging behaviors in persons with intellectual disabilities: an overview. | Challenging behaviors in persons with intellectual disabilities are primary target for treatment in mental health clinics and institutions. Furthermore, an increasing number of people are receiving psychotropic medications for the management of their challenging behaviors. Many people are often treated with high doses of multiple psychotropic medications for extended periods of time with little or no data collected to determine treatment efficacy. Similarly, data demonstrating treatment effectiveness is at best questionable at this time. It is for these reasons that controversy exists regarding the use of psychotropic medication for challenging behaviors. The purpose of this paper was to summarize past and current studies of drug related interventions for challenging behaviors for persons with intellectual disabilities. Based on the results of this review, the effectiveness of psychotropic medications in managing challenging behaviors is best described as minimal and a need exists for controlled studies of higher scientific quality in this area. Considering alternative psychologically based interventions and careful functional assessments appear to be advisable. | 18,845,418 |
Interactions of Bacillus spp. and plants--with special reference to induced systemic resistance (ISR). | Biological control of soil-borne pathogens comprises the decrease of inoculum or of the disease producing activity of a pathogen through one or more mechanisms. Interest in biological control of soil-borne plant pathogens has increased considerably in the last few decades, because it may provide control of diseases that cannot or only partly be managed by other control strategies. Recent advances in microbial and molecular techniques have significantly contributed to new insights in underlying mechanisms by which introduced bacteria function. Colonization of plant roots is an essential step for both soil-borne pathogenic and beneficial rhizobacteria. Colonization patterns showed that rhizobacteria act as biocontrol agents or as growth-promoting bacteria form microcolonies or biofilms at preferred sites of root exudation. Such microcolonies are sites for bacteria to communicate with each other (quorum sensing) and to act in a coordinated manner. Elicitation of induced systemic resistance (ISR) by plant-associated bacteria was initially demonstrated using Pseudomonas spp. and other Gram-negative bacteria. Several strains of the species Bacillus amyloliquefaciens, B. subtilis, B. pasteurii, B. cereus, B. pumilus, B. mycoides, and B. sphaericus elicit significant reductions in the incidence or severity of various diseases on a diversity of hosts. Elicitation of ISR by these strains has been demonstrated in greenhouse or field trials on tomato, bell pepper, muskmelon, watermelon, sugar beet, tobacco, Arabidopsis sp., cucumber, loblolly pine, and two tropical crops (long cayenne pepper and green kuang futsoi). Protection resulting from ISR elicited by Bacillus spp. has been reported against leaf-spotting fungal and bacterial pathogens, systemic viruses, a crown-rotting fungal pathogen, root-knot nematodes, and a stem-blight fungal pathogen as well as damping-off, blue mold, and late blight diseases. This progress will lead to a more efficient use of these strains which is worthwhile approach to explore in context of biocontrol strategies. | 18,845,426 |
Comparative analysis of the street generation of inorganic urban solid waste (IUSW) in two neighborhoods of Mexico City. | Inorganic urban solid waste (IUSW) is a serious problem in developing countries, and IUSW in the street that does not have adequate final disposal is responsible for serious environmental effects. The aim of this work was to determine the dynamics of the generation of IUSW in the streets of two neighborhoods of different socioeconomic strata in Mexico City during 5 weeks in 2006. The amount of IUSW was recorded every day from 9:00 to 12:00 h, separated, classified, and registered. It was found that plastic (50%) and paper (44.5%) wastes were found most frequently, whereas, textiles (0.4%) and glass (0.5%) wastes were present less frequently in all samples. The IUSWs without commercial brands were more abundant. Branded plastic wrappers of PepsiCo and Bimbo, as well as polyethylene terephthalate (PET) containers of Coca Cola, registered the highest values, while Gatorade, Barrilitos, and Peñafiel registered the lowest. The neighborhood with a higher income and more vegetation on sidewalks or in jardinières, which are used to hide solid waste, had more IUSW than the neighborhood with lower income, where IUSW was thrown out directly into the street. The knowledge of the real generation and composition of IUSW will contribute to the prevention of its negative environmental and social impacts, as well as guarantee the efficiency of its sustainable management. | 18,845,430 |
Interaction of kendomycin and semi-synthetic analogues with the anti-apoptotic protein Bcl-xl. | The cytotoxic macrolide kendomycin was identified as a ligand of Bcl-xl, an anti-apoptotic member of the Bcl-2 protein family. Hydrolysis-stable and protonable semi-synthetic analogues have been obtained that retain cytotoxicity and Bcl-xl binding. | 18,845,435 |
Piperidine dispiro-1,2,4-trioxane analogues. | Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)(2) catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting beta-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity. | 18,845,438 |
Evaluation of peptide-aldehyde inhibitors using R188I mutant of SARS 3CL protease as a proteolysis-resistant mutant. | The 3C-like (3CL) protease of the severe acute respiratory syndrome (SARS) coronavirus is a key enzyme for the virus maturation. We found for the first time that the mature SARS 3CL protease is subject to degradation at 188Arg/189Gln. Replacing Arg with Ile at position 188 rendered the protease resistant to proteolysis. The R188I mutant digested a conserved undecapeptide substrate with a K(m) of 33.8 microM and k(cat) of 4753 s(-1). Compared with the value reported for the mature protease containing a C-terminal His-tag, the relative activity of the mutant was nearly 10(6). Novel peptide-aldehyde derivatives containing a side-chain-protected C-terminal Gln efficiently inhibited the catalytic activity of the R188I mutant. The results indicated for the first time that the tetrapeptide sequence is enough for inhibitory activities of peptide-aldehyde derivatives. | 18,845,442 |
A versatile microfluidic chip for millisecond time-scale kinetic studies by electrospray mass spectrometry. | An electrospray coupled microfluidic reactor for the measurement of millisecond time-scale, solution phase kinetics is introduced. The device incorporates a simple two-channel design that is etched into polymethyl methacrylate (PMMA) by laser ablation. The outlet of the device is laser cut to a sharp tip, facilitating low dead volume 'on chip' electrospray. Fabrication is fast, straightforward and highly reproducible, supporting rapid prototyping and large-scale reproduction. Device performance is characterized using a cytochrome c unfolding reaction. Unfolding processes with rates in excess of 30 s(-1) are easily measured, including the appearance of a 'native-like' intermediate that is maximally populated 180 ms post reaction initiation. To extract reliable rates from the data, a theoretical framework for the analysis of kinetics acquired under square-channel laminar flow is introduced. | 18,845,447 |
Herpesviruses and the transplanted lung: looking at the air side. | Herpesviruses may cause substantial complications after lung transplantation. Especially their interaction with lung tissue cells may result in adverse effects for the transplant patients, and may lead to severe end organ disease or to chronic transplant rejection and to development of bronchiolitis obliterans (BOS). However, the determination of the patients' local virus replication in the lung is still problematic. While the virus load in blood can be easily quantified nowadays, the determination of the virus load in the lung compartment can not be easily achieved, especially due to the individually different and not predictable dilution of virus during sampling of the bronchoalveolar lavage (BAL). In the following a short overview will be given about the different herpesviruses and their possible influence on the transplanted lung as well as about a method to determine the original virus load at the air surface of the lung. The quantitative data achieved by this method underline that some herpesviruses are often present at much higher levels at the air surface of the transplanted lung than in the blood, and that their influence on transplant survival may have been substantially underestimated so far. | 18,845,472 |
Toll-like receptors and cytokines in immune responses to persistent mycobacterial and Salmonella infections. | Bacterial persistence is of major concern worldwide in the control of a number of bacterial infections. The carriers who are asymptomatic act as reservoirs of the bacteria. Knowledge of the host response, of the persistence process, and of the potential of biological mediators as diagnostic markers is essential towards development of prophylactic and treatment modalities for these diseases. Immune mechanisms related to recognition and elimination of the bacteria play pivotal roles in the control of bacterial infections. The majority of the studies on bacterial infections detail the immune mechanisms in the active phase of infection, and reports on the immune status in carriers are scanty. The present review describes the role of recognition molecules (TLRs) and the immune mediators (cytokines) in bacterial persistence. It appears that the TLR-mediated induction of cytokine profiles differs in active infection and bacterial persistence, with an active Th1 response being beneficial for the clearance of a high load of bacteria and at the same time conducive for the persistence of low bacterial load. Immunomodulation aiming at stimulation of the immune responses should be carried out with care as it could give rise to a carrier state in individuals with low load of the bacteria. | 18,845,475 |
Listening to the voices of patients with cancer, their advocates and their nurses: A hermeneutic-phenomenological study of quality nursing care. | This article presents the findings from a hermeneutic-phenomenological study looking at the meanings of "quality nursing care" through the experiences of patients with cancer, their advocates and their nurses. Twenty-five patients were interviewed from which fifteen also participated in two focus groups. Six patients' advocates participated in a focus group and twenty nurses were individually interviewed. The informants came from the three major hospitals in Cyprus which provide in-patient cancer care. Patients' advocates came from the two major cancer associations in Cyprus. Having analysed the data, seven major themes were identified: receiving care in easily accessible cancer care services, being cared for by nurses who effectively communicate with them and their families and provide emotional support, being empowered by nurses through information giving, being cared for by clinically competent nurses, nurses addressing their religious and spiritual needs, being cared for in a nursing environment which promotes shared decision-making, and patients being with and involving the family in the care. These findings stress the need to integrate these aspects in the care of patients with cancer. In doing so, nurses will need support and adequate training in order to acquire the relevant skills towards better caring for the patients. | 18,845,478 |
Can oligomeric T-cell receptor be used as a tool to detect viral peptide epitopes on infected cells? | We have utilized soluble HIV Gag-specific T-cell receptor (TCR) D3 with low affinity and TCR-like antibody 25-D1.16 recognizing its natural peptide-MHC (pMHC) ligand with high affinity to determine how affinity and off-rate of the receptor-pMHC interactions affect the sensitivity of pMHC detection on the cell surface. We found that with soluble TCR cognate pMHCs can be detected only at relatively high cell surface densities when the TCR was oligomerized using either Streptavidin or quantum dot (QD) scaffolds. While the higher affinity probe led to a greater sensitivity of pMHC detection, monomers and oligomers of the probe showed essentially the same detection limit, which is restricted by the sensitivity of standard flow cytometry technique. We have also shown that imaging of QD/TCR specifically bound to cognate pMHC on the cell surface yielded a very bright fluorescent signal that can enhance the sensitivity of viral peptide detection on infected cells. | 18,845,488 |
Prenatal inflammation and lung development. | Prenatal exposure of very low birth weight infants to chronic indolent chorioamnionitis with organisms such as mycoplasma and ureaplasma is frequent. Chorioamnionitis is inconsistently associated with changed risks of respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), probably because the diagnosis of chorioamnionitis does not quantify the extent or duration of the fetal exposures to infection and inflammation. The correlations between prenatal exposures and postnatal lung disease also are confounded by the imprecision of the diagnoses of RDS and BPD. In animal models, chorioamnionitis caused by pro-inflammatory mediators or live ureaplasma induces lung maturation, but also causes alveolar simplification and vascular injury. Intra-amniotic endotoxin administration also modulates the fetal innate immune system, resulting in maturation of monocytes to alveolar macrophages and the induction or paralysis of inflammatory responses depending on exposure history. Prenatal inflammation can have profound effects on the fetal lung and subsequent immune responses. | 18,845,493 |
[Tumor vasculature as a therapeutic target in non-small cell lung cancer]. | Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC. | 18,845,495 |
[Fifty-year-old history of cobalt radiotherapy in Hungary]. | The first patient in Hungary was treated by cobalt therapy fifty years ago at the National Institute of Oncology with a Gravicert type equipment. On the occasion of this anniversary, the 50-year history of the Hungarian cobalt therapy is reviewed, and its present role is discussed. The first cobalt unit (Gravicert) was designed by László Bozóky seven years after the first cobalt unit installation in the world in Canada. The megavoltage energy of the Co-60 source (average: 1.25 MeV) resulted in more successful treatments of deep-seated tumors compared to the X-ray therapy. In the next two-three decades, until the widespread use of the high-energy linear accelerators, the Co-60 teletherapy meant the modern radiation treatment throughout the world. Improvements of quality in radiation techniques necessitated exact localization of the tumors and developments of treatment planning methods. At the beginning, the localization was performed with X-ray machines, while the treatment planning was done manually. In 1965 a Rotacert type cobalt unit was installed at our institute. This machine was already capable of making irradiation in multiple directions and it worked in rotating mode, too. In Hungary, more cobalt units - first the Gravicert type, then foreign made machines - were gradually installed in other radiotherapy centers too. The quality of treatments was significantly improved by the introduction of the computerized treatment planning, and the foundation of the IAEA-supported National Treatment Planning Network in 1978 was an important step in this process. The next important development was the commencement of the CT image based treatment planning in 1981. With the spread of modern linear accelerators the role of the cobalt units has greatly decreased by now, however, nearly 2,500 cobalt units are still in use worldwide. Their usage could be further increased with technical developments. At present, radiation treatments are performed with cobalt units in eight out of twelve radiotherapy centers in Hungary. | 18,845,501 |
[The elderly driver's perception of risk: do older drivers still express comparative optimism? ]. | People frequently express comparative optimism ; that is, they believe they are less likely than average to experience negative events. The aim of the present study is, first, to observe whether people of more than 65 years are still optimists when they evaluate driving-related risks; and second, to test the assumption that older drivers show less optimism when they compare themselves with average-age drivers than when they compare themselves with same-age drivers. Our results reveal that drivers of more than 65 years do, indeed, express comparative optimism, but, contrary to our expectation, only in a limited number of cases does the age of the comparison target appear to have an effect. These results are particularly discussed in terms of self-image enhancement. | 18,845,511 |
A questionnaire survey of physicians' perspectives regarding the assessment of chemotherapy-induced peripheral neuropathy in patients with breast cancer. | Since there is now growing interest in the incorporation of patient-reported outcome measures in cancer clinical trials, a patient-based questionnaire, the Patient Neurotoxicity Questionnaire (PNQ) was developed to quantify the symptoms and severity of chemotherapy-induced peripheral neuropathy (CIPN). The aim of this study was to evaluate the physicians' perspectives regarding the utility and diagnostic value of PNQ. A questionnaire was sent to 61 physicians who participated in a Phase III randomized trial of adjuvant chemotherapy in breast cancer (AC followed by taxane versus taxane alone) that used the PNQ to assess CIPN. Forty-seven out of 61 physicians (77%) responded. The majority considered neurosensory symptoms the diagnostic hallmark for CIPN and most regarded interference with activities of daily living (ADLs) as definite justification for treatment modifications. For neurosensory disturbance, the majority of physicians indicated that Grade D severity (moderate to severe symptoms interfering with ADLs) should result in treatment postponement and Grade E severity (severe symptoms preventing most ADLs) should result in treatment discontinuation. Similarly, for neuromotor disturbance, over half of the physicians replied that Grade C (moderate symptoms not interfering with ADLs), D and E severity should result in dose reduction, treatment postponement and treatment discontinuation, respectively. Eighty-four percentage of the physicians reported that the use of the PNQ was helpful in the diagnosis and assessment of patients at risk of CIPN. The PNQ appears to be a useful instrument for the diagnosis and grading of CIPN, as well as for clinical decision-making regarding treatment modifications secondary to CIPN. | 18,845,520 |
Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase. | Eg5 is a motor protein of the kinesin family that is critical for spindle assembly during mitosis and has recently been implicated in tumorigenesis. It is largely unknown how Eg5 expression is regulated in cells. In this study, we present the first evidence that the cellular Eg5 level is down-regulated by Parkin, an E3 ubiquitin ligase well known for its role in the development of Parkinson disease. Our data show that Parkin does not trigger Eg5 protein degradation through the ubiquitin-proteasome pathway. Instead, Parkin represses Eg5 gene transcription by blocking c-Jun binding to the activator protein 1 site present in the Eg5 promoter. Our data further show that Parkin inactivates c-Jun NH2-terminal kinase (JNK), resulting in decreased phosphorylation of c-Jun. The inactivation of JNK is further mediated by multiple monoubiquitination of Hsp70. Importantly, both the ubiquitination of Hsp70 and the subsequent inactivation of the JNK-c-Jun pathway are crucial for Parkin to down-regulate Eg5 expression. These results thus uncover a novel function for Parkin in modulating the expression of Eg5 through the Hsp70-JNK-c-Jun signaling pathway. | 18,845,538 |
Evidence for variable selective pressures at a large secondary structure of the human mitochondrial DNA control region. | A combined effect of functional constraints and random mutational events is responsible for the sequence evolution of the human mitochondrial DNA (mtDNA) control region. Most studies targeting this noncoding segment usually focus on its primary sequence information disregarding other informative levels such as secondary or tertiary DNA conformations. In this work, we combined the most recent developments in DNA folding calculations with a phylogenetic comparative approach in order to investigate the formation of intrastrand secondary structures in the human mtDNA control region. Our most striking results are those regarding a new cloverleaf-like secondary structure predicted for a 93-bp stretch of the control region 5'-peripheral domain. Randomized sequences indicated that this structure has a more negative folding energy than the average of random sequences with the same nucleotide composition. In addition, a sliding window scan across the complete mitochondrial genome revealed that it stands out as having one of the highest folding potential. Moreover, we detected several lines of evidence of both negative and positive selection on this structure with high levels of conservation at the structure-relevant stem regions and the occurrence of compensatory base changes in the primate lineage. In the light of previous data, we discuss the possible involvement of this structure in mtDNA replication and/or transcription. We conclude that maintenance of this structure is responsible for the observed heterogeneity in the rate of substitution among sites in part of the human hypervariable region I and that it is a hot spot for the 3' end of human mtDNA deletions. | 18,845,547 |
Effects of continuous positive airway pressure therapy on left ventricular function assessed by tissue Doppler imaging in patients with obstructive sleep apnoea syndrome. | In this study, we aimed to assess left ventricular (LV) systolic and diastolic functions by tissue Doppler imaging (TDI) in patients with obstructive sleep apnoea syndrome (OSAS) and to investigate the effects of 6 month continuous positive airway pressure (CPAP) on LV systolic and diastolic functions. We studied 28 new diagnosed moderate and severe OSAS patients (apnoea-hypopnoea index >15) and 18 control group. Exclusion criteria were the presence of structural heart disease, pulmonary disease, diabetes mellitus, dyslipidaemia, alcoholism, neuromuscular disease, renal failure, or malignancy. They were not previously considered or treated for OSA and were all free of drugs. Left ventricular lateral and septal wall early myocardial peak velocity (Em), late myocardial peak velocity (Am), Em to Am ratio, myocardial relaxation time (RTm), myocardial systolic wave (Sm) velocity, isovolumic acceleration (IVA), myocardial pre-contraction time (PCTm), contraction time (CTm), and PCTm to CTm ratio were measured. All echocardiographic parameters were calculated 6 months after CPAP therapy. No statistically significant difference was detected between the groups according to age, gender, body mass index, systolic and diastolic blood pressure, heart rate, fasting blood glucose, and serum lipid parameters. Left ventricular systolic parameters, such as LV septal and lateral wall IVA, CTm, and PCTm to CTm ratio, were significantly lower and Sm was similar in patients with the OSAS group compared with the controls. Left ventricular diastolic parameters, such as LV septal and lateral wall Em velocity and Em to Am ratio, were significantly lower; RTm was significantly prolonged; and Am velocity was similar in patients with OSAS compared with the controls. At the end of the treatment, 20 of 28 patients were compliant with CPAP therapy. Left ventricular septal and lateral wall Em velocity, Em to Am ratio, IVA and CTm, and PCTm to CTm increased significantly, PCTm, PCTm to CTm ratio, and RTm decreased significantly after the therapy, whereas Sm velocity and Am velocity did not change after CPAP therapy in compliant patients. Left ventricular systolic and diastolic dysfunctions were determined in patients with OSAS, and it was demonstrated that LV systolic and diastolic dysfunctions improved with 6 month CPAP therapy. | 18,845,553 |
Targeting calcium handling in arrhythmias. | Abnormal calcium (Ca) handling can contribute to arrhythmogenesis directly by triggering abnormal depolarizations and indirectly by modulating action potential time course and duration. Recent data have shown the importance of these mechanisms in rare genetic diseases but also in more common conditions such as heart failure. Modulating Ca release from the sarcoplasmic reticulum via the ryanodine receptor, Ca uptake via sarcoplasmic reticulum Ca ATPase or Ca removal from the cell via the Na/Ca exchanger, are potential approaches to reduce arrhythmias. New tools allow exploring these ideas. The principles underlying this approach and the first results are critically reviewed. | 18,845,561 |
Interplay of RNA Pol IV and ROS1 during post-embryonic 5S rDNA chromatin remodeling. | We have investigated the chromatin structure of 5S rDNA, a heterochromatic pericentromeric tandemly repeated family, at 2, 3, 4 and 5 days post-germination. Our results revealed a large-scale reorganization of 5S rDNA chromatin that occurs during the first days of development. Unexpectedly, there is a decondensation followed by a 're'condensation of 5S rDNA chromatin, to obtain almost mature nuclei 5 d post-germination. The reorganization of 5S rDNA chromatin is accompanied by a rapid and active demethylation of 5S rDNA mediated by the ROS1 (repressor of silencing 1) demethylase, whereas the plant-specific RNA polymerase IV (Pol IV) is essential to the 5S chromatin 're'condensation. In conclusion, Pol IV and ROS1 collaborate to unlock the 5S rDNA chromatin inherited from the seed, and establish adult features. | 18,845,569 |
Stochastic dynamics of genetic networks: modelling and parameter identification. | Identification of regulatory networks is typically based on deterministic models of gene expression. Increasing experimental evidence suggests that the gene regulation process is intrinsically random. To ensure accurate and thorough processing of the experimental data, stochasticity must be explicitly accounted for both at the modelling stage and in the design of the identification algorithms. We propose a model of gene expression in prokaryotes where transcription is described as a probabilistic event, whereas protein synthesis and degradation are captured by first-order deterministic kinetics. Based on this model and assuming that the network of interactions is known, a method for estimating unknown parameters, such as synthesis and binding rates, from the outcomes of multiple time-course experiments is introduced. The method accounts naturally for sparse, irregularly sampled and noisy data and is applicable to gene networks of arbitrary size. The performance of the method is evaluated on a model of nutrient stress response in Escherichia coli. | 18,845,579 |
Noradrenaline triggers muscle tone by amplifying glutamate-driven excitation of somatic motoneurones in anaesthetized rats. | Postural muscle tone is potently suppressed during sleep and cataplexy. Since brainstem noradrenergic cell discharge activity is tightly coupled with state-dependent changes in muscle activity, it is assumed that noradrenergic drive on to somatic motoneurones modulates basal muscle tone. However, it has never been determined whether noradrenergic neurotransmission acts to directly regulate motoneurone activity or whether it functions to modulate prevailing synaptic activity. This is an important distinction because noradrenaline regulates cell excitability by both directly depolarizing neurones and by indirectly potentiating glutamate-mediated excitation. We used reverse-microdialysis, electrophysiology, neuro-pharmacological and histological techniques in anaesthetized rats to determine whether strengthening noradrenergic drive (via exogenous noradrenaline application) on to trigeminal motoneurones affects masseter muscle tone by increasing spontaneous motoneurone activity or whether it acts to amplify prevailing glutamate-driven excitation. Although noradrenaline is hypothesized to modulate motor activity, we found that direct stimulation of trigeminal motoneurones by alpha(1)-adrenoceptor activation had no direct effect on basal masseter tone. However, when glutamate-driven excitation was increased at the trigeminal motor pool by either endogenous glutamate release (induced by the monosynaptic masseteric reflex) or exogenous AMPA application, noradrenaline triggered a potent increase in basal masseter tone. The stimulatory effects of noradrenaline were unmasked and rapidly switched on only in the presence of glutamatergic transmission. Blockade of AMPA receptors abolished this excitatory effect, indicating that noradrenergic drive requires ongoing glutamatergic activity. Our data indicate that exogenous noradrenergic drive does not directly affect spontaneous motoneurone discharge activity in anaesthetized rats; rather, it triggers postural muscle tone by amplifying prevailing glutamate-driven excitation. | 18,845,613 |
The role of glycosphingolipid metabolism in the developing brain. | Glycosphingolipids (GSLs) are amphipathic lipids ubiquitously expressed in all vertebrate cells and body fluids, but they are especially abundant in the nervous system. The synthesis of GSLs generally is initiated in the endoplasmic reticulum and completed in the Golgi apparatus, followed by transportation to the plasma membrane surface as an integral component. The amount and expression patterns of GSLs change drastically in brains during the embryonic to postnatal stages. Recent studies have revealed that GSLs are highly localized in cell surface microdomains and function as important components that mediate signal transduction and cell adhesion. Also in developing brains, GSLs are suggested to play important roles in nervous system formation. Disturbance of GSL expression and metabolism affects brain function, resulting in a variety of diseases, particularly lysosomal storage diseases. In this review, we describe some aspects of the roles of GSLs, especially of gangliosides, in brain development. | 18,845,618 |
Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. | Myostatin, a member of the TGF-beta superfamily of proteins, is known to suppress skeletal muscle mass and myocyte proliferation. The muscular component of the uterus is the myometrium, a tissue that regulates its mass in response to different physiological conditions under the influence of sex steroids. Recently, our laboratory reported effects of activin-A, another TGF-beta family member, on signalling and proliferation of rat uterine explants and human myometrial cell lines in culture. Here, we explore the expression, actions, and regulation of myostatin in uterine smooth muscle. Myostatin mRNA was demonstrated to be expressed in a myometrial cell line, pregnant human myometrial 1 cell line (PHM1). Functional assays showed that myostatin induced phosphorylation of Smad-2 and reduced proliferation of PHM1 number in a time and dose-dependent manner. Furthermore, myostatin activated smad-2 specific signalling pathways in rat uterine explants. To expand on our in vitro findings, we found that myostatin is expressed in rat uterus and determined that myostatin mRNA expression varies as a function of the phase of the estrous cycle. Uterine levels of myostatin peaked during late estrus and were the lowest at proestrus. Ovariectomy increased myostatin expression; estrogen treatment strongly decreased myostatin levels, whereas progesterone weakly decreased myostatin expression. In conclusion, myometrial cells are myostatin sensitive, myostatin mRNA levels are modulated in vivo in rats during the estrous cycle, and in response to steroid deprivation and replacement. | 18,845,635 |
Alterations in hypothalamic KiSS-1 system in experimental diabetes: early changes and functional consequences. | Using long-term streptozotocin (STZ)-treated male rats, we recently proposed that defective function of hypothalamic KiSS-1 system is mechanistically relevant for central hypogonadotropism of uncontrolled diabetes. However, the temporal pattern of such defects and its potential contribution to disturbed gonadotropin secretion in the diabetic female remain so far unexplored. To cover these issues, expression analyses and hormonal tests were conducted in diabetic male (1 wk after STZ; short term) and female (4 wk after STZ; long term) rats. Short-term diabetic males had lower basal testosterone levels and decreased gonadotropin responses to orchidectomy (ORX), which associated with significantly attenuated post-ORX rises of hypothalamic KiSS-1 mRNA. Yet kisspeptin administration to diabetic males was able to acutely elicit supramaximal LH and testosterone responses and normalize post-ORX gonadotropin secretion. Long-term diabetic females showed persistent anestrus and significantly decreased basal gonadotropin levels as well as blunted LH responses to ovariectomy; changes that were linked to lowering of basal and postovariectomy expression of hypothalamic KiSS-1 mRNA. Moreover, despite prevailing gonadotropin suppression, LH responses to acute kisspeptin administration were fully preserved, and even enhanced after its repeated injection, in diabetic females. In sum, our present findings further define the temporal course and mechanistic relevance of altered hypothalamic KiSS-1 system in the hypogonadotropic state of uncontrolled diabetes. Furthermore, our data provide the basis for the potential therapeutic intervention of the KiSS-1 system as adjuvant in the management of disturbed gonadotropin secretion of type 1 diabetes in the female. | 18,845,637 |
Transcription of steroidogenic acute regulatory protein in the rodent ovary and placenta: alternative modes of cyclic adenosine 3', 5'-monophosphate dependent and independent regulation. | Steroid hormone synthesis is a vital function of the adrenal cortex, serves a critical role in gonadal function, and maintains pregnancy if normally executed in the placenta. The substrate for the synthesis of all steroid hormones is cholesterol, and its conversion to the first steroid, pregnenolone, by the cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme complex takes place in the inner mitochondrial membranes. Steroidogenic acute regulatory protein (STAR) facilitates the rate-limiting transfer of cholesterol from the outer mitochondrial membrane to CYP11A1 located in the inner organelle membranes. The current study explored the mechanisms controlling transcription of the Star gene in primary cell cultures of mouse placental trophoblast giant cells and rat ovarian granulosa cells examined throughout the course of their functional differentiation. Our findings show that the cis-elements required for Star transcription in the rodent placenta and the ovary are centered in a relatively small proximal region of the promoter. In placental trophoblast giant cells, cAMP is required for activation of the Star promoter, and the cis-elements mediating a maximal response were defined as cAMP response element 2 and GATA. EMSA studies show that placental cAMP-responsive element binding protein (CREB)-1 and activating transcription factor-2 (ATF2) bind to a -81/-78 sequence, whereas GATA-2 binds to a -66/-61 sequence. In comparison, patterns of Star regulation in the ovary suggested tissue-specific and developmental controlled modes of Star transcription. During the follicular phase, FSH/cAMP induced CREB-1 dependent activity, whereas upon luteinization STAR expression becomes cAMP and CREB independent, a functional shift conferred by FOS-related antigen-2 displacement of CREB-1 binding, and the appearance of a new requirement for CCAAT enhancer-binding protein beta and steroidogenic factor 1 that bind to upstream elements (-117/-95). These findings suggest that during evolution, the promoters of the Star gene acquired nonconsensus sequence elements enabling expression of a single gene in different organs, or allowing dynamic temporal changes corresponding to progressing phases of differentiation in a given cell type. | 18,845,640 |
Endothelial dysfunction in mice with streptozotocin-induced type 1 diabetes is opposed by compensatory overexpression of cyclooxygenase-2 in the vasculature. | Cardiovascular complications of diabetes result from endothelial dysfunction secondary to persistent hyperglycemia. We investigated potential compensatory mechanisms in the vasculature that oppose endothelial dysfunction in diabetes. BALB/c mice were treated with streptozotocin (STZ) to induce type 1 diabetes (T1D). In mesenteric vascular beds (MVBs), isolated ex vivo from mice treated with STZ for 1 wk, dose-dependent vasorelaxation to acetylcholine (ACh) or sodium nitroprusside was comparable with that in age-matched control mice (CTRL). By contrast, MVBs from mice treated with STZ for 8 wk had severely impaired vasodilator responses to ACh consistent with endothelial dysfunction. Pretreatment of MVBs from CTRL mice with nitric oxide synthase inhibitor nearly abolished vasodilation to ACh. In MVB from 1-wk STZ-treated mice, vasodilation to ACh was only partially impaired by L-N(omega)-arginine methyl ester. Thus, vasculature of mice with T1D may have compensatory nitric oxide-independent mechanisms to augment vasodilation to ACh and oppose endothelial dysfunction. Indeed, pretreatment of MVBs isolated from 1-wk STZ-treated mice with NS-398 [selective cyclooxygenase (COX)-2 inhibitor] unmasked endothelial dysfunction not evident in CTRL mice pretreated without or with NS-398. Expression of COX-2 in MVBs, aortic endothelial cells, and aortic vascular smooth muscle cells from STZ-treated mice was significantly increased (vs. CTRL). Moreover, concentrations of the COX-2-dependent vasodilator 6-keto-prostaglandin F-1alpha was elevated in conditioned media from aorta of STZ-treated mice. We conclude that endothelial dysfunction in a mouse model of T1D is opposed by compensatory up-regulation of COX-2 expression and activity in the vasculature that may be relevant to developing novel therapeutic strategies for diabetes and its cardiovascular complications. | 18,845,644 |
High frequency of adverse health behaviors in multiple sclerosis. | Health behaviors influence chronic disease risks in the general population, and may influence health outcomes independently of comorbid diseases. Health behaviors receive less attention in multiple sclerosis (MS) than in the general population. We assessed health behaviors among participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry and the demographic characteristics associated with particular health behaviors. In October 2006, we surveyed NARCOMS participants regarding smoking using questions from the Behavioral Risk Factor Surveillance Survey; physical activity using questions from the PEPI study, alcohol use using the AUDIT-C; and height and weight. To determine the independent demographic predictors of health behaviors, we used multivariable logistic regression, either binary or polytomous as appropriate. Of 8983 responders, 4867 (54.2%) ever smoked; 1542 (17.3%) currently smoked. On the basis of the AUDIT-C, 1632 (18.2%) were at risk for alcohol abuse or dependence. A quarter of participants were obese (n = 2269), and 2780 (31.3%) were overweight. Fewer than 25% of participants reported moderate or heavy leisure-time physical activity. Generally, lower socioeconomic status was associated with a higher frequency of adverse health behaviors accounting for other demographic factors. With increasing levels of disability, the reported intensity of physical activity was lower, and the frequency of overweight or obesity was higher. Patients with MS exhibit frequent adverse health behaviors, increasing the risk of other chronic diseases. Further research is needed to determine how these behaviors influence disability progression, quality of life, and other MS-related outcomes. | 18,845,651 |
The distribution of new enhancing lesion counts in multiple sclerosis: further explorations. | A statistical distribution describing the number of new enhancing lesions seen on MRI in patients with MS is of great importance for improving the statistical methodology of clinical trials using new enhancing lesions as outcome measure. We examined whether there are superior alternatives for the currently proposed negative binomial (NB) distribution. To determine the optimal statistical distribution describing new enhancing lesion counts from a selection of six conceivable models, and to assess the effect on the distribution of a treatment effect, varying follow-up duration and selection for activity at baseline. The statistical NB, Poisson-Inverse Gaussian (P-IG), Poisson- Lognormal (P-LN), Neyman type A (NtA), Pólya-Aeppli (PA) and Zero Inflated Poisson (ZIP) distribution were fitted on new enhancing lesion data derived from one treated and two untreated cohorts of RRMS and relapsing SPMS patients and on subgroups of varying follow-up duration and selection for baseline activity. Measure of comparison was Akaike's information criterion (AIC). Both the subgroup analyses as well as a treatment had a noticeable effect on the distributional characteristics of new enhancing lesion counts. The NB distribution generally provided the most optimal fit, closely followed by the P-IG distribution and the P-LN distribution. Fits of the PA and NtA distribution were suboptimal, while the ZIP distribution was the least adequate for modelling new enhancing lesion counts. The NB distribution is the optimal distribution for modelling new enhancing lesion counts, irrespective of the effect of treatment, follow-up duration or a baseline activity selection criterion. | 18,845,655 |
Cytoskeleton interruption in human hepatoma HepG2 cells induced by ketamine occurs possibly through suppression of calcium mobilization and mitochondrial function. | Ketamine is an intravenous anesthetic agent often used for inducing and maintaining anesthesia. Cytoskeletons contribute to the regulation of hepatocyte activity of drug biotransformation. In this study, we attempted to evaluate the effects of ketamine on F-actin and microtubular cytoskeletons in human hepatoma HepG2 cells and its possible molecular mechanisms. Exposure of HepG2 cells to ketamine at <or=100 microM, which corresponds to clinically relevant concentrations for 1, 6, and 24 h, did not affect cell viability. Meanwhile, administration of therapeutic concentrations of ketamine obviously interrupted F-actin and microtubular cytoskeletons. In parallel, levels of intracellular calcium concentration- and time-dependently decreased after ketamine administration. Analysis by confocal microscopy further revealed that ketamine suppressed calcium mobilization from an extracellular buffer into HepG2 cells. Exposure to ketamine decreased cellular ATP levels. The mitochondrial membrane potential and complex I NADH dehydrogenase activity were both reduced after ketamine administration. Ketamine did not change the production of actin or microtubulin mRNA in HepG2 cells. Consequently, ketamine-caused cytoskeletal interruption led to suppression of CYP3A4 expression and its metabolizing activity. Therefore, this study shows that therapeutic concentrations of ketamine can disrupt F-actin and microtubular cytoskeletons possibly through suppression of intracellular calcium mobilization and cellular ATP synthesis due to down-regulation of the mitochondrial membrane potential and complex I enzyme activity. Such disruption of the cytoskeleton may lead to reductions in CYP3A4 activity in HepG2 cells. | 18,845,661 |
Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone. | Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance. | 18,845,662 |
Temporal control of the dephosphorylation of Cdk substrates by mitotic exit pathways in budding yeast. | The temporal phosphorylation of cell cycle-related proteins by cyclin-dependent kinases (Cdks) is critical for the correct order of cell cycle events. In budding yeast, CDC28 encodes the only Cdk and its association with various cyclins governs the temporal phosphorylation of Cdk substrates. S-phase Cdk substrates are phosphorylated earlier than mitotic Cdk substrates, which ensures the sequential order of DNA synthesis and mitosis. However, it remains unclear whether Cdk substrates are dephosphorylated in temporally distinct windows. Cdc14 is a conserved protein phosphatase responsible for the dephosphorylation of Cdk substrates. In budding yeast, FEAR (Cdc14 early anaphase release) and MEN (mitotic exit network) activate phosphatase Cdc14 by promoting its release from the nucleolus in early and late anaphase, respectively. Here, we show that the sequential Cdc14 release and the distinct degradation timing of different cyclins provides the molecular basis for the differential dephosphorylation windows of S-phase and mitotic cyclin substrates. Our data also indicate that FEAR-induced dephosphorylation of S-phase Cdk substrates facilitates anaphase progression, revealing an extra layer of mitotic regulation. | 18,845,678 |
The PIDDosome mediates delayed death of hippocampal CA1 neurons after transient global cerebral ischemia in rats. | A brief period of global brain ischemia, such as that induced by cardiac arrest or cardiopulmonary bypass surgery, causes cell death in vulnerable hippocampal CA1 pyramidal neurons days after reperfusion. Although numerous factors have been suggested to account for this phenomenon, the mechanisms underlying it are poorly understood. We describe a cell death signal called the PIDDosome, a protein complex of p53-induced protein with a death domain (PIDD), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and procaspase-2. We induced 5 min of transient global cerebral ischemia (tGCI) using bilateral common carotid artery occlusion with hypotension. Western blot analysis showed that expression of twice-cleaved fragment of PIDD (PIDD-CC) increased in the cytosolic fraction of the hippocampal CA1 subregion and preceded procaspase-2 activation after tGCI. Caspase-2 cleaved Bid in brain homogenates. Co-immunoprecipitation and immunofluorescent studies demonstrated that PIDD-CC, RAIDD, and procaspase-2 were co-localized and bound directly, which indicates the formation of the PIDD death domain complex. Furthermore, we tested inhibition of PIDD expression by using small interfering RNA (siRNA) treatment that was initiated 48 h before tGCI. Administration of siRNA against PIDD decreased not only expression of PIDD-CC, but also activation of procaspase-2 and Bid, resulting in a decrease in histological neuronal damage and DNA fragmentation in the hippocampal CA1 subregion after tGCI. These results imply that PIDD plays an important role in procaspase-2 activation and delayed CA1 neuronal death after tGCI. We propose that PIDD is a hypothetical molecular target for therapy against neuronal death after tGCI. | 18,845,684 |
Update on a clinical measure for the assessment of problem solving. | The Rapid Assessment of Problem Solving test (RAPS) is a clinical measure of problem solving based on the 20 Questions Test. This article updates clinicians on the RAPS, addresses questions raised about the test in an earlier article (R. C. Marshall, C. M. Karow, C. Morelli, K. Iden, & J. Dixon, 2003a), and discusses the clinical utility of the RAPS. The RAPS was administered to 373 normal adults. Tests were analyzed to assess the impact of demographic, psychometric, and other factors on performance on the RAPS. To determine the effects of strategy selection on test scores, participants were assigned to novel, category-focused, or mixed strategy groups based on the types of first questions asked. Normal participants exhibited a range of performance levels on the RAPS. Participants in the novel strategy group performed significantly better than the participants in 2 other strategy groups. The RAPS is a clinically useful tool to examine problem solving that is easy to administer and to score. Findings suggest clinicians can use the RAPS with greater confidence than was the case 4 years ago. The RAPS is now part of the public domain and may be used by clinicians to assess clients' problem-solving deficits. | 18,845,695 |
Environmental genomics reveals a single-species ecosystem deep within Earth. | DNA from low-biodiversity fracture water collected at 2.8-kilometer depth in a South African gold mine was sequenced and assembled into a single, complete genome. This bacterium, Candidatus Desulforudis audaxviator, composes >99.9% of the microorganisms inhabiting the fluid phase of this particular fracture. Its genome indicates a motile, sporulating, sulfate-reducing, chemoautotrophic thermophile that can fix its own nitrogen and carbon by using machinery shared with archaea. Candidatus Desulforudis audaxviator is capable of an independent life-style well suited to long-term isolation from the photosphere deep within Earth's crust and offers an example of a natural ecosystem that appears to have its biological component entirely encoded within a single genome. | 18,845,759 |
Ibn al-Nafis, the pulmonary circulation, and the Islamic Golden Age. | Ibn al-Nafis (1213-1288) was an Arab physician who made several important contributions to the early knowledge of the pulmonary circulation. He was the first person to challenge the long-held contention of the Galen School that blood could pass through the cardiac interventricular septum, and in keeping with this he believed that all the blood that reached the left ventricle passed through the lung. He also stated that there must be small communications or pores (manafidh in Arabic) between the pulmonary artery and vein, a prediction that preceded by 400 years the discovery of the pulmonary capillaries by Marcello Malpighi. Ibn al-Nafis and another eminent physiologist of the period, Avicenna (ca. 980-1037), belong to the long period between the enormously influential school of Galen in the 2nd century, and the European scientific Renaissance in the 16th century. This is an epoch often given little attention by physiologists but is known to some historians as the Islamic Golden Age. Its importance is briefly discussed here. | 18,845,773 |
Individualization of transfer function in estimation of central aortic pressure from the peripheral pulse is not required in patients at rest. | Central aortic pressure gives better insight into ventriculo-arterial coupling and better prognosis of cardiovascular complications than peripheral pressures. Therefore transfer functions (TF), reconstructing aortic pressure from peripheral pressures, are of great interest. Generalized TFs (GTF) give useful results, especially in larger study populations, but detailed information on aortic pressure might be improved by individualization of the TF. We found earlier that the time delay, representing the travel time of the pressure wave between measurement site and aorta is the main determinant of the TF. Therefore, we hypothesized that the TF might be individualized (ITF) using this time delay. In a group of 50 patients at rest, aged 28-66 yr (43 men), undergoing diagnostic angiography, ascending aortic pressure was 119 +/- 20/70 +/- 9 mmHg (systolic/diastolic). Brachial pressure, almost simultaneously measured using catheter pullback, was 131 +/- 18/67 +/- 9 mmHg. We obtained brachial-to-aorta ITFs using time delays optimized for the individual and a GTF using averaged delay. With the use of ITFs, reconstructed aortic pressure was 121 +/- 19/69 +/- 9 mmHg and the root mean square error (RMSE), as measure of difference in wave shape, was 4.1 +/- 2.0 mmHg. With the use of the GTF, reconstructed pressure was 122 +/- 19/69 +/- 9 mmHg and RMSE 4.4 +/- 2.0 mmHg. The augmentation index (AI) of the measured aortic pressure was 26 +/- 13%, and with ITF and GTF the AIs were 28 +/- 12% and 30 +/- 11%, respectively. Details of the wave shape were reproduced slightly better with ITF but not significantly, thus individualization of pressure transfer is not effective in resting patients. | 18,845,775 |
A further analysis of why pulmonary venous pressure rises after the onset of LV dysfunction. | Based on a dynamic computational model of the circulation, Burkhoff and Tyberg (Am J Physiol Heart Circ Physiol 265: H1819-H1828, 1993) concluded that the rise in pulmonary venous pressure (Pvp) with left ventricular (LV) dysfunction requires a decrease in vascular capacitance and transfer of unstressed volume to stressed volume (nu). We argue that the values they used for venous resistance (Rvs), venous compliance (Cvs), and nu were too low, and changing these values significantly changes the conclusion. We used a computational model of the circulation that was similar to theirs, but we made Rvs four times higher (0.06 versus 0.015 mmHg.s.ml(-1)), Cvs larger (110 versus 70 ml/mmHg), and nu larger (1,400 versus 750 ml); all other parameters, including those for the heart, were essentially the same. We simulated left ventricular dysfunction by decreasing end-systolic elastance (Eeslv) as they did and examined changes in cardiac output, arterial blood pressure, and Pvp. We then examined the effect of changes in Rvs, heart rate, and nu when Eeslv was depressed with and without pericardial constraint. In contrast to their findings, with our parameters the model predicts that decreasing Eeslv substantially increases Pvp. Furthermore, increasing systemic vascular resistance or decreasing Rvs or heart rate produces large increases in Pvp when Eeslv is reduced. Pericardial constraint limits the changes in Pvp. In conclusion, when Rvs and Cvs are increased, baseline nu must be higher to maintain normal cardiac output. This increased volume can shift between compartments under flow conditions and account for the increase in Pvp with decreased left ventricular function even without recruitment of unstressed volume. | 18,845,783 |
Outcrossing as an explanation of the apparent unconventional genetic behavior of Arabidopsis thaliana hth mutants. | The reappearance of HTH alleles in the offspring of homozygous Arabidopsis hth mutants is not consistent with classical Mendelian genetics. It has been suggested that stored RNA may be used to restore genetic information. However, Peng et al. reported that hth mutants tend to display outcrossing and suggested that outcrossing might provide an alternative explanation for the apparent genetic instability. We have confirmed and extended these results, corroborating that the apparent non-Mendelian behavior of hth mutants can be explained by their susceptibility to outcrossing. | 18,845,842 |
The effect of hydrodynamic flow regimes on the algal bloom in a monomictic reservoir. | The effectiveness of a proposed curtain weir to be installed in the transitional zone of a eutrophic reservoir located in monsoon areas on the control of algal blooms in the lacustrine zone where drinking water withdrawals occur was assessed with various hydrodynamic flow regimes. A two-dimensional hydrodynamic and eutrophication model that can accommodate vertical displacement of the weir following the water surface changes was developed and validated using field data obtained from two distinctive hydrological years; drought (2001) and wet (2004). The model adequately reproduced the temporal and spatial variations of temperature, nutrients and phytoplankton concentrations in the reservoir. The efficacy of the curtain weir method found to be diverse for different hydrological conditions and dependent on the inflow densimetric Froude number (Fr(i)). Algal blooming was considerably mitigated by curtailing the transport of nutrients and algae from riverine zone to lacustrine epilimnion zone during the drought year as long as Fr(i) < 1.0. However, some flood events with Fr(i) > 1.0 transported nutrients and algae built upstream of the weir into the downstream euphotic zone by strong entrainments in 2004. Numerical experiments revealed that the efficiency of the weir on the control of algal blooming becomes marginal if the Fr(i) > 3.0. | 18,845,869 |
Micro-solvent cluster extraction using aqueous mixed solvents of ionic liquid. | Organic compounds (2-naphthol, phenol, 4-chlorophenol, 4-nitrophenol, and 1,3,5-naphthalenetrisulfonic acid) were sufficiently separated from mixtures during flow in a fused silica capillary tube (50 microm in i.d. and 45 cm in length) with an aqueous mixed solvent of an ionic liquid, 1-butyl-3-methylimidazolium chloride (BMIM(+)Cl(-)), without a specific separation column. The method is based on micro-solvent cluster formation in aqueous mixed solvents of ionic liquid and preferential solvation of solvent clusters to analytes. The measurement of large angle X-ray scattering (LAXS) of aqueous mixed solvents with an ionic liquid of tetrafluoroborate (BMIM(+)BF(4)(-)) indicated the formation of micro-solvent clusters of water and ionic liquid in the mixed solvent. A neutral polymer (polyvinylpyrrolidone, PVP) enhanced the separation. Polarized or ionic molecules eluted slowly. The theoretical plate numbers were 6320, 22907, 63645, and 37184 for 2-naphthol, phenol, 4-chlorophenol, and 4-nitrophenol, respectively, under the conditions of 1.0 M of BMIM(+)Cl(-) and 0.1 M of PVP; the flow rate was 1 microL min(-1). The separation mechanism is discussed from the viewpoint of the partition of analytes between micro-solvent clusters of water and organic solvent molecules. | 18,845,880 |
Aggregation of imidazolium ionic liquids in molecular liquids studied by small-angle neutron scattering and NMR. | The aggregation of two imidazolium-based ionic liquids, 1-ethly-3-methylimidazolium chloride (EMI(+)Cl(-)) and EMI(+) bis-(trifluoromethanesulfonyl)amide (EMI(+)TFSA(-)), in molecular liquids, water, methanol, acetonitrile, and benzene, has been studied by using the small-angle neutron scattering (SANS) technique. The SANS results have shown that the heterogeneity of EMI(+)Cl(-)-acetonitrile mixtures is significant at high acetonitrile contents, thus, EMI(+)Cl(-) forms clusters in acetonitrile solutions. On the other hand, it has been revealed that EMI(+)Cl(-) is homogeneously dissolved in water and methanol. EMI(+)TFSA(-) remarkably aggregates in methanol solutions, while the mixtures of EMI(+)TFSA(-) with acetonitrile and benzene are homogeneous. Furthermore, aggregation of EMI(+)Cl(-) and EMI(+)TFSA(-) in acetonitrile and methanol, respectively, has been examined by using (1)H NMR spectroscopy. The mechanism of aggregation of the ionic liquids in the molecular liquids has been discussed on the basis of the properties of cations, anions, and molecular liquids. | 18,845,888 |
Mild electrical stimulation increases ubiquitinated proteins and Hsp72 in A549 cells via attenuation of proteasomal degradation. | To explore the cellular effects of mild electrical stimulation (MES), we treated A549 cells with low-intensity direct current at 5 V applied for 10 min. MES did not induce cell cytotoxicity or the unfolded protein response (UPR). Interestingly, the expression of ubiquitinated proteins and heat shock protein (Hsp) 72 was increased but not that of other Hsps. MES attenuated the degradation of Hsp72, which is a substrate of the proteasome-ubiquitin system. These results, along with the observed increase in expression of ubiquitinated proteins, imply that MES may affect the proteasome system, which regulates the fate of many proteins. | 18,845,908 |
Public health practice vs research: implications for preparedness and disaster research review by State Health Department IRBs. | Under the current US Department of Health and Human Services regulatory and ethical system for research involving human subjects, research is defined in terms of several key concepts: intent, systematic investigation, and generalizability. If an investigator engages in a systematic investigation designed or intended to contribute to generalizable knowledge, then he or she is engaged in research. If that research involves living individuals and the investigator will either interact or intervene with people or obtain their identifiable personal information, then the research must be prospectively reviewed by an institutional review board (IRB), a federally mandated committee that ensures the ethical and regulatory appropriateness of proposed research. In public health institutions, and especially at state departments of health, this definition of research may prove vexing for determining when particular public health activities must be reviewed by IRBs. This article outlines several reasons for such vexation and 2 key responses from major public health stakeholders. In the current climate of public health preparedness initiatives at state health departments for disasters and bioterrorism, how research is defined vis-à-vis public health interventions may add even more confusion to preparedness initiatives and pose difficulties in determining when IRB review and the added protections it affords are appropriate. This article suggests several practical ways to avoid confusion and attempts to strike a balance between the need for expeditious approvals of research-based responses to public health disasters and to ensure proper protections for human subjects at state health departments. It is hoped that these suggestions can assist not only state health departments but also academically based researchers who either collaborate with those departments or whose research will need to be reviewed by their IRBs. | 18,845,930 |
Rapid CD4+ cell decrease after transient cART initiated during primary HIV infection (ANRS PRIMO and SEROCO cohorts). | To modelize the rate of CD4 cell count decline and its determinants after cessation of combination antiretroviral therapy (cART) started during primary HIV infection (PHI) and compare it with never-treated patients. Kinetics of CD4 counts were analyzed on the square root scale by using a mixed-effects model in 170 patients who received cART during PHI from the Primary Infection (PRIMO) cohort and 123 never-treated patients from the Seroconverters (SEROCO) cohort. After cART interruption in the PRIMO cohort, the CD4 cell count fell rapidly during the first 5 months and more slowly thereafter. The timing of treatment initiation had no influence on the rate of CD4 cell decline. In contrast, a larger increase in CD4 cell counts during cART was associated with a steeper decline and a larger loss of CD4 cells after treatment interruption. The mean CD4 cell loss 3 years postinterruption was 383 cells per microliter. In the SEROCO cohort, the CD4 T-cell decline was less steep (3-year CD4 loss 239 cells/microL). As a result, the mean CD4 cell counts were similar (416 cells/microL) 3 years after cART interruption (PRIMO) or after infection (SEROCO). These data question the benefit of a limited course of cART even when initiated within 3 months after PHI diagnosis. | 18,845,951 |
Influences of normobaric hypoxia training on metabolic risk markers in human subjects. | Endurance exercise and hypoxia regulate pathways that are crucial to glucose and lipid metabolism. We hypothesized that training under hypoxia results in similar or even greater metabolic improvement compared with exercise under normoxia at a lower workload. We randomly assigned 20 healthy men to single blind training under hypoxia (FiO2 = 15%) or normoxia (FiO2 = 21%). Subjects trained thrice weekly for 60 min over a 4-wk period at a heart rate measured at 3 mmol x L(-1) lactate during pretraining exercise testing. Before and after the training period, we determined body composition, venous blood parameters, oral glucose tolerance, and blood pressure. Furthermore, we assessed oxygen uptake (VO2), lactate, and respiratory quotient, and heart rate (HR) during incremental exercise testing, both in hypoxia and in normoxia. Training workload was 1.39 +/- 0.2 W x kg(-1) in the hypoxia and 1.67 +/- 0.15 W x kg(-1) in the normoxia group (P< 0.001) with an identical training heart rate in both groups. Exercise capacity improved similarly with both interventions. With hypoxia training, body fat content, triglycerides, HOMA-Index, fasting insulin (P < 0.05), and area under the curve for insulin (P < 0.01) during the oral glucose tolerance test improved more than with the training in normoxia. We did not observe major changes in adipokine measurements. Endurance training in hypoxia over a 4-wk period elicits a similar or even better response in terms of cardiovascular and metabolic risk factors than endurance exercise in normoxia. The fact that workload and, therefore, mechanic strain can be reduced in hypoxia could be particularly beneficial in obese patients and in patients with orthopedic conditions. | 18,845,972 |
No influence of noradrenaline manipulation on acute exercise-induced increase of brain-derived neurotrophic factor. | To examine the influence of a selective noradrenaline reuptake inhibitor (SNRI) on the exercise-induced increase in circulating brain-derived neurotrophic factor (BDNF). In a double-blind, placebo-controlled, crossover design, 11 young, healthy male subjects were treated with either placebo or reboxetine. On each occasion, they performed a 60-min cycling exercise at 55% of their maximal power output (Wmax) followed by a time trial (TT) at 75% of Wmax. HR and ratings of perceived exertion were measured. Blood samples were taken at four time points. An increase in serum BDNF was found after exercise without any influence of drug administration on BDNF levels. Serum BDNF returned to resting levels after 15 min of recovery. Time trial (TT) performance was significantly worse after reboxetine intake. Serum cortisol increased in both trials during and after exercise and was significantly higher in the reboxetine trial. Also, HR was increased with reboxetine intake, probably because of the sympathomimetic effect of SNRI. Midterm memory was significantly impaired after the exercise protocol without difference between reboxetine and placebo trial. The administration of an SNRI has no effect on the exercise-induced increase in BDNF. However, effects were seen on serum cortisol, HR, and memory. Future research should focus on the effect of regular exercise training in combination with several reuptake inhibitors in both healthy and depressed subjects on BDNF and memory. | 18,845,978 |
Pneumonia after implementation of the pneumococcal conjugate vaccine program in the province of Quebec, Canada. | In Canada, a pneumococcal conjugate vaccine was licensed in 2001, and in the province of Quebec, a publicly-funded program was implemented for high-risk children in 2002, using a 4-dose schedule, and for all children in 2004, using a 3-dose schedule. To describe the epidemiology of hospitalized pneumonia in the population aged <5 years. Hospital discharge records with a main diagnosis of pneumonia, pleurisy, or empyema were analyzed regarding monthly frequencies by diagnostic categories, duration of stay, proportion of cases admitted to the intensive care unit, and case fatality. Lobar pneumonia represented 32% of 25,319 all-cause pneumonia admissions during the period April 1997 to March 2006. Beginning in the spring of 2004, there was a marked decrease in the frequency of lobar pneumonia, whereas unspecified pneumonia tended to increase to a lesser extent. Compared with the pre-pneumococcal conjugate vaccine period, admissions for all-causes pneumonia decreased by 13% after program implementation and there was no increase in empyema cases. Results are reassuring as to the effectiveness of the pneumococcal vaccination program in Quebec. | 18,845,982 |
Quantitative PCR assay used to monitor serum Trichosporon asahii DNA concentrations in disseminated trichosporonosis. | A bone marrow transplant recipient with disseminated trichosporonosis was successfully treated with voriconazole. Quantitative PCR assay results for Trichosporon asahii DNA in the sera were well correlated with the patient's clinical course. Based on the in vitro susceptibility test, the organism was susceptible to voriconazole. | 18,845,986 |
Age and grade trends in prostate cancer (1974-2003): a Surveillance, Epidemiology, and End Results Registry analysis. | Age and pathologic grade are 2 critical factors used to guide clinical decisions and comparative outcomes studies in prostate cancer. The objective of this investigation was to use the Surveillance, Epidemiology, and End Results (SEER) registry to examine time trends in age and grade. The SEER public-use registry was queried by year of diagnosis from 1974 to 2003 for age at diagnosis (40-49, 50-59, 60-69, 70-79, and 80+ years) and for pathologic grade [well differentiated (WD), moderately differentiated (MD), and poorly differentiated (PD) disease]. Results were tabulated by 5-year interval; a total of 455,170 patients were included in the analysis. Time-trends analyses were performed for age, for grade, and for age and grade simultaneously, in each case applying a multivariate chi test. Five-year cause specific survival (CSS) rates were also tabulated by age and grade. Overall, there was a nonsignificant (P = 0.68) change in distribution of age at diagnosis. However, a significant (P < 0.001) grade migration took place over the study period, principally from WD to MD disease, and occurred across all age groups. Five-year cause specific survival time trends were similar for all age groups, but WD appeared to converge with MD disease in later years. An overall grade migration has occurred in prostate cancer, primarily observed as a shift from WD to MD disease; this may weaken grade-based prognostic categorizations. This migration occurred independent of patient age, reinforcing that the grade migration is likely due to changes in pathologic interpretation rather than to screening-related changes in disease characteristics. | 18,845,997 |
Apoptosis and cell proliferation: the paradox of salivary glands in Sjögren's disease. | To assess apoptosis and proliferation in salivary glands of patients with primary Sjögren's syndrome. Studies were performed in twenty four minor salivary glands from patients with primary Sjögren's syndrome and an equal number of controls. Apoptosis was studied by immunohistochemistry using monoclonal antibodies anti-Fas FasL and Caspase 3 and apoptotic features by TUNEL. Proliferation was assessed with monoclonal anti-PCNA and anti-Ki67 antibodies. All salivary glands from Sjögren's display apoptotic molecules along the epithelia of salivary ducts and in a smaller amount in acinar tissue. The presence of Caspase 3 Fas FasL was concordant with the expression of apoptosis by TUNEL. Proliferation markers were encountered in inflammatory emigrant cells but not in ductal epithelia nor in acini. Control biopsies poorly expressed apoptotic or proliferation markers. Present data suggests that the ductal epithelial and acinar cells of salivary glands from Sjögren's disease patients exhibit increased apoptosis. Proliferation was mainly observed in infiltrating lymphoid cells. Both events constitute a biological paradox related to the inflammatory process of salivary glands in Sjögren's disease. | 18,846,009 |
Testosterone therapy improves the clinical response to conventional treatment for male patients with metabolic syndrome associated to late onset hypogonadism. | Recently, the clinic characterization of the gonadic male function has been put in tight correlation on the pathogenetic level with the main variables forming the condition of metabolic syndrome (MS); probably the serum testosterone (T) concentration in males is to be considered as an additional parameter completely related to the traditional clinical-metabolic findings. Currently the matter of the substitutive hormonal therapy with androgens is apparently influenced by some important unresolved aspects: 1) who really benefits from the T therapy? 2) are the actual dosage methods of T reliable? 3) which vascular and metabolic targets are to be monitored during the T therapy? In an analytical longitudinal study, carried out 12 months long on 60 men (average age 58 years, range 54-63 years) affected by metabolic syndrome (MS) and combined hypogonadism late onset (LOH), authors have evaluated the clinical response (androgenic asset, non-invasive hospital monitoring of the arterial pressure, lipidic asset study, body composition and the biologic resistance to the insulinic action) after conventional medical therapy (insulin-sensibilizing and anti-hypertensive) and after substitutive hormonal therapy with testosterone (T) by transdermic way. A group of five patients with MS and LOH, not treated, was used as group of control. The group of patients treated with T showed a profile of clinical response better than the group of controls. In conclusion, the seric determination of T is useful to better characterize the dismetabolic patient at the moment of the first level active medical therapy planning on the controls of the main risk factors constituting MS, expressing a potential role of conditioning. | 18,846,023 |
PET imaging in neuroendocrine tumors: current status and future prospects. | Neuroendocrine tumors (NET) are relatively rare diverse group of tumors that possess several unique characteristics and occur most commonly in the gastrointestinal tract. An important feature of these tumors is that they express somatostatin (SST) receptors, and thus can be successfully targeted with specific radiolabeled SST receptor related compounds. This has led to the introduction of multitude of single photon emission computed tomography (SPECT) and positron emission tomography (PET) tracers, which have significantly improved the ability for imaging these neoplastic lesions with high spatial resolution in the abdomen and elsewhere in the body. The introduction of Gallium-68 labeled radiopharmaceuticals as viable PET agents have added a new dimension to the management of patients with NET by providing high quality images compared with planar or SPECT with single photon emitting preparations. (18)F-labeled DOPA has demonstrated impressive results in differentiating between focal and diffuse disease in hyperinsulinism of the newborn which appears to be of crucial clinical benefit and has altered the management of these patients significantly. With regard to other types of NET, the current experience with such agents is relatively limited and therefore prospective studies are required to further define the role of PET in this complicated group of patients. | 18,846,029 |
Age at arrival and risk of obesity among US immigrants. | Although immigrants are a rapidly growing subgroup, little is known about overweight/obesity among the foreign-born in the United States, especially regarding the effect of age at arrival. This study determined whether overweight/obesity prevalence is associated with age at arrival of immigrants to the United States. We analyzed data on 6,421 adult immigrants from the New Immigrant Survey (NIS), a study that is nationally representative of adult immigrants with newly acquired legal permanent residence (LPR). Multiple regression analyses tested the effects of duration of residence and age at arrival on overweight/obesity, defined by BMI of > or = 25 kg/m(2), and self-reported dietary change score. We found the relationship between duration of residence and overweight/obesity prevalence varied by age at arrival (P < 0.001). Immigrants < or = 20-years old at arrival who had resided in the United States > or = 15 years were 11 times (95% confidence interval: 5.33, 22.56) more likely to be overweight/obese than immigrants < 20-years old at arrival who had resided in the United States < or = 1 year. By comparison, there was no difference in overweight/obesity prevalence by duration among immigrants who arrived at >50 years of age. Higher self-reported dietary change is also associated with overweight/obesity. In conclusion, immigrants younger than 20 at arrival in the United States may be at higher risk of overweight/obesity with increasing duration of residence than those who arrive at later ages. Obesity prevention among young US immigrants should be a priority. | 18,846,044 |
hnRNP A1 regulates UV-induced NF-kappaB signalling through destabilization of cIAP1 mRNA. | cIAP1 is an important member of the inhibitor of apoptosis family of proteins and is involved in the regulation of the NF-kappaB-signalling pathway downstream of the TNF receptor. We report here that UV irradiation leads to downregulation of cIAP1 expression because of enhanced cIAP1 mRNA destabilization. An AU-rich element located within the 3' untranslated region of cIAP1 mRNA is sufficient to mediate cIAP1 mRNA instability. Furthermore, we have identified hnRNP A1 as a cIAP1 3'UTR-binding protein. hnRNP A1 is a primarily nuclear protein, but accumulates in the cytoplasm after exposure of cells to UV irradiation. Indeed, we find that hnRNP A1 enhances the destabilization of cIAP1 mRNA during UV irradiation. Moreover, siRNA-mediated knockdown of hnRNP A1 restores cIAP1 levels and prevents UV irradiation-induced activation of the NF-kappaB signal transduction pathway, suggesting that hnRNP A1 is an essential post-transcriptional modulator of cIAP1 expression, and thus cIAP1 activity. | 18,846,111 |
[Seizure exacerbation caused by antiepileptic drugs]. | In certain types of epilepsy, antiepileptic drugs can exacerbate the disease instead of improving it. This review is based on a non-systematic literature search in Medline for the time-period 1990-2007, and our own clinical experience. As a consequence of treatment with antiepileptic drugs, patients with epilepsy may have more frequent and severe seizures of the type they had before, but also new seizure types or patterns, and even series of seizures or status epilepticus. Both old and new antiepileptic drugs may exacerbate seizures, but carbamazepine-induced generalized seizures (such as absence and myoclonic) are best documented. More than one pathophysiological mechanism is probably involved in drug-related exacerbation of seizures, such as sedative and pro-convulsive effects of high serum levels, drug-associated encephalopathy, and a paradoxical pharmacodynamic effect. Accurate epilepsy- and seizure classification is important in the treatment of all types of epilepsy. Atypical absences are sometimes mistaken for complex partial seizures. Such patients may be given drugs with a narrow spectrum such as sodium channel blockers (e.g. carbamazepine, phenytoin, oxcarbazepine) or GABAergic agents (e.g. vigabatrin, tiagabine) with an increased risk of seizure exacerbation. Those at greatest risk of experiencing drug-related seizure exacerbation are learning-disabled patients, children with severe epileptic encephalopathies, those with high seizure frequency and several seizure types, and those using polytherapy. | 18,846,119 |
[Motor symptoms in Parkinson disease]. | Early Parkinson's disease is dominated by a motor syndrome called parkinsonism, but as the disease develops motor complications and non-motor problems may occur as well. This paper describes how to diagnose Parkinson's disease and the various motor complications and gives recommendations on how to treat the symptoms in these patients. The paper builds on international evidence-based publications and the Norwegian guidelines for treatment of Parkinson's disease. Motor symptoms such as tremor at rest, akinesia, rigidity and postural instability are the cardinal signs in Parkinson's disease. After diagnosing a patient with the disease we recommend to start with selegiline as a disease-modifying treatment strategy. When symptoms lead to functional impairment, symptomatic treatment should be started in addition. Dopamine agonists are primarily recommended in younger patients and levodopa in the older ones. When the patients develop motor complications it is important to first thoroughly evaluate the problems to arrive at the best possible treatment strategy. If a sufficient response is not obtained both deep brain stimulation and treatment with continuous delivery of medication should be considered. | 18,846,123 |
[Neuropsychiatric and cognitive symptoms in Parkinson disease]. | A variety of neuropsychiatric symptoms commonly occur in Parkinson's disease. Extensive research the last 10 years has provided new knowledge in the field. This review is based on literature retrieved from a Medline search and own research and clinical experience. Neuropsychiatric symptoms occur in the majority of patients with Parkinson's disease, and are associated with impaired quality of life for patients and relatives, additional deterioration of function and increased use of health resources. Medical and surgical therapies can induce or worsen such symptoms. Cognitive impairment and dementia are among the most common and severe complications to Parkinson's disease. No disease-modifying treatment is available, but rivastigmine was effective in one large randomised trial. Visual hallucinations are common and often persistent, but can be treated with klozapin if reducing the number and dose of antiparkinson agents are not helpful. Depression occurs frequently, usually mild, but there is little evidence of treatment efficacy. Apathy, anxiety and sleep disturbances are additional commonly occurring neuropsychiatric symptoms. Neuropsychiatric symptoms are so frequent in Parkinson's disease that they should be considered an integral part of the disease; it is important that clinicians are aware of these symptoms. | 18,846,124 |
Segment Coupling to a Highly Hindered N-Terminal, Alamethicin-Related alpha-Aminoisobutyric Acid (Aib) Residue. | A model [6 + 5] segment coupling process involving a C-terminal valine hexapeptide acid and a resin-attached pentapeptide amide which N-terminated in a hindered Aib unit was examined using a variety of HOAt-derived coupling reagents. Best results were observed with HAPyU in DCM solvent in which loss of configuration amounted to 5.8%. | 18,846,198 |
Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis. | The cell's cytoplasm is crowded by its various molecular components, resulting in a limited solvent capacity for the allocation of new proteins, thus constraining various cellular processes such as metabolism. Here we study the impact of the limited solvent capacity constraint on the metabolic rate, enzyme activities, and metabolite concentrations using a computational model of Saccharomyces cerevisiae glycolysis as a case study. We show that given the limited solvent capacity constraint, the optimal enzyme activities and the metabolite concentrations necessary to achieve a maximum rate of glycolysis are in agreement with their experimentally measured values. Furthermore, the predicted maximum glycolytic rate determined by the solvent capacity constraint is close to that measured in vivo. These results indicate that the limited solvent capacity is a relevant constraint acting on S. cerevisiae at physiological growth conditions, and that a full kinetic model together with the limited solvent capacity constraint can be used to predict both metabolite concentrations and enzyme activities in vivo. | 18,846,199 |
Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping. | Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505-180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533-182,688 kb) and PSARL (184,386 kb; 95% CI 184,356-184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p<10(-7), p<10(-10), and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial-led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia. | 18,846,214 |
Time to Guide: Evidence for Delayed Attentional Guidance in Contextual Cueing. | Contextual cueing experiments show that, when displays are repeated, reaction times (RTs) to find a target decrease over time even when the observers are not aware of the repetition. Recent evidence suggests that this benefit in standard contextual cueing tasks is not likely to be due to an improvement in attentional guidance (Kunar, Flusberg, Horowitz & Wolfe, 2007). Nevertheless, we ask whether guidance can help participants find the target in a repeated display, if they are given sufficient time to encode the display. In Experiment 1 we increased the display complexity so that it took participants longer to find the target. Here we found a larger effect of guidance than in a condition with shorter RTs. Experiment 2 gave participants prior exposure to the display context. The data again showed that with more time participants could implement guidance to help find the target, provided that there was something in the search stimuli locations to guide attention to. The data suggest that although the benefit in a standard contextual cueing task is unlikely to be a result of guidance, guidance can play a role if it is given time to develop. | 18,846,248 |
Male behavioural maturation rate responds to selection on pollen hoarding in honeybees. | Division of labour in social insect colonies relies on behavioural functional differentiation (specialization) of individuals with similar genomes. However, individual behavioural traits do not evolve independently of each other (behavioural syndromes). A prime example is the suite of behavioural differences in honeybee workers that has evolved in response to bidirectional selection on pollen hoarding of honeybee colonies (pollen-hoarding syndrome). More generally, these differences reflect functional differentiation between nectar and pollen foragers. We demonstrate here that this pollen-hoarding syndrome extends to drones. Similar to what has been shown in workers, drones from the high-pollen-hoarding strain had a higher locomotion activity after emergence, and they initiated flight earlier than did males derived from the low-pollen-hoarding strain, with hybrids intermediate. However, these two behavioural traits were unlinked at the individual level. We also found that social environment (the colony) affects the age at which drones initiate flight. The indirect selection responses of male behaviour suggest that male and worker evolution are not independent and may constrain each other's evolution. Furthermore, we identified three distinct peaks in the probability of flight initiation over the course of the experiment and a decreased phenotypic variability in the 'hybrid' males, contrary to quantitative genetic expectations. | 18,846,249 |
Low-dose-radiation stimulated natural chemical and biological protection against lung cancer. | Research is being conducted world-wide related to chemoprevention of future lung cancer among smokers. The fact that low doses and dose rates of some sparsely ionizing forms of radiation (e.g., x rays, gamma rays, and beta radiation) stimulate transient natural chemical and biological protection against cancer in high-risk individuals is little known. The cancer preventative properties relate to radiation adaptive response (radiation hormesis) and involve stimulated protective biological signaling (a mild stress response). The biological processes associated with the protective signaling are now better understood and include: increased availability of efficient DNA double-strand break repair (p53-related and in competition with normal apoptosis), stimulated auxiliary apoptosis of aberrant cells (presumed p53-independent), and stimulated protective immune functions. This system of low-dose radiation activated natural protection (ANP) requires an individual-specific threshold level of mild stress and when invoked can efficiently prevent the occurrence of cancers as well as other genomic-instability-associated diseases. In this paper, low, essentially harmless doses of gamma rays spread over an extended period are shown via use of a biological-based, hormetic relative risk (HRR) model to be highly efficient in preventing lung cancer induction by alpha radiation from inhaled plutonium. | 18,846,259 |
Infliximab for pediatric Crohn's disease. | The natural history of Crohn's disease (CD) is characterized by recurrent flares combined with periods of inactive disease. The goal of therapy should be to induce and maintain clinical remission, to strive for endoscopic healing of the intestinal mucosa and to improve the quality of life. The nineties have been characterized by the introduction of biological therapies designed to block or neutralize pro-inflammatory cytokines which play a role in the pathogenesis of the disease. Biologic treatment with the anti-human tumor necrosis factor alpha antibody infliximab has dramatically changed the therapeutic approach even in pediatric patients. Numerous studies are available and report the beneficial effect of infliximab in pediatric CD patients with moderate to severe disease, refractory and steroid-dependent patients. The safety profile of infliximab is overall favorable although continued vigilance, especially for the occurrence of infrequent but serious events, including opportunistic infection and lymphomas, remains necessary. | 18,846,272 |
Capecitabine in gastric cancer. | Double and triplet regimens comprising a fluoropyrimidine and a platinum compound, with or without an anthracycline or taxane are accepted standards of care for advanced gastric cancer. Capecitabine, an oral fluoropyrimidine designed to selectively deliver 5-fluorouracil (5-FU) to tumor cells, is safe and effective in combination chemotherapy regimens for advanced gastric cancer, and it is noninferior to 5-FU for survival. As capecitabine is more convenient to administer than infused 5-FU, avoiding the need for central venous access and the associated risk of complications, it is also an accepted alternative to 5-FU within perioperative combination chemotherapy regimens for resectable gastric cancer. | 18,846,273 |
Synthesis of pyrazole substituted methyl pheophorbide-a derivatives and their preliminary in vitro cell viabilities. | The unique ability of chlorophyll derivatives to accumulate in tumorous tissues and to cause a photodynamic effect under laser radiation has been successively used in photodynamic therapy. In this connection, enormous research on modifications of the peripheral substituents in chlorophyll has shown that the presence and position of the substituents in the chlorin derivatives make a remarkable difference in biological activity. As a result, we directed our attention to synthesize methyl pheophorbide-a derivatives, chlorophyll-a derivatives, possessing heterocyclic aromatic substituents or pyrazole moieties on the peripheral positions and to examine preliminary in vitro effects of these new derivatives on A549 cancer cells for PDT. From our experimental results, it was observed that the biological effect induced by photosensitizers on cancer cells may also depend upon the chemical structure of the photosensitizers. | 18,846,294 |
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