title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Children's performance in mental rotation tasks: orientation-free features flatten the slope. | Studies of the development of mental rotation have yielded conflicting results, apparently because different mental rotation tasks draw on different cognitive abilities. Children may compare two stimuli at different orientations without mental rotation if the stimuli contain orientation-free features. Two groups of children (78 6-year-olds and 92 8-year-olds) participated in an experiment investigating development of the ability to mentally rotate and the ability to recognize and use orientation-free features. Children compared two stimuli, one upright and one rotated, and responded as quickly as possible indicating whether the stimuli were the same or different. The stimuli were either two panda bears or two ice-cream cones with three scoops of ice-cream of different colors. The panda bears were either identical or mirror images. The cones were either identical, mirror images, or non-mirror images. Response times increased linearly as a function of the angle of orientation when stimuli were the same and when the stimuli were mirror images. But response times were much less dependent on angle of orientation for non-mirror image stimuli. Children as young as 6 years recognized orientation-free stimulus features and responded without mentally rotating when the task permitted this strategy. | 18,801,129 |
Quality of psoriasis care in Germany--results of the national study PsoHealth 2007. | Many different forms of treatment are available for psoriasis. The German standard is the national AWMF S3 guideline. A national survey on psoriasis care in 2005 indicated deficits in psoriasis care in Germany. Assessment of the health care situation of patients with psoriasis in Germany. Nation-wide cross-sectional study, in 142 dermatological practices and clinics. The following data were documented: a) Doctor Questionnaire: Treatment, illnesses, clinical characteristics and severity (PASI). b) Patient Questionnaire: Quality of life (QoL), patient relevant therapeutic benefits and satisfaction with the quality of the care. A panel of experts developed and analyzed 8 criteria as indicators of the quality of care. Of the 2009 evaluated patients, 11.6% suffered from severe psoriasis (PASI > 20) and 27.4% from moderate psoriasis (PASI 10-20). The average PASI value was 10.1, and the DLQI 7.5. 32.2% of patients had a serious reduction in their QoL (DLQI > 10). The share of patients with preceding systemic therapy was 47.3%, in severe psoriasis 62.1%, while 20.1% of the patients had received inpatient treatment. The average number of days absent from work was 3.4. Compared to 2005, all 8 indicators improved. Significant numbers of psoriasis patients show serious quality of life reductions and high grades of clinical severity. In comparison to 2005, there has been a notable, nation-wide improvement in psoriasis care. | 18,801,145 |
On the origin of trisomy 21 Down syndrome. | Down syndrome, characterized by an extra chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 most often originates from the mother, the incidence increases with maternal age, there may be aberrant maternal chromosome 21 recombination and there is a higher recurrence in young women. In spite of intensive efforts to understand the underlying reason(s) for these characteristics, the origin still remains unknown. We hypothesize that maternal trisomy 21 ovarian mosaicism might provide the major causative factor. We used fluorescence in situ hybridization (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in ovarian cells from eight female foetuses at gestational age 14-22 weeks. All eight phenotypically normal female foetuses were found to be mosaics, containing ovarian cells with an extra chromosome 21. Trisomy 21 occurred with about the same frequency in cells that had entered meiosis as in pre-meiotic and ovarian mesenchymal stroma cells. We suggest that most normal female foetuses are trisomy 21 ovarian mosaics and the maternal age effect is caused by differential selection of these cells during foetal and postnatal development until ovulation. The exceptional occurrence of high-grade ovarian mosaicism may explain why some women have a child with Down syndrome already at young age as well as the associated increased incidence at subsequent conceptions. We also propose that our findings may explain the aberrant maternal recombination patterns previously found by family linkage analysis. | 18,801,168 |
Frequency, factors and costs associated with injection site infections: findings from a national multi-site survey of injecting drug users in England. | Injection site infections among injecting drug users (IDUs) have been associated with serious morbidity and health service costs in North America. This study explores the frequency, factors and costs associated with injection site infections among IDUs in England. Unlinked-anonymous survey during 2003/05 recruiting IDUs from community settings at seven locations across England. Self-reported injecting practice, symptoms of injection site infections (abscess or open wound) and health service utilisation data were collected using a questionnaire, participants also provided dried blood spot samples (tested for markers blood borne virus infections). Cost estimates were obtained by combining questionnaire data with information from national databases and the scientific literature. 36% of the 1,058 participants reported an injection site infection in the last year. Those reporting an injection site infection were more likely to be female and aged over 24, and to have: injected into legs, groin, and hands in last year; injected on 14 or more days during the last four weeks; cleaned needles/syringes for reuse; injected crack-cocaine; antibodies to hepatitis C; and previously received prescribed substitute drug. Two-thirds of those with an injection site infection reported seeking medical advice; half attended an emergency department and three-quarters of these reported hospital admission. Simple conservative estimates of associated healthcare costs range from pound 15.5 million per year to as high as pound 30 million; though if less conservative unit costs assumptions are made the total may be much higher (pound 47 million). The vast majority of these costs are due to hospital admissions and the uncertainty is due to little data on length of hospital stays. Symptoms of injection site infections are common among IDUs in England. The potential costs to the health service are substantial, but these costs need more accurate determination. Better-targeted interventions to support safer injection need to be developed and evaluated. The validity of self-reported symptoms, and the relationship between symptoms, infection severity, and health seeking behaviour require further research. | 18,801,177 |
Lung adenocarcinoma with micropapillary component presenting with metastatic scrotum tumor and cancer-to-cancer metastasis: A case report. | A 54-year-old man was admitted to the hospital presenting with a 3-month history of sclerosing dermal lesion in the external genitalia. A scrotal skin biopsy revealed a poorly-differentiated adenocarcinoma, immunohistochemically positive for cytokeratin 7 (CK7) and for thyroid transcription factor 1 (TTF-1), and negative for CK20. One month after admission, he died of respiratory failure. At autopsy, a consolidating lesion with vague margin was noted in the left lung as well as a well-circumscribed nodule in the right lobe of the thyroid. Histopathologically, pulmonary lesion was adenocarcinoma with a micropapillary component. On the other hand, thyroid tumor was diagnosed as a follicular variant of papillary carcinoma with foci of micropapillary adenocarcinoma. Positive immunohistochemistry for surfactant protein on micoropapillary component was useful to confirm that micropapillary component was of lung adenocarcinoma origin. | 18,801,198 |
Humeral biepicondylar fracture dislocation in a child: A case report and review of the literature. | Humeral biepicondylar fracture dislocation is a very rare injury reported only once in English literature by G R Taylor et al. We report a case of humeral biepicondylar fracture dislocation in a 13-year-old girl with a unique mechanism of injury. A 13-year-old girl presented with trauma elbow. Radiographs showed biepicondylar fracture of humerus with dislocation of elbow. In humeral biepicondylar fracture dislocation, reduction is always unstable. So treatment is open reduction and internal fixation. | 18,801,199 |
Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease. | The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history. Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h2 48% - 70%; P < 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi-point analysis (LOD score 7.42, P < 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (P < 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (P < 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (P < 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis. The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians. | 18,801,202 |
Cognitive performance and quality of life in bipolar disorder. | In patients with bipolar disorder (BD), quality of life (QOL) scores have been largely attributed to mood symptoms. However, impairments in QOL may occur even in euthymia, and differential factors have been put forward as important determinants of QOL. Our study was designed to assess the role of cognitive performance in self-reported QOL in patients with BD. In this cross-sectional study, we examined the relation between cognitive variables and self-reported QOL in 55 bipolar I euthymic patients and 50 healthy subjects. Participants were administered the World Health Organization Quality of Life Assessment--Abbreviated version and a battery of neuropsychological tests. BD patients showed lower scores in all QOL domains as compared with control subjects. Poorer self-reported QOL correlated significantly with worse cognitive performance, especially on tests of executive functioning and verbal abstraction. A linear regression model revealed that all QOL domains were significantly predicted by cognitive variables, with variances ranging from 12% to 37%, and from 24% to 54% when clinical variables were added to the model. Deficits in executive functioning and verbal abstraction were strong predictors of poor self-reported QOL. Our findings suggest that, along with mood stabilization, adequate cognitive functioning is desirable for achieving better QOL. These findings suggest that cognitive rehabilitation may be an important factor for restoring QOL to baseline levels among BD patients. | 18,801,213 |
Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. | Systematic reviews show that repetitive transcranial magnetic stimulation (rTMS) is superior to sham control conditions in patients with major depressive disorder, but the clinical relevance is not clear. None have specifically examined outcomes in patients with treatment-resistant depression (TRD). A systematic review was conducted by identifying published randomized controlled trials of active rTMS, compared with a sham control condition in patients with defined TRD (that is, at least one failed trial). The primary outcome was clinical response as determined from global ratings, or 50% or greater improvement on a rating scale. Other outcomes included remission and standardized mean differences in end point scores. Metaanalysis was conducted for absolute risk differences using random effects models. Sensitivity and subgroup analyses were also conducted to explore heterogeneity and robustness of results. A total of 24 studies (n = 1092 patients) met criteria for quantitative synthesis. Active rTMS was significantly superior to sham conditions in producing clinical response, with a risk difference of 17% and a number-needed-to-treat of 6. The pooled response and remission rates were 25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively. Sensitivity and subgroup analyses did not significantly affect these results. Dropouts and withdrawals owing to adverse events were very low. For patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggest that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD. | 18,801,225 |
Accurate concentration measurements using surface-enhanced Raman and deuterium exchanged dye pairs. | Quantitative applications of surface-enhanced resonance Raman scattering (SERRS) are often limited by the reproducibility of SERRS intensities, given the difficulty of controlling analyte-substrate interactions and the associated local field enhancement. As demonstrated here, SERRS from dye molecules even within the same structural class that compete with similar substrates display distinct spectral intensities that are not proportional to analyte concentrations, which limits their use as internal standardization probes and/or for multiplex analysis. Recently, we demonstrated that isotopic variants of rhodamine 6G (R6G), namely R6G-d0 and R6G-d4, can be used for internal standards in SERRS experiments with a linear optical response from picomolar to micromolar concentrations (of total analytes). Here we extend these results by describing a straightforward method for obtaining isotopomeric pairs of other Raman active dyes by hydrogen-deuterium exchange conditions for substitution at electron rich aromatic heterocycles. Most of the known SERRS active probes can be converted into the corresponding isotopomeric molecule by this exchange method, which significantly expands the scope of the isotopic edited internal standard (IEIS) approach. The relative quantification using IEIS enables accurate, reproducible (residual standard deviation+/-2.2%) concentration measurements over a range of 200 pM to 2 microM. These studies enable easy access to a variety of isotopically substituted Raman active dyes and establish the generality of the methodology for quantitative SERRS measurements. For the first time, three rhodamine 6G isotopomers have been created and show distinct Raman spectra, demonstrating the principle of the approach for application as a multiplex technique in biomolecular detection/quantification. | 18,801,239 |
Potential of far-ultraviolet absorption spectroscopy as a highly sensitive analysis method for aqueous solutions. Part II: monitoring the quality of semiconductor wafer cleaning solutions using attenuated total reflection. | Far-ultraviolet (FUV) spectroscopy combined with attenuated total reflection (ATR) is employed for direct measurement of the concentrations of semiconductor wafer cleaning fluids such as SC-1 (aqueous solution of NH3 and H2O2) and SC-2 (aqueous solution of HCl and H2O2). FUV spectra of these aqueous solutions in the 170-200 nm region are highly sensitive to changes in both hydrogen bonding and hydration. Although ATR measurement results in lower absorptivity compared to transmittance measurement, it is possible to increase absorption with greater evanescent wave penetration depth using a low refractive index internal reflection element (IRE). We adopt quartz as an IRE material. Since the refractive index of quartz becomes lower than that of water in the low energy side of an intense absorption band due to the n-->sigma* transition of water, the quartz IRE yields non-total reflection wavelength regions. However, near 175 nm the effective absorptivity of the tail of water's absorption band can be successfully enlarged, making the FUV-ATR technique suitable for measuring the concentrations of the components in the semiconductor wafer cleaning fluids. In the present study we prepared the same cleaning fluids as those used in actual semiconductor fabrication and measured their FUV-ATR spectra in the 150-300 nm wavelength range. It was found that even with the quartz IRE one can measure FUV-ATR spectra under total reflection conditions at 175 nm or above. We created calibration models for predicting both NH3 and H2O2 in the concentration ranges of 0-10% in SC-1 using multiple linear regression (MLR). The standard deviations of the models were 0.033% and 0.265% for NH3 and H2O2, respectively. The same procedure was repeated under the same conditions for HCl and H2O2 in SC-2, yielding corresponding values of 0.018% for HCl and 0.178% for H2O2. | 18,801,242 |
Multipartite symbioses among fungi, mites, nematodes, and the spruce beetle, Dendroctonus rufipennis. | The spruce beetle, Dendroctonus rufipennis, is an eruptive forest pest of significant economic and ecological importance. D. rufipennis has symbiotic associations with a number of microorganisms, especially the ophiostomatoid fungus Leptographium abietinum. The nature of this interaction is only partially understood. Additionally, mite and nematode associates can mediate bark beetle-fungal interactions, but this has not yet been studied for spruce beetles. In this study, we found eight mite species associated with spruce beetles: Tarsonemus ips, T. endophloeus, Histiogaster arborsignis, Dendrolaelaps quadrisetus, Proctolaelaps hytricoides, Trichouropoda alascae, T. n. sp. nr dalarenaensis, and Urobovella n. sp 767. The most prevalent species was H. arborsignis. In addition, 75% of beetles examined carried nematodes, with six species represented. These included a new species of Parasitorhabditis, Ektaphelenchus obtusus, Bursaphelenchus n. sp. 727, Aphelenchoides n. sp., Panagrolaimus sp., and Mykoletzkya ruminis. H. arborsignis showed strong feeding and oviposition preferences for L. abietinum among four fungal species tested in laboratory assays. Information on our attempts to culture the various nematode species collected from D. rufipennis is also provided. Bursaphelenchus were cultured from D. rufipennis nematangia plated on agar containing L. abietinum but not sterile agar. Thus, L. abietinum plays an important role in these gallery communities, affecting the tree-killing bark beetle, its phoretic mites, and nematodes. These data add to our understanding of bark beetle-microorganism interactions. | 18,801,261 |
Vitamin D deficiency treated by consuming UVB-irradiated mushrooms. | Deficiency of vitamin D is usually caused by dietary deficiency and/or lack of exposure to sunlight in dark skinned individuals living at northern latitudes. Simple vitamin D deficiency is commonly treated by prescribing a vitamin D containing calcium supplement. This report presents a patient who rejected this approach and instead, after researching alternative treatment options independently, opted to self-treat by consuming UVB-irradiated mushrooms. The beneficial effect of this on the patient's plasma biochemical markers is shown. Further research into the beneficial effect of consuming UVB-irradiated mushrooms is required. | 18,801,283 |
Correlation of lipid peroxidation and glutathione levels with severity of systemic lupus erythematosus: a pilot study from single center. | Systemic Lupus Erythematosus (SLE) is a multifactoral chronic autoimmune disease with unidentified etiology. Imbalance of oxidative status is one possible cause of active disease. Plasma malondialdehyde (MDA) and plasma glutathione (GSH) level have been used as a determinate of oxidative status. Limited data has examined these 2 parameters by severity of SLE. We determined whether there was an association between plasma MDA and plasma GSH level with the severity of SLE. Forty four SLE patients (2 Men and 42 Women) and twenty healthy volunteers (3 Men, 17 women) participated in this study. SLE participants were classified by the severity of disease (mild, moderate or severe). The plasma MDA and plasma Glutathione levels were measured. The correlation of plasma MDA and plasma GSH levels with the severity of SLE disease were determined. Plasma MDA levels with different severity of SLE (mild, moderate, and severe of SLE patients) were not significantly different from those of the control group (p=1.0). Plasma GSH levels were significantly lower in the moderate and severe SLE groups than the control group (p=0.001). In addition, a significant correlation between plasma GSH and severity of SLE was observed. (Pearson correlation coefficient = -0.428, p<0.001). The relationship could be described by the equation GSH level (microM) = (-7.624) SLEDAI score +545.90. A significant correlation between plasma GSH and SLE severity exists that may aid evaluation of the disease severity and usefulness of the treatment of SLE. | 18,801,305 |
Emergence of power laws in the pharmacokinetics of paclitaxel due to competing saturable processes. | This study presents the results of power law analysis applied to the pharmacokinetics of paclitaxel. Emphasis is placed on the role that the power exponent can play in the investigation and quantification of nonlinear pharmacokinetics and the elucidation of the underlying physiological processes. Forty-one sets of concentration-time data were inferred from 20 published clinical trial studies, and 8 sets of area-under-the-curve (AUC) and maximum concentration (Cmax) values as a function of dose were collected. Both types of data were tested for a power law relationship using least squares regression analysis. Thirty-nine of the concentration-time curves were found to exhibit power law tails, and two dominant fractional exponents emerged. Short infusion times led to asymptotic tails with a single power exponent of - 1.57 +/- 0.14, while long infusion times resulted in steeper tails characterized by roughly twice the exponent. The curves following intermediate infusion times were characterized by two consecutive power laws; an initial short slope with the larger alpha value was followed by a crossover to a long-time tail characterized by the smaller Beta exponent. The AUC and Cmax parameters exhibited a power law dependence on the dose, with fractional power exponents that agreed with each other and with the exponent characterizing the shallow decline. Computer simulations revealed that a two- or three-compartment model with both saturable distribution and saturable elimination can produce the observed behaviour. Analogous linear models did not provide good fits over the range of values collected empirically. Furthermore, there is preliminary evidence that the nonlinear dose-dependence is correlated with the power law tails. Assessment of data from published clinical trials suggests that power laws accurately describe the concentration-time curves and nonlinear dose-dependence of paclitaxel, and the power exponents provide new\ insights into the underlying drug mechanisms. The interplay between two saturable processes can produce a wide range of behaviour, including concentration-time curves with exponential, power law, and dual power law tails. | 18,801,309 |
In vivo activity of perifosine against Leishmania amazonensis. | Miltefosine has been established as the first oral administration drug against cutaneous and visceral leishmaniasis. Other alkyl-phospholipids such as edelfosine have been tested against Leishmania showing an in vitro antiparasitic activity. Perifosine in vitro activity has been previously demonstrated against different Leishmania species including Leishmania amazonensis. In this study edelfosine and perifosine were orally administered to BALB/c mice at doses of 1 and 2.5 mg/kg/day during 28 days and 5 mg/kg/day during 14 days, starting the treatment 2 weeks after the first treatment scheme. Lesion sizes and parasitic burden as well as viability were determined in order to establish the treatment effectiveness. An assay to compare miltefosine at standard dose of 2.5 mg/kg/day during 28 days to an in vivo treatment with perifosine at the most effective treatment scheme observed in this study 5 mg/kg/day during 14 days, was also developed. Perifosine showed the higher activity in the in vivo assay and is showing as a new possibility within the alkyl-phospholipids group for the treatment against cutaneous leishmaniasis caused by L. amazonensis. | 18,801,328 |
Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1. | Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The present study investigated whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9C2 through microRNA regulated insulin-like growth factor (IGF-1) signaling pathway. Our data showed that H9C2 cells exposed to high glucose have increased miR-1 expression level, decreased mitochondrial membrane potential, increased cytochrome-c release, and increased apoptosis. Glucose induced mitochondrial dysfunction, cytochrome-c release and apoptosis was blocked by IGF-1. Using prediction algorithms, we identified 3'-untranslated regions of IGF-1 gene are the target of miR-1. miR-1 mimics, but not mutant miR-1, blocked the capacity of IGF-1 to prevent glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis. In conclusion, our data demonstrate that IGF-1 inhibits glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis and IGF-1's effect is regulated by miR-1. | 18,801,338 |
Ferroplasma acidarmanus RPA2 facilitates efficient unwinding of forked DNA substrates by monomers of FacXPD helicase. | The strand-separation activity that is important for many cellular DNA processing machineries is provided by DNA helicases. In order to understand the physiological properties of a helicase acting in the context of its macromolecular machinery, it is imperative to identify the proteins that interact with the enzyme and to analyze how these proteins affect its helicase activities. The archaeal Rad3 helicase XPD (xeroderma pigmentosum group D protein) from Ferroplasma acidarmanus (FacXPD) is a superfamily II 5'-->3' DNA helicase. Similar to its mammalian homolog working as an integral part of the transcription factor IIH complex, FacXPD may play an important role in nucleotide excision repair (NER) and transcription initiation. Interaction between FacXPD and other archaeal NER proteins likely modulates their respective activities. Replication protein A (RPA), a single-stranded DNA (ssDNA)-binding protein, is one of the NER proteins that functionally interact with the human transcription factor IIH complex. There are two RPA proteins in F. acidarmanus: FacRPA1, a homodimer of two monomers consisting of two oligonucleotide/oligosaccharide binding folds, and FacRPA2, a monomer containing a single oligonucleotide/oligosaccharide binding fold. In this study, we analyzed the effect of these ssDNA-binding proteins on FacXPD helicase activity. We found that FacRPA2 stimulates DNA unwinding by FacXPD helicase through a novel mechanism by providing a helix-destabilizing function. In contrast, FacRPA1 fails to stimulate helicase activity to the same extent as FacRPA2 and competes with FacXPD for binding to the ssDNA-double-stranded DNA junction. We conclude that the FacRPA2-coated fork is a preferred and likely physiological substrate that a monomer of FacXPD can unwind with a processivity sufficient for expansion of the NER or transcription bubble. We also suggest that duplex melting by a cognate ssDNA-binding protein coordinated with translocation by a helicase may represent a common strategy for duplex unwinding by the Rad3 family of helicases. | 18,801,373 |
A critical band of phase alignment for discrimination but not recognition of human faces. | We investigated the processes underlying the discrimination and recognition of human faces as a function of spatial phase alignment to assess whether face processing can be understood in terms of the amplitude spectrum alone. Specifically, we varied the amount of aligned Fourier phase in different regions of the face frequency spectrum and argue that the properties of the underlying neural processes are best understood in terms of the number of phase alignments as opposed to octave bandwidths. Additionally, we observed performance differences for face discrimination tasks compared to face recognition tasks. For face recognition, our results show that a narrower range of phase alignment is needed for face frequencies near 9cpf when compared to 3 and 27cpf, thereby supporting the notion of a critical frequency for face recognition. However, for face discrimination where participants were required to discriminate between an average face and different unique faces along a face morph continuum, performance depended on a fixed signal-to-noise ratio of phase alignment within a contiguous range of face frequencies (termed critical band of phase alignments), regardless of the central face frequency of that range within the face frequency spectrum when compared to non-phase randomized control thresholds. | 18,801,383 |
Hyperthermia amplifies brain cytokine and reactive oxygen species response in a model of perinatal inflammation. | Chorioamnionitis, a perinatal infection of the fetal membranes, and maternal fever, which often accompanies infection are both risk factors for cerebral palsy (CP). Inflammation is a typical reaction to infection. Thus the aim of this study was to determine if hyperthermia alters newborn rat brain inflammatory response and oxidant stress after a maternal rat lipopolysaccaharide (LPS) injection. Since chorioamnionitis can predispose the fetus to perinatal hypoxia, we also explored the interaction with postnatal hypoxia. Exposure of newborn pups to brief hypoxia alone significantly increased brain tumor necrosis factor-alpha (TNF-alpha) and slightly increased levels of nitrite/nitrate. When maternal LPS was combined with postnatal hypoxia, the levels of TNF-alpha in were further increased when compared with hypoxia alone. Exposure of newborn pups to hyperthermia at 39 degrees C following maternal LPS and hypoxia caused yet more significant increases in brain TNF-alpha, nitrite/nitrate, and MDA/4-HAD compared to that under normal temperature conditions. This study supports the hypothesis that fever is a significant modifier of brain inflammatory response in developing brain particularly in a setting of hypoxia. | 18,801,411 |
Neuromuscular synaptic function in mice lacking major subsets of gangliosides. | Gangliosides are a family of sialylated glycosphingolipids enriched in the outer leaflet of neuronal membranes, in particular at synapses. Therefore, they have been hypothesized to play a functional role in synaptic transmission. We have measured in detail the electrophysiological parameters of synaptic transmission at the neuromuscular junction (NMJ) ex vivo of a GD3-synthase knockout mouse, expressing only the O- and a-series gangliosides, as well as of a GM2/GD2-synthase*GD3-synthase double-knockout (dKO) mouse, lacking all gangliosides except GM3. No major synaptic deficits were found in either null-mutant. However, some extra degree of rundown of acetylcholine release at high intensity use was present at the dKO NMJ and a temperature-specific increase in acetylcholine release at 35 degrees C was observed in GD3-synthase knockout NMJs, compared with wild-type. These results indicate that synaptic transmission at the NMJ is not crucially dependent on the particular presence of most ganglioside family members and remains largely intact in the sole presence of GM3 ganglioside. Rather, presynaptic gangliosides appear to play a modulating role in temperature- and use-dependent fine-tuning of transmitter output. | 18,801,416 |
Similar compounds searching system by using the gene expression microarray database. | Numbers of microarrays have been examined and several public and commercial databases have been developed. However, it is not easy to compare in-house microarray data with those in a database because of insufficient reproducibility due to differences in the experimental conditions. As one of the approach to use these databases, we developed the similar compounds searching system (SCSS) on a toxicogenomics database. The datasets of 55 compounds administered to rats in the Toxicogenomics Project (TGP) database in Japan were used in this study. Using the fold-change ranking method developed by Lamb et al. [Lamb, J., Crawford, E.D., Peck, D., Modell, J.W., Blat, I.C., Wrobel, M.J., Lerner, J., Brunet, J.P., Subramanian, A., Ross, K.N., Reich, M., Hieronymus, H., Wei, G., Armstrong, S.A., Haggarty, S.J., Clemons, P.A., Wei, R., Carr, S.A., Lander, E.S., Golub, T.R., 2006. The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929-1935] and criteria called hit ratio, the system let us compare in-house microarray data and those in the database. In-house generated data for clofibrate, phenobarbital, and a proprietary compound were tested to evaluate the performance of the SCSS method. Phenobarbital and clofibrate, which were included in the TGP database, scored highest by the SCSS method. Other high scoring compounds had effects similar to either phenobarbital (a cytochrome P450s inducer) or clofibrate (a peroxisome proliferator). Some of high scoring compounds identified using the proprietary compound-administered rats have been known to cause similar toxicological changes in different species. Our results suggest that the SCSS method could be used in drug discovery and development. Moreover, this method may be a powerful tool to understand the mechanisms by which biological systems respond to various chemical compounds and may also predict adverse effects of new compounds. | 18,801,419 |
Molecular diversity and association mapping of fiber quality traits in exotic G. hirsutum L. germplasm. | The narrow genetic base of cultivated cotton germplasm is hindering the cotton productivity worldwide. Although potential genetic diversity exists in Gossypium genus, it is largely 'underutilized' due to photoperiodism and the lack of innovative tools to overcome such challenges. The application of linkage disequilibrium (LD)-based association mapping is an alternative powerful molecular tool to dissect and exploit the natural genetic diversity conserved within cotton germplasm collections, greatly accelerating still 'lagging' cotton marker-assisted selection (MAS) programs. However, the extent of genome-wide linkage disequilibrium (LD) has not been determined in cotton. We report the extent of genome-wide LD and association mapping of fiber quality traits by using a 95 core set of microsatellite markers in a total of 285 exotic Gossypium hirsutum accessions, comprising of 208 landrace stocks and 77 photoperiodic variety accessions. We demonstrated the existence of useful genetic diversity within exotic cotton germplasm. In this germplasm set, 11-12% of SSR loci pairs revealed a significant LD. At the significance threshold (r(2)>/=0.1), a genome-wide average of LD declines within the genetic distance at <10 cM in the landrace stocks germplasm and >30 cM in variety germplasm. Genome wide LD at r(2)>/=0.2 was reduced on average to approximately 1-2 cM in the landrace stock germplasm and 6-8 cM in variety germplasm, providing evidence of the potential for association mapping of agronomically important traits in cotton. We observed significant population structure and relatedness in assayed germplasm. Consequently, the application of the mixed liner model (MLM), considering both kinship (K) and population structure (Q) detected between 6% and 13% of SSR markers associated with the main fiber quality traits in cotton. Our results highlight for the first time the feasibility and potential of association mapping, with consideration of the population structure and stratification existing in cotton germplasm resources. The number of SSR markers associated with fiber quality traits in diverse cotton germplasm, which broadly covered many historical meiotic events, should be useful to effectively exploit potentially new genetic variation by using MAS programs. | 18,801,424 |
Effect of dietary ascorbic acid on growth and non-specific immune responses of tiger puffer, Takifugu rubripes. | We report nutritional physiology and non-specific immune responses of ascorbic acid (AA) in puffer fish for the first time. This study aimed to examine the essentiality and requirements of AA in diets for the tiger puffer, Takifugu rubripes based on growth performance, liver AA and bone collagen concentration, and non-specific immune responses. Five casein-gelatin based semi-purified diets were formulated to contain five graded levels of l-ascorbyl-2-monophosphate at 0, 40, 80, 160 and 700mg/kg (designated as AMP0, AMP40, AMP80, AMP160 and AMP700, respectively) and fed to triplicate groups of fish. After 10weeks of feeding trial, growth performances of fish (initial body weight, 35g) fed the AMP0 were significantly lower compared to that of fish fed diets supplemented with AMP. The fish fed the AMP0 diet also exhibited significantly lower hematocrit, condition factor and hepatosomatic index compared to the fish fed diets supplemented with AMP. Phagocytic activity (NBT assay) was significantly lower in fish fed the AMP0 diet than in fish fed the AMP containing diets. Plasma lysozyme activity of fish fed the AMP80 and AMP160 was significantly higher than that of fish fed the AMP0. Dietary supplementation of AMP significantly increased the liver superoxide dismutase in the fish. Myeloperoxidase activity of fish fed the AMP0 was significantly lower compared to that of fish fed the AMP containing diets. Bone collagen level tended to increase numerically and total AA concentration in liver of fish was significantly increased in a dose dependent manner by the supplementation of AMP. Therefore, tiger puffer requires exogenous ascorbic acid and the optimum dietary level could be 29mg AA/kg diet for normal growth and physiology. Dietary AA concentration over 82mg/kg could be required to enhance non-specific immune responses of the fish. However, it does not seem that the fish needs an overdose of dietary AA (>160mg/kg) for better non-specific immune responses. | 18,801,440 |
Dissociable neural mechanisms for determining the perceived heaviness of objects and the predicted weight of objects during lifting: an fMRI investigation of the size-weight illusion. | In size-weight (SW) illusions, people learn to scale their fingertip forces for lifting small and big objects of equal weight even though they fail to learn perceptually that both objects have the same weight. The question then arises as to what the separate neural mechanisms are for determining the perceived heaviness of objects and the predicted weight of these objects during lifting. To answer this question, we used fMRI to first identify areas that code for the size, weight, and density of objects using an adaptation paradigm. We then contrasted BOLD in the SW illusion condition in which subjects falsely perceived the smaller of two equally weighted objects as heavier versus a condition in which size and weight did not differ between objects. Sensory areas in the parietal and temporal cortex adapted to the size of objects and the primary motor area (M1) contralateral to the lifting hand adapted to the weight of objects. The ventral premotor area (PMv), which did not adapt to either the size or the weight of objects, adapted instead to the density of objects, and responded more when subjects falsely perceived differences in weight between objects in the SW illusion condition. Taken together, we conclude that the real-world properties of objects, such as size and weight, are computed by sensory areas and by M1 respectively, whereas the perceived heaviness of objects, presumably based on their apparent density, is computed by PMv, a higher-order area well placed to integrate sensory information about the size of objects and the weight of objects. | 18,801,445 |
Phylogeny and biogeography of the family Salamandridae (Amphibia: Caudata) inferred from complete mitochondrial genomes. | Phylogenetic relationships of members of the salamander family Salamandridae were examined using complete mitochondrial genomes collected from 42 species representing all 20 salamandrid genera and five outgroup taxa. Weighted maximum parsimony, partitioned maximum likelihood, and partitioned Bayesian approaches all produce an identical, well-resolved phylogeny; most branches are strongly supported with greater than 90% bootstrap values and 1.0 Bayesian posterior probabilities. Our results support recent taxonomic changes in finding the traditional genera Mertensiella, Euproctus, and Triturus to be non-monophyletic species assemblages. We successfully resolved the current polytomy at the base of the salamandrid tree: the Italian newt genus Salamandrina is sister to all remaining salamandrids. Beyond Salamandrina, a clade comprising all remaining newts is separated from a clade containing the true salamanders. Among these newts, the branching orders of well-supported clades are: primitive newts (Echinotriton, Pleurodeles, and Tylototriton), New World newts (Notophthalmus-Taricha), Corsica-Sardinia newts (Euproctus), and modern European newts (Calotriton, Lissotriton, Mesotriton, Neurergus, Ommatotriton, and Triturus) plus modern Asian newts (Cynops, Pachytriton, and Paramesotriton).Two alternative sets of calibration points and two Bayesian dating methods (BEAST and MultiDivTime) were used to estimate timescales for salamandrid evolution. The estimation difference by dating methods is slight and we propose two sets of timescales based on different calibration choices. The two timescales suggest that the initial diversification of extant salamandrids took place in Europe about 97 or 69Ma. North American salamandrids were derived from their European ancestors by dispersal through North Atlantic Land Bridges in the Late Cretaceous ( approximately 69Ma) or Middle Eocene ( approximately 43Ma). Ancestors of Asian salamandrids most probably dispersed to the eastern Asia from Europe, after withdrawal of the Turgai Sea ( approximately 29Ma). | 18,801,447 |
Binding to protein surfaces by supramolecular multivalent scaffolds. | Multivalency plays a pivotal role in biological recognition, particularly at protein-protein and protein-carbohydrate interaction sites. Scaffolds of diverse structure, flexibility, and valency are gaining increasing biomedical importance in the development of artificial multivalent ligands for these interfaces. Relevant examples range from small C(4) symmetric calix[4]arenes and porphyrin ligands, which may achieve nanomolar affinity for protein surfaces of pharmaceutical interest, to large-sized dendrimers that provide promising adherence-inhibition for toxins and other relevant lectins. In addition, highly flexible supramolecular platforms like rotaxanes and polymers have been proposed as challenging alternatives to more rigid designs. Finally, nanoparticles are being exploited for this aim as they present important advantages from the biological and synthetic points of view. | 18,801,458 |
Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. | Major depressive disorder (MDD) occurs in a subset of patients receiving interferon-alpha treatment, although many are resilient to this side effect. Genetic differences in the serotonin reuptake transporter promoter (5-HTTLPR) may interact with the inflammatory system and influence depression risk. A cohort of 71 nondepressed hepatitis C patients about to receive interferon-alpha was prospectively followed, employing a diagnostic structured clinical interview (Structured Clinical Interview for DSM-IV Axis I Disorders [SCID-I]) and self-report questionnaires. Patients were genotyped for the 5-HTTLPR (L(G), L(A), and S) and the variable number of tandem repeats (VNTR) polymorphism in the second intron. Kaplan-Meier analyses were used to compare major depression incidence. Genotype effects on sleep quality (Pittsburgh Sleep Quality Index) and Beck Depression Inventory (BDI) were assessed using mixed-effect repeated-measure analyses. The L(A) allele was associated with a decreased rate of developing MDD (Mantel-Cox log rank test p < .05) with the L(A)/L(A) genotype being the most resilient. This genotype was also associated with better sleep quality [F(61.2,2) = 3.3, p < .05]. The ability of baseline sleep quality to predict depression incidence disappeared when also including genotype in the model. Conversely, the relationship of neuroticism with depression incidence (B = .07, SE = .02, p < .005) was not mitigated when including genotype. Using a prospective design, 5-HTTLPR is associated with MDD incidence during interferon-alpha treatment. Preliminary evidence that this effect could be mediated by effects on sleep quality was observed. These findings provide support for a possible interaction between inflammatory cytokine (interferon-alpha) exposure and 5-HTTLPR variability in MDD. | 18,801,474 |
Application and limitations of the methyl imidate protection strategy of N-acetylglucosamine for glycosylations at O-4: synthesis of Lewis A and Lewis X trisaccharide analogues. | We describe here the synthesis of the allyl Le(a) trisaccharide antigen as well as that of an analogue of the Le(x) trisaccharide antigen, in which the galactose residue has been replaced by a glucose unit. Although successful fucosylations at O-4 of N-acetylglucosamine acceptors have been reported using perbenzylated thioethyl fucosyl donors under MeOTf activation, such conditions led in our case to the conversion of our acceptor to the corresponding alkyl imidates. Indeed, in this synthesis of the Le(a) analogue, we demonstrate that the temporary protection of the N-acetyl group as a methyl imidate is advantageous to fucosylate at O-4. In contrast, we report here that glucosylation at O-4 of an N-acetylglucosamine monosaccharide acceptor using the alpha-trichloroacetimidate of peracetylated glucopyranose as a donor proceeded in better yields under activation with excess BF(3) x OEt(2) than that of the corresponding methyl imidate. Therefore, we conclude that activation of thioglycoside donors by MeOTf to glycosylate at O-4 of a glucosamine acceptor is best accomplished following the temporary protection of the N-acetyl group as a methyl imidate, especially when the donors are highly reactive and prone to degradation. In contrast, if donor and acceptor can withstand multiple equivalents of BF(3) x OEt(2), glycosylations at O-4 of a glucosamine acceptor with a trichloroacetimidate donor does not benefit from the temporary protection of the N-acetyl group as a methyl imidate. | 18,801,477 |
Practical solvent system selection for counter-current separation of pharmaceutical compounds. | Counter-current chromatography (CCC) is a technique that shows a lot of potential for large scale purification. Its usefulness in a "research and development" pharmaceutical environment has been investigated, and the conclusions are shown in this article. The use of CCC requires the development of an appropriate solvent system (a parameter of critical importance), a process which can be tedious. This article presents a novel strategy, combining a statistical approach and fast HPLC to generate a three-dimensional partition coefficient map and rapidly predict an optimal solvent system. This screen is performed in half a day and involves 9 experiments per solvent mixture. Test separations were performed using that screen to ensure the validity of the method. | 18,801,491 |
How to use an article about therapy. | Most surgical interventions have inherent benefits and associated risks. Before implementing a new therapy we should ascertain the benefits and risks of the therapy and assure ourselves that the resources consumed in the intervention will not be exorbitant. We suggest a 3-step approach to using an article from the urological literature to guide patient care. We recommend asking whether the study can provide valid results, reviewing the results and considering how the results can be applied to patient care. Key methodological characteristics that have an impact on the validity of a surgical trial include randomization, allocation concealment, stratification, blinding, completeness of followup and intent to treat analysis. To the extent that the quality is poor inferences from this study are weakened. However, if its quality is acceptable, one must determine the range within which the true treatment effect lies (95% CI). One must then consider whether this result can be generalized to a patient and whether the investigators have provided information about all clinically important outcomes. It is then necessary to compare the relative benefits of the intervention with its risks. If one perceives that the benefits outweigh the risks, the intervention may be of use to the patient. Given the time constraints of busy urological practices and training programs, applying this analysis to every relevant article would be challenging. However, the basics of this process are essentially what we all do hundreds of times each week when treating patients. Making this process explicit with guidelines to assess the strength of the available evidence will serve to improve patient care. It will also allow us to defend therapeutic interventions based on available evidence and not on anecdote. | 18,801,503 |
Western Equine Encephalitis submergence: lack of evidence for a decline in virus virulence. | The incidence of Western Equine Encephalitis (WEE) in humans and equids peaked during the mid-20th century and has declined to fewer than 1-2 human cases annually during the past 20 years. Using the mouse model, changes in WEE virus (WEEV) virulence were investigated as a potential explanation for the decline in the number of cases. Evaluation of 10 WEEV strains representing a variety of isolation locations, hosts, and all decades from the 1940's to the 1990's yielded no evidence of a decline in virulence. These results suggest that ecological factors affecting human and equine exposure should be investigated to explain the decline in WEE. | 18,801,549 |
Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques. | Angiotensin converting enzyme 2 (ACE2) is the receptor that severe acute respiratory syndrome coronavirus (SARS-CoV) utilizes for target cell entry and, therefore, plays an important role in SARS pathogenesis. Since Chinese rhesus (rh) macaques do not usually develop SARS after SARS-CoV infection, it has been suggested that rh-ACE2 probably does not support viral entry efficiently. To determine the role of rh-ACE2 in early lung pathogenesis in vivo, we studied eleven Chinese rhesus monkeys experimentally infected with a pathogenic SARS-CoV(PUMC01) strain. Rh-ACE2 genes were amplified from all animals by reverse transcription polymerase chain reaction, and their function was studied in vitro using a pseudovirus entry assay. Many natural non-synonymous (NS) changes were found in rh-ACE2 genes. Compared to human (hu) ACE2, thirty-eight consensus NS changes were found in rh-ACE2. Since these changes do not interact with the receptor binding domain of SARS-CoV, rh-ACE2 in general is as effective as human homolog in supporting viral entry. Rh-ACE2, however, is more polymorphic than hu-ACE2. Additional sporadic NS substitutions in clone Rh11-7 reduced the level of rh-ACE2 protein expression and did not support viral entry effectively. Further mutagenesis analysis showed that a natural mutation Y217N dramatically alters ACE2 expression and entry efficiency. Moreover, introduction of the Y217N mutation into hu-ACE2 caused the down-regulation of expression and reduced viral entry efficiency. These results indicate that the Y217N mutation plays a role in modulating SARS-CoV infection. Our results provide insights for understanding the role of rh-ACE2 in SARS lung pathogenesis in a non-human primate model. | 18,801,550 |
Temperature-dependent production of pseudoinfectious dengue reporter virus particles by complementation. | Dengue virus (DENV) is a mosquito-borne flavivirus responsible for 50 to 100 million human infections each year, highlighting the need for a safe and effective vaccine. In this study, we describe the production of pseudoinfectious DENV reporter virus particles (RVPs) using two different genetic complementation approaches, including the creation of cell lines that release reporter viruses in an inducible fashion. In contrast to studies with West Nile virus (WNV), production of infectious DENV RVPs was temperature-dependent; the yield of infectious DENV RVPs at 37 degrees C is significantly reduced in comparison to experiments conducted at lower temperatures or with WNV. This reflects both a significant reduction in the rate of infectious DENV RVP release over time, and the more rapid decay of infectious DENV RVPs at 37 degrees C. Optimized production approaches allow the production of DENV RVPs with titers suitable for the study of DENV entry, assembly, and the analysis of the humoral immune response of infected and vaccinated individuals. | 18,801,552 |
The accuracy and clinical application of predictive models for primary open-angle glaucoma in ocular hypertensive individuals. | This report compares the accuracy of 3 prediction models for the development of primary open-angle glaucoma (POAG). The models differ primarily in their handling of these eye-specific variables: intraocular pressure (IOP), central corneal thickness (CCT), vertical cup-to-disc ratio (VCD), and visual field pattern standard deviation (PSD). The "means" model includes age and the means of right and left eyes; the "means plus asymmetry" model includes age, the means of right and left eyes as well as the absolute difference between eyes for eye-specific variables; and the "worse" eye model includes age and values from the eye at higher risk for developing POAG. This report uses data from the observation group of the Ocular Hypertension Treatment Study (OHTS) and the placebo group of the European Glaucoma Prevention Study (EGPS) who have complete data on both eyes at baseline. Performance of the prediction models is assessed using the c-statistic, calibration chi-square, and Pearson correlation coefficient. The OHTS observation group (n = 717; 6.7 years median follow-up) and the EGPS placebo group (n = 324; 4.9 years median follow-up). Baseline data included demographic characteristics, medical history, ocular examination, visual fields, and optic disc photographs. Development of reproducible visual field abnormality or optic disc deterioration as determined by masked readers and attributed to POAG by a masked end point committee. Baseline factors that were statistically significant in all predictive models were age, IOP, CCT, VCD, and PSD. Also, statistically significant were baseline asymmetry in IOP and asymmetry in VCD. The c-statistics for the "means" model, "means plus asymmetry" model, and "worse" eye model were 0.74, 0.77, and 0.75, respectively. The calibration chi-square values were 7.32, 11.19, and 1.81, respectively. Correlation coefficients between risk estimates calculated by different models ranged from 0.94 to 0.98. The high agreement between the risk estimates from 3 different predictive models for the development of POAG suggests little difference in their statistical or clinical performance. The predictive model that uses the means of both eyes for eye-specific variables is the simplest to use and the most robust to measurement variability and error. | 18,801,578 |
Alteration of frontal EEG asymmetry during tryptophan depletion predicts future depression. | Tryptophan depletion (TD) reduces brain serotonin and may induce acute depressive symptomatology, especially among those with a history of Major Depression. Depressive response to TD among euthymic patients with a history of depression also predicts future depression. Better prediction might result by assessing a putative endophenotype for depressive risk, frontal electroencephalographic (EEG) asymmetry, in the context of TD. Nine euthymic history-positive participants and nine controls were administered TD. Symptomatic and EEG frontal asymmetry data were collected for 6 h following TD, and clinical status was followed for the next 12 months. The magnitude of TD-induced change in frontal EEG asymmetry significantly predicted the development of depression during the ensuing six to twelve months, and with greater sensitivity than symptomatic response. The results are tempered by the small sample size. Despite the limited sample size, these preliminary results suggest that TD-induced changes in frontal EEG asymmetry may provide a more sensitive indicator of risk for imminent depression than symptomatic response to TD. | 18,801,582 |
Kinetic study of the degradation of the insecticide pymetrozine in a vegetable-field ecosystem. | The disappearance kinetics of pymetrozine was studied in a broccoli-field ecosystem, and an efficient method for the determination of pymetrozine in broccoli and soil was also developed. Pymetrozine residues were extracted from samples using acetonitrile. The extracts were cleaned up by liquid-liquid partitioning with dichloromethane, followed by purification with ethyl acetate, and were then determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detector. The average recovery was 87-93% from broccoli, and 84-90% from soil. The relative standard deviation (R.S.D.) was less than 4% in broccoli, and in soil less than 11%. These results are all within the accepted range for residue determination. The limit of detection (LOD) of pymetrozine calculated as a sample concentration (S/N ratio of 3) was 0.005 mg kg(-1). The minimum detectable quantity (MDQ) was 1 x 10(-10)g. The results of the kinetics study of pymetrozine residue showed that pymetrozine degradation in broccoli and soil coincided, with C=1.9826 e(-0.1965t) and C=15.352e(-0.4992t), respectively; the half-lives were 3.5 and 1.4 days, respectively. The final residue level was lower than the new maximum residue limit (MRL) for pymetrozine on vegetables with a harvest interval of 23 days. A dosage of 300 g a.i.hm(-2) was suggested, which is considered to be safe for human beings. These results contribute to establishing the scientific basis of the dosage of pymetrozine for use in vegetable-field ecosystems. | 18,801,616 |
Cross-cultural invalidity of alcohol dependence measurement across Hispanics and Caucasians in 2001 and 2002. | Do assessments of alcohol dependence demonstrate similarly validity across Hispanics and non-Hispanic Caucasians? This investigation examined this question. It employed confirmatory factor analyses for ordered-categorical measures to search for measurement bias on the AUDADIS, a standardized measure of alcohol dependence, across Hispanic (n=4819) and non-Hispanic Caucasians (n=16, 109) in a nationally representative survey of alcohol use in the United States conducted in 2001 and 2002. Analyses considered whether 27 items operationalizing the DSM-IV alcohol dependence construct provided equivalent measurement. Nine items revealed statistically significant bias, suggesting strong caution regarding the cross-ethnic validity of alcohol dependence. Sensitivity analyses established that item level differences erroneously impact alcohol dependence estimates among the 2001-2002 US Hispanic population. Biased measurement underestimates differences between Hispanics and non-Hispanic Caucasians, underestimates Hispanics' true use levels, and falsely minimizes current increases in drinking behavior evidenced among Hispanics. Findings urge improved public health efforts among the Hispanic community and underscore the necessity for cultural sensitivity when generalizing measures and constructs developed in the majority to Hispanic individuals. | 18,801,620 |
Examiner repeatability of patellar cartilage T2 values. | The purpose of this study was to evaluate the intra- and interexaminer resegmentation precision of patellar cartilage T2 mapping measurements in healthy subjects. T2-weighted images of patellar cartilage for 10 subjects were acquired. Two individuals manually segmented patellar cartilage at each slice location twice, once on each of two separate days. Bulk average and zonal T2 values for the superficial, middle, and deep layers of cartilage were calculated. The root mean square (RMS) and coefficient of variation (COV) were calculated using the repeated measurements of each slice of each subject by each examiner. The intraexaminer bulk T2 differences were 0.2+/-1.0 ms, with an RMS error of 0.7 ms and a COV of 1.9%. The differences of interexaminer bulk T2 values was 1.0+/-1.4 ms, with an RMS error of 1.2 ms and a COV of 3.3%. The superficial zone of cartilage had the highest zonal variability of T2 values. The average interexaminer T2 values for the superficial, middle and deep zones were 42.2+/-5.6, 38.1+/-5.3 and 31.9+/-4.6 ms, respectively. The interexaminer variability of calculated T2 values highlights the difficulty of interpreting significant differences of T2 values which are similar in magnitude. The repeatability measurements of patellar cartilage T2 values were less than reported intersession T2 repeatability. | 18,801,631 |
Characterization of cardiac-related noise in fMRI of the cervical spinal cord. | Magnetic resonance imaging (MRI) has recently been applied to study spinal cord function in humans. However, spinal functional MRI (fMRI) encounters major technical challenges with cardiac noise being considered a major source of noise. The present study relied on echo-planar imaging of the cervical cord at short TR (TR=250 ms; TE=40 ms; flip=45 degrees), combined with plethysmographic recordings to characterize the spatiotemporal properties of cardiac-induced signal changes in spinal fMRI. Frequency-based analyses examining signal change at the cardiac frequency confirmed mean fluctuations of about 10% (relative to the mean signal) in the spinal cord and surrounding cerebrospinal fluid (CSF), with maximal responses reaching up to 66% in some voxels. A spatial independent component analysis (sICA) confirmed that cardiac noise is an important source of variance in spinal fMRI with several components showing a response coherent with the cardiac frequency spectrum. The time course of the main cardiac components approximated a sinusoidal function tightly coupled to the cardiac systole with at least one component showing a comparable temporal profile across runs and subjects. Spatially, both the frequency-domain analysis and the sICA demonstrated cardiac noise distributed irregularly along the full rostrocaudal extent of the segments scanned with peaks concentrated in the ventral part of the lateral slices in all scans and subjects, consistent with the major channels of CSF flow. These results confirm that cardiac-induced changes are a significant source of noise likely to affect the detection of spinal Blood Oxygen Level Dependent (BOLD) responses. Most importantly, the complex spatiotemporal structure of cardiac noise is unlikely to be accounted for adequately by ad hoc linear methods, especially in data acquired using long TR (i.e. aliasing the cardiac frequency). However, the reliable spatiotemporal distribution of cardiac noise across scanning runs and within subjects may provide a valid means to identify and extract cardiac noise based on sICA methods. | 18,801,632 |
Metrologic approaches to setting acceptance criteria: unacceptable and unusual characteristics. | Decisions regarding acceptance criteria in regulatory or compendial contexts are among the most difficult to make. Acceptance criteria aid in the identification, on the one hand, of materials with unacceptable characteristics that should not pass the tests and procedures or, on the other hand, of unusual characteristics that indicate materials that are unlikely to pass the tests and procedures. For relatively complex procedures metrological approaches can differentiate between intra- and inter-laboratory variation and clarify unacceptable and unusual data. Such testing requires collaborative studies in which each participating laboratory essentially compares itself to the other laboratories in the collaborative study. Laboratories that use the reference standard established by the collaborative study are conducting a performance verification test in which they compare their capabilities to those of laboratories in the collaborative study. This paper considers aspects of a series of complex issues involving unacceptable/unusual characteristics primarily in the context of USP's work but with implications for manufacturing science via considerations of process capability and Quality by Design and to measurement science. Ultimately, acceptance criteria support the availability of good quality, safe, and effective medicines for patients and consumers. | 18,801,635 |
Right-sided vagus nerve stimulation in humans: an effective therapy? | Vagus nerve stimulation (VNS) is an additive treatment option for refractory epilepsy. The electrode is placed on the cervical trunk of the left vagus nerve. In patients who are not suitable for left-sided vagus nerve stimulation (L-VNS) right-sided vagus nerve stimulation (R-VNS) may be as effective. In animal models epilepsy is sufficiently suppressed by R-VNS. In a 16 years old boy suffering from medically refractory psychomotoric seizures with secondary generalisation, L-VNS reduced the frequency of generalized seizures. A deep wound infection required the removal of the system eight weeks later. Cicatrisation did not allow preparation of the left vagus nerve, therefore we implanted R-VNS with sufficient seizure suppression. However, compared to L-VNS, the effect occurred months later and cardiac symptoms were induced by stimulation of the right vagus nerve. R-VNS seems to be an effective and alternative therapy in selected patients responding to L-VNS where a left-sided reimplantation is not possible. Placement and adjustment of the device should be performed under ECG control. Further studies are necessary to compare the efficacy of L-VNS and R-VNS. | 18,801,642 |
"Resting" CBF in the epileptic baboon: correlation with ketamine dose and interictal epileptic discharges. | Photosensitive epileptic (SZ) baboons demonstrate different cerebral blood flow (CBF) activation patterns from asymptomatic controls (CTL) during intermittent light stimulation (ILS). This study compares "resting" CBF between PS and CTL animals, and CBF correlations with ketamine dose and interictal epileptic discharges (IEDs) between PS and CTL animals. Continuous intravenous ketamine was administered to eight PS and eight CTL baboons (matched for gender and weight), and maintained at subanesthetic doses (4.8-14.6 mg/kg/hr). Three resting H(2)(15)O-PET studies were attempted in each animal (CTI/Siemens HR+ scanner). Images were acquired in 3D mode (63 contiguous slices, 2.4mm thickness). PET images were co-registered with MRI images (3T Siemens Trio, T1-weighted 3D Turboflash sequence, TE/TR/TI=3.04/2100/785 ms, flip angle=13 degrees ). EEG was used to monitor depth of sedation and for quantification of IED rates. Regional CBF was compared between PS and CTL groups and correlations were analyzed for ketamine dose and IED rates. When subsets of animals of either group, receiving similar doses of ketamine were compared, PS animals demonstrated relative CBF increases in the occipital lobes and decreases in the frontal lobes. Correlation analyses with ketamine dose confirmed the frontal and occipital lobe changes in the PS animals. The negative correlations of CBF with ketamine dose and IED rate overlapped frontally. While frontal lobe CBF was also negatively correlated with IED rate, positive correlations were found in the parietal lobe. "Resting" CBF differs between PS and CTL baboons. Correlation analyses of CBF and ketamine dose reveal that occipital lobe CBF increases and frontal lobe in PS animals are driven by ketamine. While frontal lobe CBF decreases may be related to ketamine's propensity to activate IEDs, positive CBF correlations with IED rate suggest involvement of the parietal lobes in their generation. | 18,801,644 |
Endoscopically assisted enucleation and curettage of large mandibular odontogenic keratocyst. | This article reports a case of a mandibular multilocular keratocyst treated with endoscopically assisted enucleation and curettage. An ectopic third molar displaced in the coronoid process area was also removed.Odontogenic keratocysts (OKCs) are known for their propensity to recur. The incomplete removal of the cyst is one of the mechanisms for which it is thought that the keratocyst recurs. The endoscopic assistance allowed us to explore accurately the operative field and the areas of difficult access, improving the complete removal of the cystic lesion. Moreover, it allowed us to monitor closely the separation of the cyst lining from the inferior alveolar nerve and limit the extension of the surgical approach. At 3-year follow-up no evidence of recurrence was evidenced by radiological and clinical controls. | 18,801,672 |
Fungal infection as a complication of sinus bone grafting and implants: a case report. | Sinus bone grafts have been used successfully to augment atrophic posterior maxilla for dental implant placement. Even though sinus bone grafting is generally considered to be a safe surgical procedure, postoperative maxillary sinus infections can occur and therefore need to be considered. Bacteria, as well as viruses and fungi, have been identified as causative agents. Because fungal infection of the maxillary sinus after sinus bone grafting is not well known, we report a case of a middle-aged male patient along with the clinical, radiographic, and histologic findings. The patient was referred from his private dentist because of failed sinus bone grafting and osseointegration of implants. The surgical approach to the sinus yielded a friable mass of brownish-red material from the sinus. Review of pathology slides revealed a noninvasive hyphal mass caused by Aspergillus and polypous mucosa. After surgical removal of the mycotic masses, sinus bone grafting, using allograft, was performed. Bone formation after the healing period was favorable and dental implants were placed. There was no recurrence of fungal sinusitis. | 18,801,673 |
Spectral studies of Fe(III) complexes of dipodal tridentate chelating agents. | The dipodal ligands (Im) and (BIm) as well as complexes [FeLCl(3)] [L=Im (1) and BIm (2)] have been prepared and studied using spectroscopic techniques. The magnetic moment, IR, electronic (ligand field), FAB-mass and NMR spectral data indicate a hexa-coordinate geometry around high-spin state Fe(3+) where the ligands coordinate as a tridentate [N,N,N] chelating agent. (57)Fe-Mössbauer spectral data confirmed the presence of a ligand asymmetry around Fe(3+) in a high-spin state electronic configuration (t(2g)(3),e(g)(2), S=5/2) with nuclear transition Fe(+/-3/2-->+/-1/2) exhibiting Kramer's double degeneracy. The molecular computations provided the optimum energy perspective plots for the molecular geometries giving the important structural data. | 18,801,699 |
Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice. | Whole genome oligo-microarrays were used to characterize age-dependent and tissue-specific changes in gene expression in pancreatic lymph nodes, spleen, and peripheral blood cells, obtained from up to 8 individual NOD mice at 6 different time points (1.5 to 20 weeks of age), compared to NOD.B10 tissue controls. "Milestone Genes" are genes whose expression was significantly changed (approximately 3 fold) as the result of splicing or changes in transcript level. Milestone Genes were identified among genes within type one diabetes (T1D) susceptibility regions (Idd). Milestone Genes showing uniform patterns of changes in expression at various time points were identified, but the patterns of distribution and kinetics of expression were unique to each tissue. Potential T1D candidate genes were identified among Milestone Genes within Idd regions and/or hierarchical clusters. These studies identified tissue- and age-specific changes in gene expression that may play an important role in the inductive or destructive events of T1D. | 18,801,706 |
AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3beta and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. | AMP-activated protein kinase (AMPK) activation reportedly suppresses transcriptional activity of the cAMP-responsive element (CRE) in the phosphoenolpyruvate carboxykinase C (PEPCK-C) promoter and reduces hepatic PEPCK-C expression. Although a previous study found TORC2 phosphorylation to be involved in the suppression of AMPK-mediated CRE transcriptional activity, we herein present evidence that glycogen synthase kinase 3beta (GSK3beta) phosphorylation induced by AMPK also plays an important role. We initially found that injecting fasted mice with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) markedly increased Ser-9 phosphorylation of hepatic GSK3beta within 15 min. Stimulation with AICAR or the GSK3beta inhibitor SB-415286 strongly inhibited CRE-containing promoter activity in HepG2 cells. Using the Gal4-based transactivation assay system, the transcriptional activity of cAMP-response element-binding protein (CREB) was suppressed by both AICAR and SB415286, whereas that of TORC2 was repressed significantly by AICAR but very slightly by SB415286. These results show inactivation of GSK3beta to directly inhibit CREB but not TORC2. Importantly, the AICAR-induced suppression of PEPCK-C expression was shown to be blunted by overexpression of GSK3beta(S9G) but not wild-type GSK3beta. In addition, AICAR stimulation decreased, whereas Compound C (AMPK inhibitor) increased CREB phosphorylation (Ser-129) in HepG2 cells. The time-courses of decreased CREB phosphorylation (Ser-129) and increased GSK3beta phosphorylation were very similar. Furthermore, AMPK-mediated GSK3beta phosphorylation was inhibited by an Akt-specific inhibitor in HepG2 cells, suggesting involvement of the Akt pathway. In summary, phosphorylation (Ser-9) of GSK3beta is very likely to be critical for AMPK-mediated PEPCK-C gene suppression. Reduced CREB phosphorylation (Ser-129) associated with inactivation of GSK3beta by Ser-9 phosphorylation may be the major mechanism underlying PEPCK-C gene suppression by AMPK-activating agents such as biguanide. | 18,801,732 |
An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. | Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-kappaB-sensitive miRNA-146a highly complementary to the 3'-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1beta, Abeta42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-kappaB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-kappaB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-kappaB-sensitive miRNA-146a-mediated modulation of CFH gene expression may in part regulate an inflammatory response in AD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling. | 18,801,740 |
Functional modules integrating essential cellular functions are predictive of the response of leukaemia cells to DNA damage. | Childhood B-precursor lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Despite the fact that 80% of ALL patients respond to anti-cancer drugs, the patho-physiology of this disease is still not fully understood. mRNA expression-profiling studies that have been performed have not yet provided novel insights into the mechanisms behind cellular response to DNA damage. More powerful data analysis techniques may be required for identifying novel functional pathways involved in the cellular responses to DNA damage. In order to explore the possibility that unforeseen biological processes may be involved in the response to DNA damage, we have developed and applied a novel procedure for the identification of functional modules in ALL cells. We have discovered that the overall activity of functional modules integrating protein degradation and mRNA processing is predictive of response to DNA damage. Supplementary material including R code, additional results, experimental datasets, as well as a detailed description of the methodology are available at http://www.bip.bham.ac.uk/vivo/fumo.html. Supplementary data are available at Bioinformatics online. | 18,801,750 |
Running in new and worn shoes: a comparison of three types of cushioning footwear. | In this study, the effect of shoe degradation on running biomechanics by comparing the kinetics and kinematics of running in new and worn shoes was investigated. Three types of footwear using different cushioning technologies were compared. Longitudinal study. Pre- and post-tests on overground running at 4.5 m s(-1) on a 20-m laboratory runway; performance measured using a force platform and a motion capture system. 24 runners (14 men and 10 women) 200 miles of road running in the same pair of shoes. Within-group factor: shoe condition (new/worn); between-group factor: footwear type (air/gel/spring). Stance time was calculated from force data. External loads were measured by maximum vertical force and loading rate. Kinematic changes were indicated by sagittal plane angles of the torso, hip, knee and ankle at critical events during the stance phase. Stance time increased (p=0.035) in worn shoes. The torso displayed less maximum forward lean (p<0.001) and less forward lean at toe-off (p<0.001), while the ankle displayed reduced maximum dorsiflexion (p=0.013) and increased plantar flexion at toe-off (p<0.001) in worn shoes. No changes in the hip and knee angles. No between-group difference among the three footwear groups or condition by type interaction was found in any measured variables. As shoe cushioning capability decreases, runners modify their patterns to maintain constant external loads. The adaptation strategies to shoe degradation were unaffected by different cushioning technologies, suggesting runners should choose shoes for reasons other than cushioning technology. | 18,801,775 |
The impact of allogenic red cell transfusion and coated bypass circuit on the inflammatory response during cardiopulmonary bypass: a randomized study. | This study is designed to determine and compare the effects of transfusion and coated circuits on the inflammatory response during cardiopulmonary bypass. Forty patients were randomized into two groups according to the type of extracorporeal circuit used and later prospectively enrolled into two subgroups according to the need for red cell transfusion during CPB (leading to 4 groups--10 patients per group; group 1: with no transfusion and standard oxygenator, group 2: with transfusion and standard oxygenator, group 3: with no transfusion and coated oxygenator, group 4: with transfusion and coated oxygenator). Serum lactate, interleukin 6, human tumor necrosis factor alpha (TNF-alpha), D-dimer and CRP levels were measured at three time points (T1: start of CPB, T2: before removal of aortic cross-clamp, T3: 45 min after the completion of proximal anastomoses). Protein adsorption of oxygenator fibers was measured. Outcome parameters were recorded. Interleukin 6, TNF-alpha, D-dimer and lactate levels increased at T2 and T3 in all groups (P<0.05 within groups). The increase in interleukin 6 was significant at T2 in group 2 when compared to group 1 (8.0+/-3.9 vs. 4.4+/-1.8, P=0.03). The increase in TNF-alpha was higher at T2 in group 1 when compared to group 3 (16.0+/-4.2 vs. 11.7+/-2.8, P=0.05) and in group 2 when compared to group 3 at T2 and T3 (15.3+/-4.6 vs. 11.7+/-2.8, P=0.06; 17.6+/-5.0 vs. 13.7+/-3.9, P=0.06). Protein adsorption was higher in group 1 and group 2 (group 1 vs. group 3, 2.2+/-0.8 vs. 1.4+/-0.3, P=0.01; group 2 vs. group 3, 2.4+/-0.7 vs. 1.4+/-0.3, P=0.02; group 2 vs. group 4, 2.4+/-0.7 vs. 1.8+/-0.3, P=0.04), it was also higher at group 4 when compared to group 3 (1.8+/-0.3 vs. 1.4+/-0.3, P=0.03). Allogenic red cell transfusion enhances inflammatory response during CPB; coated circuit systems have a limiting effect on this inflammatory reaction. | 18,801,802 |
Liking and wanting of drug and non-drug rewards in active cocaine users: the STRAP-R questionnaire. | Few studies have examined the subjective value attributed to drug rewards specifically as it compares with the value attributed to primary non-drug rewards in addicted individuals. The objective of this study is to assess 'liking' and 'wanting' of expected 'drug' rewards as compared to 'food' and 'sex' while respondents report about three different situations ('current', and hypothetical 'in general', and 'under drug influence'). In all, 20 cocaine-addicted individuals (mean abstinence = 2 days) and 20 healthy control subjects were administered the STRAP-R (Sensitivity To Reinforcement of Addictive and other Primary Rewards) questionnaire after receiving an oral dose of the dopamine agonist methylphenidate (20 mg) or placebo. The reinforcers' relative value changed within the addicted sample when reporting about the 'under drug influence' situation (drug > food; otherwise, drug < food). This change was highest in the addicted individuals with the youngest age of cocaine use onset. Moreover, 'drug' 'wanting' exceeded 'drug' 'liking' in the addicted subjects when reporting about this situation during methylphenidate. Thus, cocaine-addicted individuals assign the highest subjective valence to 'drug' rewards but only when recalling cue-related situations. When recalling this situation, they also report higher 'drug' 'wanting' than hedonic 'liking', a motivational shift that was only significant during methylphenidate. Together, these valence shifts may underlie compulsive stimulant abuse upon pharmacological or behavioural cue exposure in addicted individuals. Additional studies are required to assess the reliability of the STRAP-R in larger samples and to examine its validity in measuring the subjective value attributed to experienced reinforcers or in predicting behaviour. | 18,801,822 |
Better sexual acceptability of agomelatine (25 and 50 mg) compared with paroxetine (20 mg) in healthy male volunteers. An 8-week, placebo-controlled study using the PRSEXDQ-SALSEX scale. | Sexual dysfunction (SD) is a common and underestimated effect of antidepressants. Healthy volunteers are the most adequate group to study this adverse event avoiding influence of depression itself. Sexual acceptability of agomelatine (a melatonergic agonist and 5HT(2C) antagonist) paroxetine and placebo by using the Psychotropic-Related Sexual Dysfunction Salamanca Sex Questionnaire (PRSEXDQ-SALSEX) was explored. A total of 92 healthy male volunteers were randomised to agomelatine (25 or 50 mg), paroxetine 20 mg or placebo for 8 weeks. SD, defined as at least one sexual impairment in one of the following PRSEXDQ-SALSEX items (decreased libido, delayed orgasm/ejaculation, anorgasmia/no ejaculation and erectile dysfunction), was evaluated at baseline and after 2, 4 and 8 weeks. At the last post-baseline assessment, SD was significantly lower in each agomelatine group (22.7% on 25 mg and 4.8% on 50 mg) than in the paroxetine group (85.7%; p < 0.0001). In the placebo group, 8.7% of volunteers reported a SD. The percentages of volunteers with moderate or severe SD were 4.5% for agomelatine 25 mg, 4.8% for agomelatine 50 mg, 61.9% for paroxetine 20 mg and 0% in the placebo group (p < or = 0.0001 agomelatine versus paroxetine). There is a much lower risk of having SD with agomelatine than paroxetine in healthy male volunteers, which confirms the better sexual acceptability profile of agomelatine compared with the SSRIs. | 18,801,825 |
Olanzapine-induced hyperglycaemic coma and neuroleptic malignant syndrome: case report and review of literature. | Although the relationship between antipsychotic medication, particularly second-generation antipsychotics (SGAs), and metabolic disturbance is increasingly accepted, there is an important, but little recognised, potential interaction between this and the other important serious adverse effect of neuroleptic malignant syndrome (NMS). We report a case of a 35-year old female who developed new onset type II diabetes mellitus with hyperosmolar hyperglycaemic coma and acute renal failure following treatment with a SGA for a first manic episode. The history is strongly suggestive of concurrent NMS. This case raises important questions about non-ketotic, hyperosmolar diabetic coma with antipsychotics, the possible association between hyperglycaemia and hyperthermia, and the direction of causality in this, the recognition of either syndrome when they co-exist and management issues in such patients. These questions are considered in the context of currently available literature. | 18,801,826 |
Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. | Weight-bearing exercise has been contraindicated among people with diabetic peripheral neuropathy (DM+PN). However, recent cohort studies have suggested that daily weight-bearing activity is associated with lower risk for foot ulceration. The objective of this study was to determine the effect of a lower-extremity exercise and walking intervention program on weight-bearing activity and foot ulcer incidence in people with DM+PN. This was an observer-blinded, 12-month randomized controlled trial. The settings were physical therapy offices in part 1 of the intervention and the community in part 2 of the intervention. The participants were 79 individuals with DM+PN who were randomly assigned either to a control group (n=38) or an intervention group (n=41) group. Intervention components included leg strengthening and balance exercises; a graduated, self-monitored walking program (part 1); and motivational telephone calls every 2 weeks (part 2). Both groups received diabetic foot care education, regular foot care, and 8 sessions with a physical therapist. Total and exercise bout-related daily steps at baseline and at 3, 6, and 12 months were measured by accelerometers. Foot lesions/ulcers were photographed and classified by an independent panel of dermatologists. Use of adequate footwear was monitored. At 6 months, bout-related daily steps increased 14% from baseline in the intervention group and decreased 6% from baseline in the control group. Although the groups did not differ statistically in the change in total daily steps, at 12 months steps had decreased by 13% in the control group. Foot ulcer rates did not differ significantly between groups. Promoting weight-bearing activity did not lead to significant increases in foot ulcers. Weight-bearing activity can be considered following adequate assessment and counseling of patients with DM+PN. | 18,801,859 |
The association between water supply and inflammatory bowel disease based on a 1990-1993 cohort study in southeastern Norway. | Inflammatory bowel disease refers to a group of chronic diseases of unknown etiology related to both genetic and environmental factors. In this 1990-1993 study, the authors investigated associations between the content and quality of drinking water and the incidence of inflammatory bowel disease. They used data from a population-based cohort recruited in southeastern Norway and a registry of water quality derived from Norwegian waterworks that contained measurements of iron, aluminum, acidity (pH), color, turbidity, and coliform bacteria. The authors found that risk of developing inflammatory bowel disease, including ulcerative colitis and Crohn's disease, was associated with high iron content. The relative risk of developing inflammatory bowel disease increased by 21% (95% confidence interval: 9, 34) when the iron content in the drinking water increased by 0.1 mg/L. They found no association between the diseases and aluminum in the water, color of the water, and turbidity of the water. The authors suggest that the observations can be explained by 2 mechanisms. First, high iron concentration works as a catalyst for oxidative stress, which will cause inflammation and/or increase the rate of cell mutations. Second, iron content stimulates the growth of bacteria and increases the likelihood of inappropriate immune responses in genetically predisposed individuals. | 18,801,890 |
Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. | The receptors for IGF-I (IGF-IR) and insulin (IR) have been implicated in physiological cardiac growth, but it is unknown whether IGF-IR or IR signaling are critically required. We generated mice with cardiomyocyte-specific knockout of IGF-IR (CIGF1RKO) and compared them with cardiomyocyte-specific insulin receptor knockout (CIRKO) mice in response to 5 wk exercise swim training. Cardiac development was normal in CIGF1RKO mice, but the hypertrophic response to exercise was prevented. In contrast, despite reduced baseline heart size, the hypertrophic response of CIRKO hearts to exercise was preserved. Exercise increased IGF-IR content in control and CIRKO hearts. Akt phosphorylation increased in exercise-trained control and CIRKO hearts and, surprisingly, in CIGF1RKO hearts as well. In exercise-trained control and CIRKO mice, expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and glycogen content were both increased but were unchanged in trained CIGF1RKO mice. Activation of AMP-activated protein kinase (AMPK) and its downstream target eukaryotic elongation factor-2 was increased in exercise-trained CIGF1RKO but not in CIRKO or control hearts. In cultured neonatal rat cardiomyocytes, activation of AMPK with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) prevented IGF-I/insulin-induced cardiomyocyte hypertrophy. These studies identify an essential role for IGF-IR in mediating physiological cardiomyocyte hypertrophy. IGF-IR deficiency promotes energetic stress in response to exercise, thereby activating AMPK, which leads to phosphorylation of eukaryotic elongation factor-2. These signaling events antagonize Akt signaling, which although necessary for mediating physiological cardiac hypertrophy, is insufficient to promote cardiac hypertrophy in the absence of myocardial IGF-I signaling. | 18,801,929 |
Quantification of thyroglobulin, a low-abundance serum protein, by immunoaffinity peptide enrichment and tandem mass spectrometry. | Quantification of serum tumor markers plays an important role in determining whether patients treated for cancer require further therapy. Whereas large-scale proteomic efforts aim to identify novel tumor markers to facilitate early detection, optimization of methods for quantifying known tumor markers offers another approach to improving management of malignancies. For example, immunoassays used in clinical practice to measure established tumor markers suffer from potential interference from endogenous immunoglobulins and imperfect concordance across platforms-problems that also plague many other immunoassays. To address these important limitations, this study used peptide immunoaffinity enrichment in concert with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify thyroglobulin, a well-characterized tumor marker. We identified 3 peptides in tryptic digests of thyroglobulin that were detected at low concentrations by tandem mass spectrometry, raised polyclonal antibodies to those peptides, and used the antibodies to extract the 3 corresponding peptides from tryptic digests of human serum. We quantified each endogenous peptide using LC-MS/MS and multiple reaction monitoring with external calibrators. The detection limit for endogenous thyroglobulin in serum was 2.6 microg/L (4 pmol/L). Direct comparison with immunoassay revealed good correlation (r(2) = 0.81). Immunoaffinity peptide enrichment-tandem mass spectrometry can detect tryptic peptides of thyroglobulin at picomolar concentrations while also digesting the endogenous immunoglobulins that can potentially interfere with traditional immunoassays. Our observations suggest a general analytical strategy for using immunoaffinity isolation together with tandem mass spectrometry to quantify tumor antigens and other low-abundance proteins in human serum. | 18,801,935 |
Habitual physical activity and sports participation after total ankle arthroplasty. | There is a lack of detailed information about habitual physical activity levels and the sports participation of patients after total ankle arthroplasty. The proportion of sports active patients increases after total ankle arthroplasty, and the majority of patients will meet current recommendations for health-enhancing physical activity. Case series; Level of evidence, 4. The authors assessed the pre- and postoperative participation in sports and recreational activities of 101 patients at a mean of 3.7 years after total ankle arthroplasty. Activity levels were determined with use of the University of California at Los Angeles (UCLA) activity scale. The International Physical Activity Questionnaire (IPAQ) was used to quantify habitual physical activity levels and to calculate the proportion of patients meeting current guidelines for health-enhancing physical activity. The American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score was used as the clinical outcome measure. Radiographs were studied for tibial and talar radiolucencies, and any association between radiolucencies, activity levels, and sports participation was determined. Preoperatively, 62.4% of the patients were active in sports; 66.3% were active after surgery (P=.56). The patients were active in 3.0 +/- 1.8 different sports and recreational activities preoperatively and in 3.0 +/- 1.6 activities after surgery (P =1.0). The sports frequency remained unchanged, with 2.0 +/- 1.6 sessions per week before total ankle arthroplasty and 2.3 +/- 1.7 sessions per week postoperatively (P=.19). Overall, the patients were active in sports and recreation for 3.9 +/- 3.8 hours per week pre-operatively, and for 4.7 +/- 3.9 hours per week after surgery (P=.14). The most common disciplines after total ankle arthroplasty were swimming, cycling, and fitness/weight training. Sixty-five percent of the patients stated that surgery had improved their sports ability. The UCLA activity levels increased significantly from 4.3 +/- 2.2 to 6.2 +/- 1.6 (P<.001); AOFAS scores also improved significantly from 45.5 +/- 16.6 to 84.3 +/- 13.3 (P<.001). Patients suffering from posttraumatic ankle osteoarthritis were less satisfied with surgery than those with primary or inflammatory ankle osteoarthritis. Seventy-nine percent of the patients met the current guidelines for health-enhancing physical activity according to the IPAQ. Neither sports participation nor activity levels were associated with the presence of periprosthetic radiolucencies. Two-thirds of the patients were active in sports after total ankle arthroplasty, and the majority of the patients met current health-enhancing physical activity recommendations. The clinical outcome as determined by AOFAS scores and the patient satisfaction were favorable. The present study found no association between sports participation, increased physical activity levels, and the appearance of periprosthetic radiolucencies 3.7 years after total ankle arthroplasty. However, these results have to be confirmed after longer follow-up, in particular of those patients regularly participating in sports with higher impact. | 18,801,943 |
NIM811 (N-methyl-4-isoleucine cyclosporine), a mitochondrial permeability transition inhibitor, attenuates cholestatic liver injury but not fibrosis in mice. | Cholestasis causes hepatocyte death, possibly because of mitochondrial injury. This study investigated whether NIM811 (N-methyl-4-isoleucine cyclosporine), an inhibitor of the mitochondrial permeability transition (MPT), attenuates cholestatic liver injury in vivo. Cholestasis was induced in mice by bile duct ligation (BDL). NIM811 was gavaged (20 mg/kg) before BDL and daily (10 mg/kg) afterward. Mitochondrial depolarization, cell death, and MPT onset were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. After BDL, serum alanine aminotransferase (ALT), hepatic necrosis, and apoptosis all increased. NIM811 decreased ALT, necrosis, and apoptosis by 60 to 86%. In vehicle-treated mice at 6 h after BDL, viable hepatocytes with depolarized mitochondria were 18/high-power field (hpf), and nonviable cells were approximately 1/hpf, showing that depolarization preceded necrosis. Calcein entered mitochondria after BDL, indicating MPT onset in vivo. NIM811 decreased depolarization by 72%, prevented calcein entry into mitochondria, and blocked release of cytochrome c. Hepatic tumor necrosis factor alpha, transforming growth factor-beta1, procollagen alpha1(I) mRNA, alpha-smooth muscle actin, and Sirius red staining for collagen increased after BDL but were not different in vehicle- and NIM811-treated mice. Taken together, NIM811 decreased cholestatic necrosis and apoptosis but did not block fibrosis, indicating that the MPT plays an important role in cholestatic cell death in vivo. | 18,801,946 |
Evidence of skeletal muscle damage following electrically stimulated isometric muscle contractions in humans. | It is unknown whether muscle damage at the level of the sarcomere can be induced without lengthening contractions. To investigate this, we designed a study where seven young, healthy men underwent 30 min of repeated electrical stimulated contraction of m. gastrocnemius medialis, with the ankle and leg locked in a fixed position. Two muscle biopsies were collected 48 h later: one from the stimulated muscle and one from the contralateral leg as a control. The biopsies were analyzed immunohistochemically for inflammatory cell infiltration and intermediate filament disruption. Ultrastructural changes at the level of the z-lines were investigated by transmission electron microscopy. Blood samples were collected for measurement of creatine kinase activity, and muscle soreness was assessed in the days following stimulation. The biopsies from the stimulated muscle revealed macrophage infiltration and desmin-negative staining in a small percentage of myofibers in five and four individuals, respectively. z-Line disruption was evident at varying magnitudes in all subjects and displayed a trend toward a positive correlation (r = 0.73, P = 0.0663) with the force produced by stimulation. Increased muscle soreness in all subjects, combined with a significant increase in creatine kinase activity (P < 0.05), is indirectly suggestive of muscle damage, and the novel findings of the present study, i.e., 1) macrophages infiltration, 2) lack of desmin staining, and 3) z-line disruption, provide direct evidence of damage at the myofiber and sarcomere levels. These data support the hypothesis that muscle damage at the level of the sarcomere can be induced without lengthening muscle contractions. | 18,801,957 |
Fat adaptation followed by carbohydrate restoration increases AMPK activity in skeletal muscle from trained humans. | We have previously reported that 5 days of a high-fat diet followed by 1 day of high-carbohydrate intake (Fat-adapt) increased rates of fat oxidation and decreased rates of muscle glycogenolysis during submaximal cycling compared with consumption of an isoenergetic high-carbohydrate diet (HCHO) for 6 days (Burke et al. J Appl Physiol 89: 2413-2421, 2000; Stellingwerff et al. Am J Physiol Endocrinol Metab 290: E380-E388, 2006). To determine potential mechanisms underlying shifts in substrate selection, eight trained subjects performed Fat-adapt and HCHO. On day 7, subjects performed 1-h cycling at 70% peak O2 uptake. Muscle biopsies were taken immediately before and after exercise. Resting muscle glycogen content was similar between treatments, but muscle triglyceride levels were higher after Fat-adapt (P < 0.05). Resting AMPK-alpha1 and -alpha2 activity was higher after Fat-adapt (P = 0.02 and P = 0.05, respectively), while the phosphorylation of AMPK's downstream target, acetyl-CoA carboxylase (pACC at Ser221), tended to be elevated after Fat-adapt (P = 0.09). Both the respiratory exchange ratio (P < 0.01) and muscle glycogen utilization (P < 0.05) were lower during exercise after Fat-adapt. Exercise increased AMPK-alpha1 activity after HCHO (P = 0.03) but not Fat-adapt. Exercise was associated with an increase in pACC at Ser221 for both dietary treatments (P < 0.05), with postexercise pACC Ser221 higher after Fat-adapt (P = 0.02). In conclusion, compared with HCHO, Fat-adapt increased resting muscle triglyceride stores and resting AMPK-alpha1 and -alpha2 activity. Fat-adapt also resulted in higher rates of whole body fat oxidation, reduced muscle glycogenolysis, and attenuated the exercise-induced rise in AMPK-alpha1 and AMPK-alpha2 activity compared with HCHO. Our results demonstrate that AMPK-alpha1 and AMPK-alpha2 activity and fuel selection in skeletal muscle in response to exercise can be manipulated by diet and/or the interactive effects of diet and exercise training. | 18,801,964 |
Catalytic conversion of biomass to monofunctional hydrocarbons and targeted liquid-fuel classes. | It is imperative to develop more efficient processes for conversion of biomass to liquid fuels, such that the cost of these fuels would be competitive with the cost of fuels derived from petroleum. We report a catalytic approach for the conversion of carbohydrates to specific classes of hydrocarbons for use as liquid transportation fuels, based on the integration of several flow reactors operated in a cascade mode, where the effluent from the one reactor is simply fed to the next reactor. This approach can be tuned for production of branched hydrocarbons and aromatic compounds in gasoline, or longer-chain, less highly branched hydrocarbons in diesel and jet fuels. The liquid organic effluent from the first flow reactor contains monofunctional compounds, such as alcohols, ketones, carboxylic acids, and heterocycles, that can also be used to provide reactive intermediates for fine chemicals and polymers markets. | 18,801,970 |
Comment on "Age and evolution of the Grand Canyon revealed by U-Pb dating of water table-type speleothems". | Polyak et al. (Reports, 7 March 2008, p. 1377) reported that development of the western Grand Canyon began about 17 million years ago. However, their conclusion is based on an inappropriate conflation of Plio-Quaternary incision rates and longer-term rates derived from sites outside the Grand Canyon. Water-table declines at these sites were more likely related to local base-level changes and Miocene regional extensional tectonics. | 18,801,984 |
Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity. | The nucleostemin (NS) gene encodes a nucleolar protein found at high levels in several types of stem cells and tumor cell lines. The function of NS is unclear but it may play a critical role in S-phase entry by stem/progenitor cells. Here we characterize NS expression in murine male germ cells. Although NS protein was highly expressed in the nucleoli of all primordial germ cells, only a limited number of gonocytes showed NS expression in neonatal testes. In adult testes, NS protein was expressed at high levels in the nucleoli of spermatogonia and primary spermatocytes but at only low levels in round spermatids. To evaluate the properties of cells expressing high levels of NS, we generated transgenic reporter mice expressing green fluorescent protein (GFP) under the control of the NS promoter (NS-GFP Tg mice). In adult NS-GFP Tg testes, GFP and endogenous NS protein expression were correlated in spermatogonia and spermatocytes but GFP was also ectopically expressed in elongated spermatids and sperm. In testes of NS-GFP Tg embryos, neonates, and 10-day-old pups, however, GFP expression closely coincided with endogenous NS expression in developing germ cells. In contrast to a previous report, our results support the existence in neonatal testes of spermatogonial stem cells with long-term repopulating capacity. Furthermore, our data show that NS expression does not correlate with cell-cycle status during prepuberty, and that strong NS expression is essential for the maintenance of germline stem cell proliferation capacity. We conclude that NS is a marker of undifferentiated status in the germ cell lineage during prepubertal spermatogenesis. | 18,802,033 |
Induction of a VLA-2 (CD49b)-expressing effector T cell population by a cell-based neuroblastoma vaccine expressing CD137L. | In malignancies where no universally expressed dominant Ag exists, the use of tumor cell-based vaccines has been proposed. We have modified a mouse neuroblastoma cell line to express either CD80 (B7.1), CD137L (4-1BBL), or both receptors on the tumor cell surface. Vaccines expressing both induce a strong T cell response that is unique in that among responding CD8 T cells, a T effector memory cell (T(EM)) response arises in which a large number of the T(EM) express the alpha-chain of VLA-2, CD49b. We demonstrate using both in vitro and in vivo assays that the CD49b(+) CD8 T cell population is a far more potent antitumor effector cell population than nonfractionated CD8 or CD49b(-) CD8 T cells and that CD49b on vaccine-induced CD8 T cells mediates invasion of a collagen matrix. In in vivo rechallenge studies, CD49b(+) T cells no longer expanded, indicating that CD49b T(EM) expansion is restricted to the initial response to vaccine. To demonstrate a mechanistic link between the expression of costimulatory molecules on the vaccine and CD49b on responding T cells, we stimulated naive T cells in vitro with artificial APC expressing different combinations of anti-CD3, anti-CD28, and CD137L. Although some mRNA encoding CD49b was induced by combining anti-CD3 with anti-CD28 or CD137L, the highest level was induced when all three signals were present. This indicates that CD49b expression results from additive costimulation and that the level of CD49b message serves as an indicator of the effectiveness of T cell activation by a cell-based vaccine. | 18,802,064 |
Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase. | Infiltration of activated monocytes into the brain is a prerequisite for the development of various neurological disorders such as HIV-associated dementia, multiple sclerosis, and other inflammatory processes. In these pathologies, the chemokine SDF-1alpha (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1alpha stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta(2) integrins. SDF-1alpha also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-alpha, IL-1beta, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-1. The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the beta(2) integrin LFA-1 by SDF-1alpha. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1alpha-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1alpha-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion to BMVEC through the LFA-1 integrin. These results provide a novel Lyn-mediated signaling mechanism for the regulation of monocyte movement at the blood-brain barrier. | 18,802,065 |
Goblet cell-derived resistin-like molecule beta augments CD4+ T cell production of IFN-gamma and infection-induced intestinal inflammation. | The secreted goblet cell-derived protein resistin-like molecule beta (RELMbeta) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMbeta influences CD4(+) T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMbeta in augmenting CD4(+) Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-gamma production and intestinal inflammation. In contrast, infected RELMbeta(-/-) mice exhibited a significantly reduced expression of parasite-specific CD4(+) T cell-derived IFN-gamma and TNF-alpha and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMbeta activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN-gamma expression in CD4(+) T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMbeta, can promote adaptive CD4(+) T cell responses and chronic inflammation following intestinal helminth infection. | 18,802,073 |
Vaccination-induced systemic autoimmunity in farmed Atlantic salmon. | Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming. | 18,802,084 |
Protein kinase C theta regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL. | Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8(+)) and less (CD4(+)) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8(+) but not CD4(+) CTL to lyse target cells despite having no effect of the amount of released granules by both CD8(+) and CD4(+) CTL. Consistent with this, CD4(+) CTL break their synapses more often than do CD8(+) CTL, which leads to the escape of the cytolytic molecules from the interface. CD4(+) CTL treatment with a protein kinase Ctheta inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase Ctheta, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis. | 18,802,085 |
Extracellular gelsolin binds lipoteichoic acid and modulates cellular response to proinflammatory bacterial wall components. | The various functions of gelsolin in extracellular compartments are not yet clearly defined but include actin scavenging and antiinflammatory effects. Gelsolin was recently reported to bind endotoxin (LPS) from various Gram-negative bacteria with high affinity. In this study we investigate whether gelsolin also interacts with bacterial wall molecules of Gram-positive bacteria such as lipoteichoic acid (LTA) and whether gelsolin's interaction with bacterial lipids from Gram-negative or Gram-positive bacteria affects their cellular inflammatory responses. A peptide based on the PPI binding site of gelsolin (160-169) binds purified LTA at the same molecular ratio that it binds phosphatidylinositol 4,5-bisphosphate. The OD of recombinant human plasma gelsolin was found to decrease following the addition of purified LTA, and the binding of gelsolin to LTA inhibits F-actin depolymerization by gelsolin. Simultaneously, the ability of LTA to activate translocation of NF-kappaB, E-selectin expression, and adhesion of neutrophils to LTA-treated human aortic endothelial cells was compromised by gelsolin. Gelsolin was able to partially inhibit LPS- or LTA-induced release of IL-8 from human neutrophils but was unable to prevent Gram-positive Bacillus subtilis or Gram-negative Pseudomonas aeruginosa growth and had no effect on the antibacterial activity of the cathelicidin-derived antibacterial peptide LL37. These data suggest that extracellular gelsolin is involved in the host immune recognition of LTA or LPS following release of these molecules from the bacterial outer membrane during cell division or attack by drugs and immune components. | 18,802,097 |
Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. | To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site. Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy. The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer-specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement. This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated. | 18,802,157 |
Randomized controlled trial of collaborative care management of depression among low-income patients with cancer. | To determine the effectiveness of the Alleviating Depression Among Patients With Cancer (ADAPt-C) collaborative care management for major depression or dysthymia. Study patients included 472 low-income, predominantly female Hispanic patients with cancer age >or= 18 years with major depression (49%), dysthymia (5%), or both (46%). Patients were randomly assigned to intervention (n = 242) or enhanced usual care (EUC; n = 230). Intervention patients had access for up to 12 months to a depression clinical specialist (supervised by a psychiatrist) who offered education, structured psychotherapy, and maintenance/relapse prevention support. The psychiatrist prescribed antidepressant medications for patients preferring or assessed to require medication. At 12 months, 63% of intervention patients had a 50% or greater reduction in depressive symptoms from baseline as assessed by the Patient Health Questionnaire-9 (PHQ-9) depression scale compared with 50% of EUC patients (odds ratio [OR] = 1.98; 95% CI, 1.16 to 3.38; P = .01). Improvement was also found for 5-point decrease in PHQ-9 score among 72.2% of intervention patients compared with 59.7% of EUC patients (OR = 1.99; 95% CI, 1.14 to 3.50; P = .02). Intervention patients also experienced greater rates of depression treatment (72.3% v 10.4% of EUC patients; P < .0001) and significantly better quality-of-life outcomes, including social/family (adjusted mean difference between groups, 2.7; 95% CI, 1.22 to 4.17; P < .001), emotional (adjusted mean difference, 1.29; 95% CI, 0.26 to 2.22; P = .01), functional (adjusted mean difference, 1.34; 95% CI, 0.08 to 2.59; P = .04), and physical well-being (adjusted mean difference, 2.79; 95% CI, 0.49 to 5.1; P = .02). ADAPt-C collaborative care is feasible and results in significant reduction in depressive symptoms, improvement in quality of life, and lower pain levels compared with EUC for patients with depressive disorders in a low-income, predominantly Hispanic population in public sector oncology clinics. | 18,802,161 |
Emotional responses of staff to assault in a pediatric state hospital. | In this study, we examined the emotional responses of staff to patient-on-staff assault at a state inpatient psychiatric hospital for children and adolescents. Staff (n = 93) completed self-report measures assessing general psychiatric functioning and symptoms of depression and anxiety. Staff assaulted by patients in the past six months (n = 59) were compared with those who had not been assaulted (n = 34). Direct-care staff were more likely to be assaulted than were other staff. Assaulted staff were more likely to report prior nonsexual assault by a stranger, higher anxiety, more somatic concerns, greater vulnerability and lack of control, and higher levels of impairment at work and were more likely to consider terminating employment than were non-assaulted staff. Our cross-sectional data suggest several differences in assaulted versus non-assaulted staff. Further studies are needed to determine whether differences in anxiety and traumatic events precede assaults or represent antecedent risk factors for being assaulted. | 18,802,185 |
Defining mental disorder when it really counts: DSM-IV-TR and SVP/SDP statutes. | Civil commitment under the sexually violent predator (SVP) statutes requires the presence of a statutorily defined diagnosed mental disorder linked to sexual offending. As a consequence of broad statutory definitions and ambiguously written court decisions, a bright line separating an SVP mental disorder from ordinary criminal behavior is difficult to draw. Some forensic evaluators reject whole categories of DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders: Text Revision) diagnoses as qualifying disorders (e.g., personality and substance abuse disorders), while others debate whether recurrent rape constitutes a paraphilic disorder. We argue that the ramifications of the SVP process, in representing both the balancing of public safety and the protection of an individual's right to liberty, demand that decisions about what is a legally defined mental disorder not be made in an arbitrary and idiosyncratic manner. Greater clarity and standardization must come from both sides: the legalists who interpret the law and the clinicians who apply and work under it. | 18,802,187 |
Delay to diagnosis in acute pediatric arterial ischemic stroke. | For the clinician, the diagnosis of arterial ischemic stroke (AIS) in children is a challenge. Prompt diagnosis of pediatric AIS within 6 hours enables stroke-specific thrombolytic and neuroprotective strategies. We conducted a retrospective study of prospectively enrolled consecutive cohort of children with AIS, admitted to The Hospital for Sick Children, Toronto, from January 1992 to December 2004. The data on clinical presentation, symptom onset, emergency department arrival, neuroimaging and stroke diagnosis were recorded. The putative predictors of delayed diagnosis were selected a priori for analysis. A total of 209 children with AIS were studied. The median interval from symptom onset to AIS diagnosis was 22.7 hours (interquartile range: 7.1 to 57.7 hours), prehospital delay (symptom onset to hospital arrival) was 1.7 hours (interquartile range: 49 minutes to 8.1 hours), and the in-hospital delay (presentation to diagnosis) was 12.7 hours (interquartile range: 4.5 to 33.5 hours). The initial assessment was completed in 16 minutes and initial neuroimaging in 8.8 hours. The diagnosis of AIS was suspected on initial assessment in 79 (38%) children and the initial neuroimaging diagnosed AIS in 47%. The parent's help seeking action, nonabrupt onset of symptoms, altered consciousness, milder stroke severity, posterior circulation infarction and lack of initial neuroimaging at a tertiary hospital were predictive delayed AIS diagnosis. In the diagnosis of AIS, significant prehospital and in-hospital delays exist in children. Several predictors of the delayed AIS diagnosis were identified in the present study. Efforts to target these predictors can reduce diagnostic delays and optimize the management of AIS in children. | 18,802,206 |
Retrograde catheterization of haemodialysis fistulae and grafts: angiographic depiction of the entire vascular access tree and stenosis treatment. | The European Best Practice Guidelines on Vascular Access propose magnetic resonance angiography (MRA) of dysfunctional dialysis fistulae and grafts if visualization of the complete arterial inflow and outflow vessels is needed. In a prospective multi-centre study we determined the technical success rate of complete vascular access tree depiction by digital subtraction angiography (DSA) as an alternative to MRA. Instead of a more invasive brachial artery of femoral artery approach, we performed a retrograde catheterization of the venous outflow or graft, and stenoses were treated in connection with DSA. A catheter was advanced into the central arterial inflow after retrograde puncture of the venous outflow or graft for depiction of the complete inflow, access region and complete outflow. Access DSA through femoral artery puncture was done if the retrograde approach failed to depict the complete vascular access tree. Stenoses with a luminal diameter reduction >or=50% were treated, if possible, in connection with DSA. A total of 116 dysfunctional haemodialysis fistulae and 50 grafts were included. Retrograde DSA depicted the complete vascular tree in 162 patients (97.6%). The arteriovenous anastomosis of four fistulae could not be negotiated by a catheter. DSA demonstrated 247 significant stenoses: 30, 128 and 89 were located in the arterial inflow (12.1%), AV anastomosis and graft region (51.8%) and venous outflow (36.0%), respectively. Ten patients (6.0%) had no stenosis. Eight (4.8%), 55 (33.1%) and 33 (19.9%) patients demonstrated stenoses in only inflow, access region or outflow, respectively. Stenoses in two or three vascular territories were present in 53 (31.9%) and 7 (4.2%) patients, respectively. A technically successful endovascular intervention was obtained in 135 of the 139 patients (97.1%) who underwent angioplasty and/or stent placement. Additional sheath insertion by antegrade outflow puncture was needed in 46 patients (33.1%) for the treatment of coexisting venous outflow stenoses, located downstream from the retrograde positioned sheath. Two minor complications were observed at DSA/angioplasty. As an alternative to MRA, full retrograde DSA is safe and effective for stenosis detection and stenosis treatment. However, access evaluation by a non-invasive imaging modality such as colour duplex ultrasound will be sufficient in most cases as proximal inflow stenoses are encountered in a minority of patients. Full retrograde DSA, including complete arterial inflow depiction, may then be reserved for cases with an unsuccessful outcome following endovascular intervention of stenoses depicted at ultrasound. | 18,802,208 |
Control of development of gastrointestinal system in neonates. | Our recent studies of structure and function of gastrointestinal tract mucosa revealed that the domestification of Sus scrofa corresponds with the significant slowing of the organ development. On top of genetic potential, the nutritional factors (or more precisely - lack of certain biologically active substances in the feed of pregnant sows) are responsible. Moreover, feeding neonates with milk replacers instead of mother's milk further slows down the development. This is manifested by reduced mitotic activity in the crypts and enhanced apoptosis of enterocytes. The negative effects consist of slower replacement of fetal type, vacuolated enterocytes to adult type enterocytes, modified profile of brush border enzymes, alterations in intestinal mucosa barrier, higher susceptibility to infectious agents, and many others. On the other hand, farmers in order to intensify the production, shorten the suckling period imposing the neonatal piglets to be weaned at 3-4 weeks of life and even earlier. Altogether, it makes the weaning disorders one of the most important problems in pig husbandry, and the mortality of piglets in the leading pig-producing countries still reaches 10%. A number of strategies have been developed to counteract the post-weaning problems. One of them is to stimulate the development of the gastrointestinal tract of the neonate by supplementation of the sow diet with certain biologically active substances and plants. The other idea is to speed up the postnatal development of the gut mucosa for example by plant lectins. Lessons from pig studies can be also useful in human nutrition and medicine since the development of porcine gastrointestinal tract shows a great similarity to that of humans. | 18,802,215 |
A postgenomic integrated view of prostaglandins in reproduction: implications for other body systems. | Prostaglandins are primary mediators of pain and are involved in pathological conditions such as hypertension, cancer and inflammation but are also needed for normal function of the female reproductive system. This may hold true for other systems because long term use of selective COX-2 inhibitors such as VIOXX and BEXTRA was associated with heart failure, leading to their withdrawal. A thorough study of the contribution of prostaglandins in the regulation of normal body function is clearly needed. A major drawback of the current therapeutic strategies aiming at controlling PGs is that they aim at early steps of biosynthesis thus blocking all PGs, good and bad. However, PGs often work as opposing dyads such as PGI2-TXA2 in the vascular system and PGF2alpha-PGE2 in the female reproductive system. The paradigm thus appears as effecting selective synthesis, transport and action of individual PG isoforms. In this respect, the female reproductive system appears as an ideal study model. Data from human and animal genome projects allowed identifying the corresponding members of the biosynthetic and signal transduction components of the PG system in different animal species. Of particular interest was that PG terminal synthase shared similarities or identity with enzymes previously known for steroid or sugar metabolism and free radical detoxification. We present here an integrated view of PG action based on observations in the female reproductive system, but with potential strategic implications for cardiovascular and metabolic complications. | 18,802,217 |
Postural Correction in Persons with Neck Pain (II. Integrated Electromyography of the Upper Trapezius in Three Simulated Neck Positions). | In the previous paper (Enwemeka, Bonet, Ingle, et al. 8:235-239, 1986) we showed that patients with neck pain and spasm of the upper trapezius often assume a forward head position, and that two neck positions, axial extension, and neutral neck position are frequently used by physical therapists to correct this faulty neck posture. Because there is no scientific basis for recommending either of the two corrective neck positions, we simulated the three neck positions in 10 normal adults and compared the integrated electromyography (IEMG) of the upper trapezius to determine if the muscle shows less activity in any of the two corrective positions. The results showed significantly less IEMG of the upper trapezius in each of the two corrective neck positions than in the faulty neck position (p < 0.001). No statistically significant difference was found between the IEMGs recorded in the two corrective neck positions (p > 0.10). The implications and limitations of these findings are discussed along with suggestions for future studies. J Orthop Sports Phys Ther 1986;8(5):240-242. | 18,802,224 |
Reliability of a noninvasive method for measuring the lumbar curve*. | The purposes of this paper were to describe a clinically useful and noninvasive method of characterizing the shape of the lumbar spine and to evaluate the reliability and validity of this measurement technique. A flexible ruler was applied to the skin over the lumbar spines of 23 normal adults and an angle in degrees between two spinous processes (L 1 -S2) was calculated. lntratester test-retest reliability was good (ICC = 0.97, N = 89) for two separate measures of two spinal postures. The validity of the flexible ruler measurements was also good when compared to two different measurement techniques from a limited number of patient roentgenographs. The flexible ruler was determined to be a reliable and valid measurement technique for the shape of the lumbar spine and may prove helpful in quantifying lumbar postures and the effectiveness of clinical treatments designed to affect lumbar postures. J Orthop Sports Phys Ther 1986;8(4):180-184. | 18,802,227 |
Femoral transverse torque: an assessment method. | This study compared external and internal femoral torques of asymptomatic male and female subjects. Peak torque values were recorded using the Cybex(R) II isokinetic dynamometer utilizing a prone testing position with the hip in neutral. Males produced significantly higher raw peak torques than females in both external and internal rotation (p < 0.003). However, when torques were normalized to body weight no significant differences were found between male and female subjects. External rotation torques were found to be significantly higher than internal rotation torques for all subjects combined (p c 0.016). No significant difference was found between left and right limbs. The ratio of external to internal rotation torque was 1.08 for males and 1.16 for females. These ratios are suggested as criterion measures for assessing transverse muscle imbalance at the hip joint. J Orthop Sports Phys Ther 1986;7(6):319-324. | 18,802,252 |
Fatigue Response in Human Quadriceps Femoris Muscle during High Frequency Electrical Stimulation*. | The purpose of this study was to examine the fatigue response of the quadriceps femoris muscle to two patterns of high frequency alternating electrical current. Muscle fatigue was evaluated by the comparison of isometric torque fluctuations during the 10-minute application of both stimulus patterns. Muscle fatigue was also assessed during an isokinetic fatigue test which immediately followed both stimulation patterns. The results indicated that greater amounts of electrical stimulation produced lower current-induced contraction intensities with a greater amount of fatigue. During the isokinetic fatigue test, smaller (P < 0.01) exponential peak torque declines were observed following greater amounts of electrical stimulation. This suggested that high frequency current may selectively fatigue fast twitch (FT) muscle fibers. Therefore, it was concluded that selective stimulation of FT muscle fibers may be an important component explaining the mechanism of strength increases following application of high frequency alternating current. J Orthop Sports Phys Ther 1986;7(4):145-153. | 18,802,271 |
Biomechanics of the shoulder. | The terminology of engineering has made biomechanics unnecessarily confusing and intimidating to many clinicians. Frankel and Burnstein's4 classic text on orthopedic biomechanics was so difficult to understand that it was not fully appreciated. Fortunately, the gap between mechanical engineers and clinicians has been ~losing.'C~o - operation between engineers and clinicians has led to the translation of the confusing mathematical properties of biomechanics into readable and clinically applicable terms (for example, see Frankel and Nordin5). This review will be in keeping with the current trend of basic, clinically applicable biomechanics. Specifically, we propose to review the function of the shoulder girdle, particularly scapulohumeral control of the arm, describing the pertinent mechanical properties. The function of the bones and joints will be,related to their structure and forces applied to them. This review should not be considered an exhaustive biomechanical analysis of the structures involved. References have been provided for that purpose. J Orthop Sports Phys Ther 1985;6(4):229.334. | 18,802,308 |
The effects of passive joint mobilization on pain and hypomobility associated with adhesive capsulitis of the shoulder. | The purpose of this investigation was to determine the effects of passive mobilization and active exercises in patients with painfully restricted shoulders. Twenty patients with painful glenohumeral restrictions were randomly placed in one of two groups. The experimental group received mobilization and active exercises two to three times per week for 4 weeks. The controls received only active exercises. Pain questionnaires were answered and isolated glenohumeral mobility measurements were taken initially and at weekly intervals during the 4 weeks of treatment. With the exception of internal rotation in the control groop, all motions increased significantly from baseline in both groups. Passive abduction improved significantly more in the mobilization group than in the control group. Pain scores decreased more in the mobilization group; however, the difference between the groups was not significant. The results suggest that joint mobilization and exercises are clinically effective in the treatment of painfully stiff shoulders. J Orthop Sports Phys Ther 1985;6(4):238-246. | 18,802,309 |
Air-borne microbial contamination of surfaces in a UK dental clinic. | Little is known about the number, type, or antibiotic resistance profiles, of air-borne microbes present in hospital settings yet such information is important in designing effective measures to reduce cross-infection. In this study settle plates were used to identify and quantify the air-borne microbes present in a dental clinic. All isolates were identified to species level using partial 16S ribosomal RNA gene sequencing and their susceptibility to ampicillin, chloramphenicol, erythromycin, gentamicin, penicillin, tetracycline or vancomycin was performed. The mean numbers of viable bacteria detected for each sampling occasion during periods of clinical activity and in the absence of such activity were 21.9 x 10(2 )cfu/m2/h and 2.3 x 10(2 )cfu/m2/h respectively. One hundred ninety-three distinct colony morphotypes, comprising 73 species, were isolated during the study and 48% of these were resistant to at least one antibiotic. The mean numbers of different morphotypes detected per sampling occasion were 14.3 and 5 during periods of clinical activity and inactivity respectively. Propionibacterium acnes, Micrococcus luteus and Staphylococcus epidermidis were frequently isolated regardless of whether any clinical activities were taking place. These findings highlight the importance of preventing surfaces from becoming reservoirs of antibiotic-resistant bacteria and thereby contributing to cross-infection in the dental clinic. | 18,802,318 |
Microbial community in the rhizosphere of young maize seedlings is susceptible to the impact of introduced pseudomonads as indicated by FAME analysis. | Two species of Pseudomonas (i.e. P. chlororaphis or P. putida) derived from a maize rhizosphere were studied for their impact on the structure of the microbial community in the rhizosphere of young maize seedlings after inoculation. The culturable bacteria and total microbial communities were analyzed based on profiles of whole-cell fatty acid methyl esters (MIDI-FAME). The introduction of Pseudomonas species resulted in the shift from the Gram-positive dominated culturable community in the rhizosphere of uninoculated maize to more Gram-negative populations in the rhizospheres of the inoculated plants. For the total rhizosphere communities, 43, 47 and 42 FAMEs were detected in the uninoculated maize and the samples inoculated with P. chlororaphis or P. putida, respectively. In contrast to the culturable communities, low concentrations of marker FAMEs for Gram-positives (i15:0, a15:0, i16:0) were found in the profiles of the total rhizosphere communities. The maize inoculations resulted in an enrichment of some Gram-negative isolates; however, Gram-positive bacteria, Cytophaga/Flavobacterium and saprophytic fungi were found in the uninoculated rhizosphere. | 18,802,319 |
Mast cells and mast cell-derived factors in the regulation of allergic sensitization. | Mast cells have been mainly regarded as effector cells in IgE-dependent mucosal immunity, including the host response to helminthic parasites but also the formidable and sometimes fatal anaphylactic reactions to inhaled or ingested allergens. Work performed mostly within the last decade revealed novel functions for mast cells as critical initiators of fast inflammatory reactions upon IgE-independent activation. Thus, their role as a sentinel in innate immunity also suggests that mast cells are able to bridge innate and adaptive immunity. Herein, we will summarize the accumulating evidence that mast cells are also able to promote and to modulate the development of adaptive immune reactions with emphasis on their role in allergic sensitization in skin and lung. Based on murine data published so far, it is becoming apparent that mast cells and their mediators are of critical relevance for allergen sensitization under conditions which more closely resemble physiological contact with allergens. Yet, the function of mast cells can sometimes be bypassed using vigorous sensitization protocols, a finding which should be taken into account when animal models for complex human diseases are investigated. | 18,802,337 |
Immune regulation and tolerance to fungi in the lungs and skin. | The balance of pro- and anti-inflammatory signaling is a prerequisite for successful host/fungal interactions and requires the coordinate actions of both innate and adaptive immune systems. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases and limit protective antifungal immune responses. The newly described Th17 develop - mental pathway may play an inflammatory role previously attributed to uncontrolled Th1 responses and serve to accommodate the seemingly paradoxical association of chronic inflammatory responses with fungal persistence in the face of an ongoing inflammation. In this scenario, unrestricted fungal growth could result from the activation of not only pathogenic Th17 cells, but also Th2 cells whose activation is strictly dependent on fungal burden. The capacity of regulatory T cells (Tregs) to inhibit aspects of innate and adaptive antifungal immunity is required for protective tolerance to fungi. Indoleamine 2,3-dioxygenase (IDO) and tryptophan catabolites contribute to such a homeostatic condition by providing the host with immune defense mechanisms adequate for protection, without necessarily eliminating fungal pathogens - which would impair immune memory - or causing an unacceptable level of tissue damage. IDO and tryptophan metabolites may prove to be potent regulators capable of taming overzealous or heightened inflammatory host responses. | 18,802,343 |
Definition and classification of acute kidney injury. | Changes in urine output and glomerular filtration rate are neither necessary nor sufficient for the diagnosis of renal pathology. Yet no simple alternative for the diagnosis currently exists. Until recently, there has been no consensus as to diagnostic criteria or clinical definition of acute renal failure. Depending on the definition used, acute renal failure has been reported to affect from 1 to 25% of ICU patients and has led to mortality rates from 15 to 60%. The RIFLE criteria were developed to standardize the diagnosis of acute renal failure and in the process the term acute kidney injury (AKI) has been proposed to encompass the entire spectrum of the syndrome from minor changes in renal function to requirement for renal replacement therapy. Thus, AKI is not acute renal failure but a more general description. Small changes in kidney function in hospitalized patients are important and are associated with significant changes in short and possibly long-term outcomes. The RIFLE criteria provide a uniform definition of AKI and have now been validated in numerous studies. | 18,802,365 |
The bioartificial kidney and bioengineered membranes in acute kidney injury. | The treatment of severe acute kidney injury (AKI) with dialysis or hemofiltration remains suboptimal with high levels of morbidity and mortality. Current renal replacement therapies substitute for the small solute clearance function of the kidney but do not replace the lost reclamation, metabolic and endocrine functions of this organ. Cell therapy and tissue engineering offer hope of fuller replacement of kidney function in renal failure patients. A renal tubule assist device (RAD) that includes a conventional hemodialysis filter and a bioreactor containing living renal proximal tubule cells has been successfully engineered. Differentiated activity of these cells and survival advantages have been demonstrated in large-animal models of sepsis and AKI. Data from phase I/II and phase II clinical studies have shown that the addition of renal tubule cell therapy to conventional continuous renal replacement therapy (CRRT) treatment resulted in a significant clinical impact on survival, and that RAD treatment demonstrated an acceptable safety profile. Another substantive advance for the treatment of AKI will be the development of nanofabrication technology to further improve the clearance function of the kidney to replicate glomerular permselectivity while retaining high rates of hydraulic permeability. New developments in this translational research area will improve the unmet medical needs of patients with renal failure. | 18,802,374 |
c-myc antisense oligonucleotides sensitize human colorectal cancer cells to chemotherapeutic drugs. | Overexpression of the c-myc oncogene frequently occurs in both colon tumors and colon carcinoma cell lines. We examined the sensitization of human colorectal cancer cells to chemotherapeutic drugs using c-myc antisense (AS) phosphorothioate oligonucleotides ([S]ODNs). Cancer cells were treated with c-myc [S]ODNs, taxol, 5-fluorouracil (5-FU), doxorubicin and vinblastine individually and in combination. The antiproliferative effects, type of interaction between c-myc [S]ODNs and cytotoxic drugs, cell cycle, apoptosis and expression of cell-cycle- and apoptosis-regulatory genes were evaluated. After treatment with c-myc AS[S]ODNs, the growth of cancer cells was markedly inhibited in a dose- and time-dependent manner and the levels of c-myc mRNA and protein were greatly decreased (p < 0.0001). The combinations of c-myc AS[S]ODNs and cytotoxic drugs produced greater growth inhibition of human colorectal cancer cells compared to single treatment with either c-myc AS[S]ODNs (p < 0.006) or cytotoxic drugs (p < 0.0001). These combinations exhibited time- and dose-dependent additive and/or synergistic antiproliferative effects. Cancer cells treated with cytotoxic drugs were growth arrested in the S phase. In contrast, cells treated with either c-myc AS[S]ODNs or by the combination of c-myc AS[S]ODNs and cytotoxic drugs were growth arrested in the G(2)/M and S phases. The combination treatments also exhibited a marked apoptotic effect compared to single treatments. c-myc AS[S]ODN treatment reduced the mRNA levels of Bcl2, BclxL, cdk2, cyclin E1, cdk1 and cyclin B1, while increasing the mRNA levels of p21, p27, bax and caspase-3. This two-hit approach may be important in the quest to overcome drug resistance in cancer patients whose tumors carry an overexpressed c-myc gene. | 18,802,399 |
Monitoring the rate of hospitalization before rotavirus immunization in Italy utilizing ICD9-CM regional databases. | Recently, two Rotavirus (RV) vaccines were licensed in Italy, rendering RV illness a vaccine preventable disease. To assess the RV hospitalization rate in Italy, a study focused on the Regional hospital discharge forms (HDD) databases was carried out. Regional HDD databases from Piemonte, Veneto, Friuli-Venezia-Giulia and Marche were analyzed. A total of 434,335 hospitalizations were counted in the study timeframe and 13,234 VE diagnoses (3% of hospitalizations) were collected. A total of 8546 RVE cases (2% of hospitalizations, 64% of all VE) were observed, of which 1.2% were primary diagnoses (PD) and 0.8% secondary diagnosis (SD). The RVE hospitalization peak (4.9%) was observed at the age of 1 year (4.5% in 7-12 months of age) with a median hospital stay of 4.4 days (s.d +/- 4.2). Two deaths (out of 8546 RVE cases) were identified. Regional HDD databases with the diagnosis of viral enteritis (VE) and RV enteritis (RVE) (ICD9-CM code 00861-69 and 008.8) in any position of the first 20 discharge diagnoses in children aged less or equal to 5 years between 2001 and 2005 were requested. Despite some limitations due to the HDD synthetic contents and low potential for clinical interpretation, the Regional HDD databases, including PD and SD, may be a useful tool for monitoring the clinical impact of RV vaccination introduction in Italy. | 18,802,404 |
Function and regulation of protein neddylation. 'Protein modifications: beyond the usual suspects' review series. | Neddylation is the post-translational protein modification that is most closely related to ubiquitination. However, ubiquitination is known to regulate a myriad of processes in eukaryotic cells, whereas only a limited number of neddylation substrates have been described to date. Here, we review the principles of protein neddylation and highlight the mechanisms that ensure the specificity of neddylation over ubiquitination. As numerous neddylation substrates probably remain to be discovered, we propose some criteria that could be used as guidelines for the characterization of neddylated proteins. | 18,802,447 |
Modeling recursive RNA interference. | An important application of the RNA interference (RNAi) pathway is its use as a small RNA-based regulatory system commonly exploited to suppress expression of target genes to test their function in vivo. In several published experiments, RNAi has been used to inactivate components of the RNAi pathway itself, a procedure termed recursive RNAi in this report. The theoretical basis of recursive RNAi is unclear since the procedure could potentially be self-defeating, and in practice the effectiveness of recursive RNAi in published experiments is highly variable. A mathematical model for recursive RNAi was developed and used to investigate the range of conditions under which the procedure should be effective. The model predicts that the effectiveness of recursive RNAi is strongly dependent on the efficacy of RNAi at knocking down target gene expression. This efficacy is known to vary highly between different cell types, and comparison of the model predictions to published experimental data suggests that variation in RNAi efficacy may be the main cause of discrepancies between published recursive RNAi experiments in different organisms. The model suggests potential ways to optimize the effectiveness of recursive RNAi both for screening of RNAi components as well as for improved temporal control of gene expression in switch off-switch on experiments. | 18,802,453 |
Computational structural analysis: multiple proteins bound to DNA. | With increasing numbers of crystal structures of proteinratioDNA and proteinratioproteinratioDNA complexes publically available, it is now possible to extract sufficient structural, physical-chemical and thermodynamic parameters to make general observations and predictions about their interactions. In particular, the properties of macromolecular assemblies of multiple proteins bound to DNA have not previously been investigated in detail. We have performed computational structural analyses on macromolecular assemblies of multiple proteins bound to DNA using a variety of different computational tools: PISA; PROMOTIF; X3DNA; ReadOut; DDNA and DCOMPLEX. Additionally, we have developed and employed an algorithm for approximate collision detection and overlapping volume estimation of two macromolecules. An implementation of this algorithm is available at http://promoterplot.fmi.ch/Collision1/. The results obtained are compared with structural, physical-chemical and thermodynamic parameters from proteinratioprotein and single proteinratioDNA complexes. Many of interface properties of multiple proteinratioDNA complexes were found to be very similar to those observed in binary proteinratioDNA and proteinratioprotein complexes. However, the conformational change of the DNA upon protein binding is significantly higher when multiple proteins bind to it than is observed when single proteins bind. The water mediated contacts are less important (found in less quantity) between the interfaces of components in ternary (proteinratioproteinratioDNA) complexes than in those of binary complexes (proteinratioprotein and proteinratioDNA).The thermodynamic stability of ternary complexes is also higher than in the binary interactions. Greater specificity and affinity of multiple proteins binding to DNA in comparison with binary protein-DNA interactions were observed. However, protein-protein binding affinities are stronger in complexes without the presence of DNA. Our results indicate that the interface properties: interface area; number of interface residues/atoms and hydrogen bonds; and the distribution of interface residues, hydrogen bonds, van der Walls contacts and secondary structure motifs are independent of whether or not a protein is in a binary or ternary complex with DNA. However, changes in the shape of the DNA reduce the off-rate of the proteins which greatly enhances the stability and specificity of ternary complexes compared to binary ones. | 18,802,470 |
Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. | Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis. | 18,802,480 |
Click chemistry step growth polymerization of novel alpha-azide-omega-alkyne monomers. | A novel step growth polymerization A-B strategy based on the click chemistry polyaddition of tailor-made alpha-azide-omega-alkyne low molar mass monomers was developed, leading to polytriazole (co)polymers with tunable structures and properties. | 18,802,508 |
Multiple molecular logic functions and molecular calculations facilitated by surfactant's versatility. | Two isomeric compounds and , combining intramolecular charge transfer (ICT) and photoinduced electron transfer (PET) mechanisms together, were designed and used as logic gates with configurable multiple outputs; ten different logic functions (AND, NAND, OR, NOR, XNOR, INHIBIT, YES, NO, PASS 1 and PASS 0) were achieved by varying the inputs threshold or by altering the inputs; furthermore, half addition and half subtraction were performed within (or ); the concept demonstrated here may provide a strategy for constructing more integrated molecular level devices with multiple functions. | 18,802,509 |
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