title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Probing phenylalanine/adenine pi-stacking interactions in protein complexes with explicitly correlated and CCSD(T) computations. | To examine the effects of pi-stacking interactions between aromatic amino acid side chains and adenine bearing ligands in crystalline protein structures, 26 toluene/(N9-methyl)adenine model configurations have been constructed from protein/ligand crystal structures. Full geometry optimizations with the MP2 method cause the 26 crystal structures to collapse to six unique structures. The complete basis set (CBS) limit of the CCSD(T) interaction energies has been determined for all 32 structures by combining explicitly correlated MP2-R12 computations with a correction for higher-order correlation effects from CCSD(T) calculations. The CCSD(T) CBS limit interaction energies of the 26 crystal structures range from -3.19 to -6.77 kcal mol (-1) and average -5.01 kcal mol (-1). The CCSD(T) CBS limit interaction energies of the optimized complexes increase by roughly 1.5 kcal mol (-1) on average to -6.54 kcal mol (-1) (ranging from -5.93 to -7.05 kcal mol (-1)). Corrections for higher-order correlation effects are extremely important for both sets of structures and are responsible for the modest increase in the interaction energy after optimization. The MP2 method overbinds the crystal structures by 2.31 kcal mol (-1) on average compared to 4.50 kcal mol (-1) for the optimized structures. | 18,922,031 |
A concise synthesis of pawhuskin A. | Pawhuskin A is an isoprenylated stilbene that was isolated from Dalea purpurea and reported to have affinity for the opioid receptor in vitro. It has been synthesized through a convergent sequence that joins a prenylated aldehyde with a geranylated phosphonate in a stereoselective Horner-Wadsworth-Emmons condensation to afford the target E olefin isomer. This synthesis confirms the structure assigned to the natural product and establishes a route that may be used to explore its biological activity and to prepare more active analogues. | 18,922,035 |
Rapid interhemispheric switching during vocal production in a songbird. | To generate complex bilateral motor patterns such as those underlying birdsong, neural activity must be highly coordinated across the two cerebral hemispheres. However, it remains largely elusive how this coordination is achieved given that interhemispheric communication between song-control areas in the avian cerebrum is restricted to projections received from bilaterally connecting areas in the mid- and hindbrain. By electrically stimulating cerebral premotor areas in zebra finches, we find that behavioral effectiveness of stimulation rapidly switches between hemispheres. In time intervals in which stimulation in one hemisphere tends to distort songs, stimulation in the other hemisphere is mostly ineffective, revealing an idiosyncratic form of motor dominance that bounces back and forth between hemispheres like a virtual ping-pong ball. The intervals of lateralized effectiveness are broadly distributed and are unrelated to simple spectral and temporal song features. Such interhemispheric switching could be an important dynamical aspect of neural coordination that may have evolved from simpler pattern generator circuits. | 18,922,044 |
Multibend endoscope facilitates endoscopic hemostasis for bleeding gastric ulcer at high lesser curvature. | Bleeding peptic ulcer located high at a lesser curvature is one of the factors that predicted the failure of endoscopic therapy. One of the reasons is the technical difficulty in targeting the bleeding point over a gastric ulcer located high at a lesser curvature. A multibend endoscope was initially developed to facilitate the performance of an endoscopic submucosal dissection over difficult positions, including lesser curvature and cardia of the stomach. In this paper, we report 3 cases of difficult hemostasis for an ulcer located at a high lesser curvature where a novel multibending endoscope was employed to facilitate the endoscopic therapy. | 18,922,060 |
Laparoscopically assisted extrahepatic cyst excision and left hemihepatectomy for a type IV-A choledochal cyst. | Some studies have reported on laparoscopic excision for treating the choledochal cyst, yet there are no reports on laparoscopic surgery for treating type IV-A choledochal cysts that require a liver resection. In this paper, we report on a case of laparoscopic cyst excision combined with left hemihepatectomy and laparoscopy-assisted Roux-en-Y hepaticojejunostomy for treating a type IV-A choledochal cyst. A 51-year-old female was admitted with symptoms of jaundice and cholangitis. Percutaneous transhepatic biliary drainage (PTBD) was done preoperatively for controlling the cholangitis. The imaging studies revealed a type IV-A choledochal cyst with an associated stricture of the left main intrahepatic duct. After the resolution of the cholangitis, total laparoscopic cyst excision and left hemihepatectomy were performed by using the four-port technique, and then a Roux-en-Y hepaticojejunostomy was done by a laparoscopy-assisted method. The total operation time was 420 minutes. The estimated blood loss was 300 mL, and no perioperative transfusion was needed. The tubogram, which was performed through the PTBD on postoperative day 5, showed good patency of the bilioenteric anastomosis and no biliary leakage. The patient was discharged at postoperative day 7 without any complications. This case shows the feasibility of performing laparoscopic surgery for treating a type IV-A choledochal cyst that requires a liver resection. We believe that laparoscopic cyst excision with a liver resection can be one of the treatment options for selected patients with type IV-A choledochal cysts. | 18,922,063 |
Laparoscopic liver resection for cancer. | The field of laparoscopic liver resection surgery has rapidly evolved, with more than 1000 cases now reported. Laparoscopic hepatic resection was initially described for small, peripheral, benign lesions. Experienced teams are now performing laparoscopic anatomic resections for cancer. Operative times improved with experience. When compared with open cases, blood loss was less in most laparoscopic series, but was the main indication for conversion to an open procedure. Patients undergoing laparoscopic resection had shorter length of hospital stay and quicker recovery. Perioperative complications were comparable between the two approaches. Importantly, basic oncologic principles were maintained in the laparoscopic liver resections. The purpose of this review is to summarize the data available on outcomes for laparoscopic hepatic resection for cancer. This includes primary hepatocellular carcinoma, as well as metastatic colorectal cancer to the liver. The evidence to date suggests that laparoscopic results are comparable with the open approach in cancer patients. | 18,922,123 |
Diurnal temperature range as a novel risk factor for COPD death. | Although the relationship between day-to-day temperature changes and COPD mortality is well established, it is not known whether temperature variation within one day, that is diurnal temperature range (DTR), is a risk factor for acute COPD death, independent of the absolute temperature level. In a time-series study, the relationship between DTR and daily COPD mortality between 2001 and 2004 in Shanghai, China was assessed. A semi-parametric generalized additive model was used to allow for long-term and seasonable trends in COPD mortality, as well as variation in air pollution and weather. There was a significant association between DTR and daily COPD mortality. A 1 degrees C increase in the 4-day moving average for DTR corresponded to a 1.25% (95% confidence interval: 0.35-2.15) increase in COPD mortality. These findings suggest that DTR is a novel risk factor for acute COPD death. | 18,922,144 |
Physical and in silico approaches identify DNA-PK in a Tax DNA-damage response interactome. | We have initiated an effort to exhaustively map interactions between HTLV-1 Tax and host cellular proteins. The resulting Tax interactome will have significant utility toward defining new and understanding known activities of this important viral protein. In addition, the completion of a full Tax interactome will also help shed light upon the functional consequences of these myriad Tax activities. The physical mapping process involved the affinity isolation of Tax complexes followed by sequence identification using tandem mass spectrometry. To date we have mapped 250 cellular components within this interactome. Here we present our approach to prioritizing these interactions via an in silico culling process. We first constructed an in silico Tax interactome comprised of 46 literature-confirmed protein-protein interactions. This number was then reduced to four Tax-interactions suspected to play a role in DNA damage response (Rad51, TOP1, Chk2, 53BP1). The first-neighbor and second-neighbor interactions of these four proteins were assembled from available human protein interaction databases. Through an analysis of betweenness and closeness centrality measures, and numbers of interactions, we ranked proteins in the first neighborhood. When this rank list was compared to the list of physical Tax-binding proteins, DNA-PK was the highest ranked protein common to both lists. An overlapping clustering of the Tax-specific second-neighborhood protein network showed DNA-PK to be one of three bridge proteins that link multiple clusters in the DNA damage response network. The interaction of Tax with DNA-PK represents an important biological paradigm as suggested via consensus findings in vivo and in silico. We present this methodology as an approach to discovery and as a means of validating components of a consensus Tax interactome. | 18,922,151 |
Rapid and reliable diagnosis of murine myeloid leukemia (ML) by FISH of peripheral blood smear using probe of PU. 1, a candidate ML tumor suppressor. | Murine myeloid leukemia (ML) provides a good animal model to study the mechanisms of radiation-induced leukemia in humans. This disease has been cytogenetically characterized by a partial deletion of chromosome 2 with G-banding. For the rapid diagnosis of ML, this study reports a FISH method using spleen cells and peripheral blood smears from ML mice exposed to gamma rays and neutrons with PU.1, a candidate ML tumor suppressor, as a probe. Among mice that were tentatively diagnosed with ML by clinical findings and blood smear examination, 85% carried spleen cells showing the loss of PU.1 although the frequency of these abnormal cells varied among individuals. Mice with very low frequencies of cells showing the loss of one copy of PU.1 (one-PU.1 frequency) were later diagnosed pathologically not with ML but with blastic or eosinophilic leukemia. Some neutron-irradiated mice had cells showing translocated PU.1, although no pathological features differentiated these ML mice from ML mice expressing the simple loss of PU.1.The one-PU.1 frequency can be detected from spleen metaphase cells, spleen interphase cells, and blood smears. There was a good correlation between the one-PU.1 frequency in spleen metaphase cells and that in spleen interphase cells (r = 0.96) and between one-PU.1 frequency in spleen interphase cells and that in blood cells (r = 0.83). The FISH method was capable of detecting aberration of copy number of the PU.1 gene on murine chromosome 2, and using a peripheral blood smear is more practical and less invasive than conventional pathological diagnosis or the cytogenetic examination of spleen cells. | 18,922,187 |
Outbreak of subclinical mastitis in a flock of dairy goats associated with atypical Staphylococcus haemolyticus. | Staphylococcus haemolyticus is a pathogen frequently isolated from dairy cows and small ruminants. However, it always appears in only a few animals and not as a major pathogen. Recently, in a dairy goat herd of approximately 250 milking animals, 25.6% (46/180 goats) had milk cultures with atypical highly mucoid colonies accompanied by elevated somatic cell counts. The isolates were identified as Staph. haemolyticus. The present study describes the steps used in an attempt to identify the bacterium and to compare it with other coagulase-negative staphylococci (CNS) including Staph. haemolyticus. Species identification performed with the API STAPH-IDENT 32 kit showed >99.4% identity confirmed by 16S rDNA sequencing tests. Microscopically the atypical Staph. haemolyticus strains showed unique cuboidal tetrad clusters reminiscent of those of the genus Sarcina. The outbreak caused by an atypical CNS underlines the need for accurate biochemical and genetic methods for ultimate identification of CNS to the species level. | 18,922,198 |
The antidepressant venlafaxine ameliorates murine experimental autoimmune encephalomyelitis by suppression of pro-inflammatory cytokines. | Antidepressants are known to impact on the immune system. In this study, we examined the immunomodulatory properties of venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor (SNRI), in murine experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated CNS demyelinating disease model of multiple sclerosis. EAE was induced in SJL/J mice by adoptive transfer of myelin-specific T cells. Mice received different doses of venlafaxine before induction and after onset of disease. Sustained daily oral treatment with 6, 20 and 60 mg/kg significantly ameliorated the clinical symptoms of the disease compared to vehicle during both preventive and therapeutic intervention. Venlafaxine suppressed the generation of pro-inflammatory cytokines IL-12 p40, TNF-alpha and IFN-gamma in encephalitogenic T-cell clones, splenocytes and peritoneal macrophages in vitro. It also diminished mRNA expression of a number of inflammatory genes in the inflamed CNS tissue, among them CD3, CD8, Granzyme B, IL-12 p40, IFN-gamma, TNF-alpha and the chemokines Ccl2 and RANTES, whereas the expression of brain-derived neurotrophic factor was increased. These findings demonstrate the strong immunomodulatory property of the selective SNRI venlafaxine. Further studies are warranted to clarify whether venlafaxine may exert similar effects in humans. | 18,922,202 |
Is there utility in the transtheoretical model? | The transtheoretical model is arguably the dominant model of health behaviour change, having received unprecedented research attention, yet it has simultaneously attracted exceptional criticism. However, the criticisms have been directed almost exclusively at the stages of change, just one of fourteen components of the transtheoretical model, which may have diverted attention away from more fruitful avenues of research based on the model. Narrative review. The evidence would suggest some flaws in the concept of stages of change as currently articulated in the transtheoretical model. On a conceptual level, even studies incorporating the five stages of change point to a model that better fits Gollwitzer (1993) and Heckhausen's (1991) idea of a motivational phase followed by a volitional phase. Potentially the processes of change components of the transtheoretical model may actually prove the most useful, yet have been under-researched, at least experimentally. Three studies that successfully utilise the processes of change to reduce alcohol consumption, encourage smoking cessation and increase physical activity are described. Elements of the transtheoretical model offer promise in developing effective health behaviour change interventions, but the question arises as to whether extracting these elements undermines completely the idea of a transtheoretical model. | 18,922,209 |
[The relationship between physical activity and plasma homocysteine level in young men]. | There is a wealth of studies indicating that elevated concentration of plasma homocysteine (hyperhomocystemia) is one of the risk factors for cardiovascular disease. Additionally, it is documented that plasma homocysteine levels are affected by gender, fat free mass, dietary habits and physical activity. However, data concerning of the physical activity effect on plasma homocysteine concentration are equivocal since both decrease or increase in plasma homocysteine has been noted in response to physical stress. It is worthy to note that in the above mentioned studies different types of physical activity have been implemented and the effect of energy expenditure during physical activity on plasma homocysteine has not been analyzed. The present study aimed at the evaluation of the relationship between activity energy expenditure and plasma homocysteine level in young, healthy men. A total of 83 men--university and physical education students volunteered to participate in the study. In all subjects body mass and height were measured. Their physical activity was briefly assessed using Seven-Day Physical Activity Recall (SDPAR) questionnaire. From the mean level of physical activity for all subjects (expressed in kcal/day) two groups were selected--with high (mean + SD) and low (mean - SD) physical activity. Plasma homocysteine concentrations were determined using fluorescent polarization immunologic analysis (FPIA) and Abbott commercial kits. It was found that in young man with high physical activity plasma homocysteine was significantly lower in comparison with their counterparts characterized by low physical activity (8,7+/-1,8 vs. 11,0+/-3,5 micromol/L, p < 0,02). Moreover, in collected data plasma homocysteine was significantly and inversely correlated with physical activity (r = -0,38, p < 0,05). It has been demonstrated that in young, healthy men characterized by high activity energy expenditure circulating homocysteine is lower than in their less active counterparts. | 18,922,224 |
[Clinical particularism of bipolar disorder: unipolar mania. About a patient's study in Tunesia]. | Although present classifications (CIM, DSM) have not included the notion of a unipolar disorder to characterise the recurrence of the same type of episode, this concept conserves its pertinence for many people. Unipolar mania, in particular, is a clinical reality in our daily practice, and a predominant form of bipolarity expression. These assertions have led us to question this notion and its nosographical place: is it a subtype, distinguished by certain characteristics, or a particular category in the bipolar disorder? We conducted a retrospective, descriptive and comparative study on medical briefs of patients with type I bipolar disorder (DSM-IV criteria), who were interned for the first time between 1997 and 2001 in the Psychiatry "E" service of the Razi hospital of Tunis, and were followed up for at least five years. Two groups were identified: Group 1 or "unipolar mania": patients who presented at least two manic episodes without depression, and Group 2: the rest of the sample; and then were compared based on their sociodemographical profile, familial psychiatric antecedents, premorbid temperament, comorbidity and clinical and progressive characteristics. Seventy-two patients were included. The average age was 36. The sex ratio was three men to two women. The first episode was a manic episode in 56.9% of the cases. The average duration of illness progression was 11.6 years. Unipolar mania represented 65.3% of the sample. Between 1997 and 2001, 92% of bipolar patients interned were hospitalised for mania. Concerning recurrences, we observed nine times as many cases of manic episodes as depression. Depressive episodes of light to medium intensity had probably not been well assessed due to the families' tolerance. The high rates of both manic episodes and unipolar mania observed in this study were also found by other authors, showing the differences of bipolarity expression between the West and the other parts of the world, and in particular Africa. There was no significant difference concerning the sociodemographical features. We noticed similar results in the literature. The two groups were comparable in familial psychiatric past history and premorbid temperament. Substance abuse or dependence was observed in 5.6% of the patients. This rate was less than others found in the literature, due to the fact that it is considered as an offence in our country. We found twice as many cases of toxic consumption in bipolar as in unipolar manic patients. A recent Tunisian study has shown the absence of substance abuse in unipolar manic patients. This is probably because of the fact that substance abuse is more related to depressive manifestations. The sample starting age was 24.6 years and was significantly more precocious in the unipolar manic group (27.6 years versus 23 years, p=0.001). A significant difference in both groups was found concerning the first episode season: two extremities were observed: "summer-autumn" in Group 1 (63.6% G1 versus 29.4% G2) and "winter-spring" in Group 2 (73.6% G2 versus 36.4% G1), p=0.03. The seasonal influence on mood disorders is dealt with by other authors. Unipolar manic patients presented less affective recurrences than the rest of the group (0.37 versus 0.49 on average per year), p=0.056. Unipolar mania is still considered as a clinical variety of bipolar disorder, which is distinguished by certain features. It is a debated notion because it is based on retrospective studies that may be insufficient, although it appears as a clinical evidence and a predominant progressive variety of bipolar disorder in Tunisia. | 18,922,234 |
Effect of phosphate group addition on the properties of denture base resins. | Acrylic resins are prone to microbial adherence, especially by Candida albicans. Surface-charged resins alter the ionic interaction between the denture resin and Candida hyphae, and these resins are being developed as a means to reduce microbial colonization on the denture surface. The purpose of this study was to investigate the physical and mechanical properties of phosphate-containing polymethyl methacrylate resins for their suitability as a denture material. Using PMMA with cross-linker (Lucitone 199) as a control, 4 experimental groups containing various levels of phosphate with and without cross-linker were generated. The properties examined were impact strength, fracture toughness, wettability (contact angle), and resin bonding ability to denture teeth. Impact strength was tested in the Izod configuration (n=16), and fracture toughness (n=13) was measured using the single-edge notched bend test. Wettability was determined by calculating the contact angle of water on the material surface (n=12), while ISO 1567 was used for bonding ability (n=12). The data were analyzed by 1- and 2-way ANOVA (alpha=.05). A trend of increased hydrophilicity, as indicated by lower contact angle, was observed with increased concentrations of phosphate. With regard to the other properties, no significant differences were found when compared with the control acrylic resin. No adverse physical effect due to the addition of a phosphate-containing monomer was found in the acrylic denture resins. Additional mechanical and physical properties, biocompatibility, and clinical efficacy studies are needed to confirm the in vivo anti-Candida activity of these novel resins. | 18,922,259 |
Adhesion of Streptococcus mutans NCTC 10449 to artificial teeth: an in vitro study. | Plaque on dentures may foster the occurrence of denture stomatitis and periodontal diseases in gingival tissues adjacent to partial dentures. Thus, it is beneficial for dental materials to have a low susceptibility to plaque adhesion. The purpose of this study was to evaluate the susceptibility of commonly used artificial teeth to adhesion of the oral bacterium Streptococcus mutans. Fifteen specimens each of 12 different artificial teeth were prepared by cutting standardized slabs from the buccal tooth surfaces. After normalizing size (round specimens, diameter of 5 mm, 2 mm thick), polishing (grinding paper, grain 1000 and 4000; universal polishing paste), and assessing surface roughness with a profilometric contact surface measurement device, specimens were incubated with Streptococcus mutans NCTC 10449 suspension for 2.5 hours at 37 degrees C. A veneering composite resin (Sinfony) was used as a control. Adherent bacteria were quantified using a fluorometric assay (Resazurin reduction); relative fluorescence intensity correlates linearly with the number of adherent bacteria. Medians and 25%/75% percentiles were calculated, and statistical analysis was performed using the Kruskal-Wallis test and the Bonferroni-adjusted Mann-Whitney U test. The highest values, indicating high adhesion of streptococci, were observed for filler-supplemented teeth with median relative fluorescence values ranging from 6356 to 18,770. Similar values were recorded for a double cross-linked resin tooth (6444). Significantly lowest values, ranging from 1173 to 3974, were found for unfilled PMMA acrylic resin teeth and acrylic resin teeth with an interpenetrating network (1436). Within the limitations of this study, it can be concluded that the adhesion of Streptococcus mutans to unfilled PMMA teeth and teeth with an interpenetrating network is lower than adhesion to artificial teeth supplemented with fillers or double cross-linked acrylic resin teeth. | 18,922,260 |
Neurovascular emergencies in the elderly. | Neurovascular diseases are major causes of disability and death in the elderly; many present as medical emergencies. With the continuing growth of the geriatric population, there has been increasing interest in the impact of aging on the cerebrovascular system. Recent advances in the clinical neurosciences have demonstrated that neurovascular emergencies in the elderly often are amenable to treatment; neuroimaging plays a critical role in diagnosis and neurointerventional techniques are becoming increasingly important therapeutic options. This article provides an overview of some of the common neurovascular disorders in the elderly that require urgent evaluation and treatment, with an emphasis on the expanding role for interventional neuroradiology in their management. | 18,922,295 |
Safely navigating around the facial nerve in three dimensions. | Although much literature discusses the anatomy and injury of the facial nerve branches, the fascial plane of the nerves, particularly where they transition from one plane to another, is rarely emphasized and information is often contradictory. This article describes in three-dimensional, accurate surgical terms where the facial nerve branches are located and how they can be protected during dissection above and below the superficial musculoaponeurotic system-platysma plane. | 18,922,299 |
Surgical results of the intraoral removal of the submandibular gland. | Most patients with benign submandibular disorders have been treated surgically without difficulty via the transcervical approach. An alternative to the standard transcervical approach has been reported such as an intraoral approach. Retrospective chart review of the 77 patients with benign submandibular disorders. All patients underwent an excision of the submandibular gland via intraoral approach. Early postoperative complications developed in 74.0% of the temporary lingual sensory paresis followed by 70.1% of temporary limitation of tongue movement. However, these complications soon resolved in all patients spontaneously. Two cases of postoperative bleeding and 1 case of abscess formation were developed. Whereas late complications developed in 4 cases of residual salivary gland and abnormal sense of mouth floor and 1 case of gustatory sweating (Frey's) syndrome. The major advantages of this approach are no external scar, no injury to the marginal mandibular nerve. The disadvantage is a more difficult dissection to transcervical approach before proper expert, especially in the severe adhesion of salivary gland to surrounding tissue. | 18,922,339 |
Paranasal sinus mucoceles with skull-base and/or orbital erosion: is the endoscopic approach sufficient? | The objective of this study was to review the management of paranasal sinus mucoceles with skull-base and/or orbital erosion in the endoscopic era. A retrospective data analysis. A chart review was performed on 57 patients treated from January 2001 to March 2007. The average age at the time of presentation was 50.6 years with a 1:1 male: female ratio. The most common site was the frontal sinus (54.4%), followed by frontoethmoid (29.8%) and sphenoid (8.8%). Areas of erosion included skull base (40.4%), orbit (50.9%), and both orbit and skull base (8.8%). Endoscopic drainage using image guidance was used in all 57 patients without complications. Fifty-six cases (98.2%) had a functionally patent mucocele opening with a median follow-up of 15 months. The endoscopic approach can be safely used for the management of mucoceles with skull-base and/or orbital erosion. Open adjunct approaches can be avoided in most cases. | 18,922,346 |
Cross-linked polyethylene in total knee arthroplasty: in opposition. | Highly cross-linked polyethylene has been used with success in total hip arthroplasty. The reduction of femoral head penetration has been a uniform finding among researchers at 5 to 7 years of follow-up. However, there have also been newly highlighted modes of failure, as increased brittleness of the material can adversely affect the integrity of the acetabular locking mechanism; and some materials can oxidize in vivo, with additional alterations in mechanical properties and early delamination. The mechanics of articulation in a knee arthroplasty are markedly different and will impose more severe stresses on the polyethylene material than hip arthroplasties. Each change that is made to improve polyethylene wear comes with mechanical trade-offs. It is not clear that the gains in wear that have been shown in hips will translate to knees without adverse ramifications from the altered mechanical properties. | 18,922,371 |
Association of cytochrome P450 1B1 gene expression in peripheral leukocytes with blood lipid levels in waste incinerator workers. | This study investigated whether CYP1B1 gene expression was associated with blood lipids levels. Workers from a municipal waste incineration plant in Taiwan participated in a questionnaire survey and physical examination and provided fasting blood samples for blood lipid analysis. CYP1B1 gene expression in workers' leukocytes was determined with the real-time reverse transcriptase polymerase chain reaction method, and 112 workers were categorized into three groups (low-, medium-, and high-expression) by their relative CYP1B1 gene expression levels. Multiple regression analyses were used to assess the association between blood lipid parameter and CYP1B1 expression. High-density lipoprotein (HDL) cholesterol was significantly lower in the high CYP1B1 expression group than in the low- and medium-expression groups (parameter estimate [standard error]=-7.16 [2.42] and -7.02 [2.46] mg/dL, respectively), after controlling for age, sex, CYP1B1 genotype, duration of employment, current number of cigarettes smoked per day, current alcohol drinking status, and body mass index. Triglycerides, low-density lipoprotein (LDL), and total cholesterol were not significantly different among the CYP1B1 expression groups. Furthermore, workers carrying the CYP1B1 *3 allele had significantly higher mean HDL, LDL, and total cholesterol, respectively, than those with CYP1B1 *1/ *1. CYP1B1 expression was associated with decreased HDL cholesterol levels in incinerator workers. | 18,922,394 |
Patient monitoring during gastrointestinal endoscopy: why, when, and how? | Patient monitoring is intended to reduce the risk of sedation-related cardiopulmonary complications. Physiological monitoring and visual assessment by a qualified individual should be routine during endoscopic procedures. Additionally, ventilatory monitoring should be considered for high-risk patients and those receiving sedation with propofol. | 18,922,405 |
A performance improvement program for community-based gastroenterology. | A robust performance improvement program based in a community gastrointestinal (GI) practice is described. The need for continual improvement and attention to both quality and the bottom line is now essential for independent GI practices. This article provides both a roadmap for developing a program and benchmarks derived from a large integrated single specialty GI practice. | 18,922,413 |
The effects of vasodilation on cardiac output measured by PiCCO. | The purpose of this study was to investigate the effects of vasodilation on cardiac output (CO) measured by pulse contour method using PiCCO (Pulsion Medical Systems AG, Munich, Germany) in comparison with CO by the thermodilution method. A prospective observational study. An operating room in a university hospital. Twenty patients scheduled for off-pump coronary artery bypass grafting. After anesthesia induction with midazolam, fentanyl, and vecuronium, the PiCCO catheter and pulmonary artery catheter were inserted. Before the initiation of surgery, progressively higher infusions of prostaglandin E1 (PGE1) were administered for vasodilation. CO was measured before PGE1 (control); at PGE1 0.01, 0.02, and 0.04 microg/kg/min; and 15 minutes after stopping PGE1 infusion. Systemic vascular resistances (SVRs) at PGE1 0.02 and 0.04 microg/kg/min were significantly lower than the control value. The correlation coefficient (R(2)) at each point, percentage error, and limits of agreement (bias +/- 2 standard deviation of bias) were 0.89, 17, -0.21 +/- 0.53 before PGE1; 0.72, 27, -0.31 +/- 0.93 at 0.01 microg/kg/min; 0.53, 40, -0.62 +/- 1.41 at 0.02 microg/kg/min; 0.57, 34, -0.61 +/- 1.26 at 0.04 microg/kg/min; and 0.97, 21, -0.14 +/- 0.69 L/min 15 minutes after the end of infusion, respectively. PiCCO may not be an alternative to thermodilution measurement without recalibration when SVR decreases by infusion of PGE1 > or = 0.02 microg/kg/min. | 18,922,424 |
Levosimendan in aortic valve surgery: cardiac performance and recovery. | The aim of the present study was to test the hypothesis that levosimendan has beneficial effects on cardiac performance and that the need for other vasoactive medications during and after cardiac surgery would be reduced by levosimendan in patients with severe aortic stenosis (AS) and left ventricular (LV) hypertrophy. A prospective, randomized, double-blind, placebo-controlled clinical study. A university hospital. Twenty-four patients scheduled for aortic valve surgery with or without coronary artery bypass graft surgery were enrolled in the study. Twelve patients received a 24-hour levosimendan infusion (0.2 microg/kg/min) beginning after the induction of anesthesia, and 12 patients received a placebo infusion. Left ventricular ejection fraction, measured before study drug infusion, was lower in the treatment group than in the control group (42% v 54%, p = 0.015). After sternum closure, the ejection fraction dropped in the control group but was maintained at the same level in the treatment group (45% v 48%, not significant). Mixed venous and central venous saturations were significantly lower in the treatment group than in the control group at the baseline, but after the beginning of the study drug infusion, the groups were similar throughout the rest of the follow-up period. The treatment group required more norepinephrine during the operation and less nitroprusside postoperatively. Low output is a result of myocardial stunning and is common after cardiopulmonary bypass. According to the present results, levosimendan may be useful in patients with severe AS and LV hypertrophy because it may prevent LV function from dropping to a critically low level postoperatively. Levosimendan causes vasodilation and thereby decreases mean arterial pressure, but this can be controlled with the use of norepinephrine. | 18,922,425 |
Acute Physiology and Chronic Health Evaluation (APACHE) III outcome prediction after major vascular surgery. | To investigate the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) III scoring system in patients admitted to the intensive care unit (ICU) after major vascular surgery. Retrospective cohort study. A tertiary referral center. Three thousand one hundred forty-eight patients who underwent major vascular surgery between October 1994 and March 2006. None. Data were abstracted from an institutional APACHE III database. Standardized mortality ratios (SMRs) (with 95% confidence intervals) were calculated. The area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow C statistic were used to assess discrimination and calibration, respectively. The mean age of 3,148 patients studied was 70.5 years (+/- standard deviation 9.6). The mean Acute Physiology Score and the APACHE III score on the day of ICU admission were 31.0 (+/- 17.5) and 45.1 (+/- 18.8), respectively. The mean predicted ICU and hospital mortality rates were 3.2% (+/- 7.8%) and 5.0% (+/- 9.5%), respectively. The median (and interquartile range) ICU and hospital lengths of stay were 4.3 (3.6-5.1) and 14 days (11.9-16.8 days), respectively. The observed ICU mortality rate was 2.4% (75/3, 148 patients) and hospital mortality rate was 3.7% (116/3,148). The ICU and hospital SMRs were 0.74 (0.58-0.91) and 0.74 (0.61-0.88), respectively. The AUC of APACHE III-derived prediction of hospital mortality was 0.840 (95% confidence interval, 0.799-0.880), indicating excellent discrimination. The Hosmer-Lemeshow C statistic was 28.492, with a p value <0.01, indicating poor calibration. The APACHE III scoring system discriminates well between survivors and nonsurvivors after major vascular surgery, but calibration of the model is poor. | 18,922,428 |
Computed tomography and magnetic resonance cholangiography. | In patients with biliary obstruction, determining the level and the cause of the obstruction is essential because it can be a key factor for the next step in diagnostic or therapeutic intervention. Noninvasive cholangiography, such as computed tomography (CT) cholangiography or magnetic resonance (MR) cholangiography, allows the diagnosis of cause and level of biliary disease with minimal risk. Traditional magnetic resonance cholangiopancreatography (MRCP) is an established and effective noninvasive diagnostic modality particularly for extrahepatic biliary tract evaluation. Intrahepatic biliary duct evaluation and functional MR, including evaluating for leaks and gallbladder dyskinesia and outlet obstruction, are evolving diagnostic techniques that show promising results. CT cholangiography techniques are especially useful when MRI is not available or contraindicated or when the quality of MRCP images is suboptimal. CT cholangiography is particularly useful as an adjunct to surgery or postsurgical cases. The primary limitation of cholangiographic contrast-enhanced CT cholangiography (the most prevalent type of CT cholangiography) is its hindrance by poor liver function and/or high-grade biliary obstruction. In this setting MRCP is clearly superior. There are different types of CT cholangiography and MRCP. This article discusses the types of CT cholangiography and MRCP techniques and their clinical applications. | 18,922,453 |
Cholangioscopy. | Direct visualization of the bile ducts and gall bladder via cholangioscopy is very useful both in treatment of complex stone cases and the assessment of indeterminate strictures or masses. It allows use of instruments that cannot be used safely with fluoroscopic guidance alone. It also increases procedural efficiency and decreases radiation doses. Careful selection of access routes is critical to ensuring successful cholangioscopy. Tract dilation to accommodate the access sheath should be deferred for several weeks after the initial drainage procedure. This allows clearance of infected material plus allows the tract to mature. Allowing time for tract maturation decreases the chances of bleeding complications. Overall complications occur in about 20% of cases, with major complications occurring in around 8%. Most complications are bleeding or infectious and the majority relate to tract dilation, with a minority being due to the cholangioscopy itself. Successful stone removal can be achieved in about 90 to 95% of cases. Successful diagnosis of indeterminate stricture can be accomplished through a combination of visual inspection and endoscopic-guided biopsy. For intraluminal masses the accuracy of endoscopic biopsy is close to 100% but for periductal metastatic lesions or mural strictures (as with primary sclerosing cholangitis) diagnostic accuracy is significantly lower. | 18,922,458 |
Percutaneous management of postoperative anastomotic biliary strictures. | Postoperative anastomotic biliary strictures can occur after surgery in bile ducts belonging to transplanted or native (nontransplanted) livers. The majority of postoperative anastomotic strictures encountered by interventional radiologists are most likely in liver transplant recipients due to the large and growing liver transplant recipient population worldwide compared with patients with native livers and biliary enteric anastomoses. They occur after 2.5 to 13% of liver transplantations and they represent at least one-half of biliary strictures encountered after liver transplantation. Anastomotic biliary strictures are considered technical in nature, accentuated by fibrosis and scarring that may be secondary to, if not exacerbated by, graft ischemia. There are numerous variables in the percutaneous transhepatic balloon dilation protocols applied to treat anastomotic biliary strictures. These include (1) types of balloons, (2) how long balloons are inflated, (3) how frequently patients return for additional dilation sessions, and (4) the interval(s) at which they return. No alteration in these variables has proven to improve long-term patency. In addition, new technology such as cutting balloons and stents has not been fully evaluated to determine their effect on long-term patency. The current article describes the overall theme of balloon dilation protocols for the management of anastomotic biliary strictures and discusses possible future management of such strictures. | 18,922,459 |
History of community health center affiliations with The New England College of Optometry. | Since the 1970s, The New England College of Optometry (NECO) has been a leader in community-based educational programming. This was accomplished through the development of affiliation agreements with health care facilities that care for the underserved, notably community health centers (CHCs). The college's clinical system, the New England Eye Institute (NEEI), develops CHC programs, manages professional services agreements, initiates teaching affiliation agreements, and leads staff recruitment and retention efforts. CHC collaborations, which effectively address disparities in access to health care and visual health status, represent a significant component of the college's primary care clinical training venues. Since their inception in 1972, these CHC academic-community partnerships have provided more than 650,000 eye examinations to the underserved and have trained more than 3,200 graduates in community-based eye care, interdisciplinary care management environment, clinical prevention strategies, and population health. This report describes NECO's longstanding success with CHCs, explains the scope of practice at CHCs, explains how students are involved in the CHCs' eye care services, and discusses the various management and business arrangements. The benefits and challenges of CHC affiliations with optometry schools and colleges are also discussed. | 18,922,496 |
Risk factors for repeat adverse asthma events in children after visiting an emergency department. | The aim of this study was to identify risk factors for long-term adverse outcomes in children with asthma after visiting the emergency department (ED). A prospective observational study was conducted at the ED of a pediatric tertiary hospital in Ontario, Canada. Patient outcomes (ie, acute asthma episodes and ED visits) were measured at baseline and at 1- and 6-months post-ED discharge. Time trends in outcomes were assessed using the generalized estimating equations method. Multiple conditional logistic regressions were used to model outcomes at 6 months and examine the impact of drug insurance coverage while adjusting for confounders. Of the 269 children recruited, 81.8% completed both follow-ups. ED use significantly reduced from 39.4% at baseline to 26.8% at 6 months (P < .001), whereas the level of acute asthma episodes remained unchanged. Children with drug insurance coverage were less likely to have acute asthma episodes (adjusted odds ratio [AOR] = 0.36; 95% CI, 0.15-0.85; P < .02) or repeat ED visits (AOR = 0.45; 95% CI, 0.20-0.99; P < .05) at 6 months. Other risk factors for adverse outcomes included previous adverse asthma events and certain asthma triggers (eg, cold/sinus infection). Washing bed linens in hot water weekly was protective against subsequent acute asthma episodes. Our study demonstrated significant improvements in long-term outcomes in children seeking acute care for asthma in the ED. Future efforts remain in targeting the sustainability of improved outcomes beyond 6 months. Risk factors identified can help target vulnerable populations for proper interventions, which may include efforts to maximize insurance coverage for asthma medications and strategies to improve asthma self-management through patient and provider education. | 18,922,500 |
Effect of WHO newborn care training on neonatal mortality by education. | Ninety-nine percent of the 4 million neonatal deaths per year occur in developing countries. The World Health Organization (WHO) Essential Newborn Care (ENC) course sets the minimum accepted standard for training midwives on aspects of infant care (neonatal resuscitation, breastfeeding, kangaroo care, small baby care, and thermoregulation), many of which are provided by the mother. The aim of this study was to determine the association of ENC with all-cause 7-day (early) neonatal mortality among infants of less educated mothers compared with those of mothers with more education. Protocol- and ENC-certified research nurses trained all 123 college-educated midwives from 18 low-risk, first-level urban community health centers (Zambia) in data collection (1 week) and ENC (1 week) as part of a controlled study to test the clinical impact of ENC implementation. The mothers were categorized into 2 groups, those who had completed 7 years of school education (primary education) and those with 8 or more years of education. ENC training is associated with decreases in early neonatal mortality; rates decreased from 11.2 per 1000 live births pre-ENC to 6.2 per 1000 following ENC implementation (P < .001). Prenatal care, birth weight, race, and gender did not differ between the groups. Mortality for infants of mothers with 7 years of education decreased from 12.4 to 6.0 per 1000 (P < .0001) but did not change significantly for those with 8 or more years of education (8.7 to 6.3 per 1000, P = .14). ENC training decreases early neonatal mortality, and the impact is larger in infants of mothers without secondary education. The impact of ENC may be optimized by training health care workers who treat women with less formal education. | 18,922,503 |
Impact of a patient-centered technology on medication errors during pediatric emergency care. | The aim of this study was to determine the impact of a patient-centered health information technology (HIT) on the error rate for ordering and prescribing of medications during emergency pediatric care. We conducted a quasi-experimental intervention study by using control and intervention periods to evaluate the effect on medication ordering and prescribing from a patient-centered HIT designed to enhance communication between parents and emergency clinicians during emergency care. Parent-child dyads presenting to 2 emergency department (ED) sites with complaints of fever, asthma, head trauma, otalgia, and dysuria were eligible. During intervention periods, parents used the HIT to enter data on symptoms and medication-related history; a printout provided recommendations to clinicians. Data on errors/adverse drug events were collected via record reviews and phone interviews with parents. The primary outcome was the number of medication errors in orders or prescriptions for drugs targeted by the HIT. Of 2002 parent-child dyads screened, 1810 (90%) were eligible, 1411 of 1810 (78%) were enrolled, and 1410 analyzed; 1097 subjects had a total of 2234 orders or prescriptions written. Of these events, 1289 of 2234 (58%) were associated with at least 1 error. Of the 1755 errors discovered, 232 errors were serious and preventable. Among 654 patients exposed to medications targeted by the HIT, the number of errors per 100 patients during control versus intervention periods was not significantly different (173 vs 134 with both sites combined; P = .35.) The patient-centered HIT demonstrated minimal impact on medication errors during ED care. | 18,922,507 |
Atherosclerosis progression affects the relationship between endothelial function and aortic stiffness. | Aortic stiffening is the most important determinant of elevated systolic blood pressure which in turn is the main contributor to the burden of disease attributable to hypertension. Endothelial function may affect arterial stiffening as has been shown for carotid-aorto-femoral segments in healthy humans or subjects with cardiovascular risk factors. We investigated whether this association is present selectively for aorta and whether it extends to patients with advanced atherosclerosis. Direct measurements of aortic pulse wave velocity (aPWV) to assess aortic stiffness and brachial artery flow-mediated dilatation (bFMD) tests to assess endothelial function were performed in 111 consecutive patients suspected of coronary artery disease. Progression of atherosclerosis was determined on the basis of the presence or absence of significant coronary artery stenosis, CAS (>or=50%) in angiography. bFMD was lower (P<0.001) and aPWV was higher (P<0.001) in a group of 72 patients with advanced atherosclerosis when compared with a group of 39 patients without significant CAS. bFMD was inversely associated with aPWV but only in patients without advanced atherosclerosis (r=-0.37, P=0.02), even after adjustment of confounding factors in a multivariate analysis model (R(2)=0.37, P<0.001). We concluded that endothelial function may influence aortic stiffness which is limited however by the progression of atherosclerosis. | 18,922,528 |
Maedi-visna: the meningoencephalitis in naturally occurring cases. | Lesions were examined at different levels of the central nervous system (CNS) in 64 sheep with natural maedi-visna (MV) meningoencephalitis. All animals showed lesions in more than one of the CNS locations examined; the lesions in the cranial regions were periventricular, while those in the spinal cord affected the white matter funicles. Lesions were found particularly in the cerebellar peduncles (non-suppurative meningoencephalitis), followed by the corpus callosum, hippocampus and thoracic spinal cord. Vascular, infiltrative and malacic histopathological patterns were recognized. One pattern predominated in each section examined, although mixed forms occurred. Vascular lesions occurred with similar frequency at all CNS levels, but infiltrative and malacic lesions predominated at rostral and caudal levels, respectively. Cells consistent with macrophages and shown immunohistochemically to be associated with MV virus were seen in malacic and infiltrative lesions, at the periphery of damaged areas. | 18,922,546 |
Energy intake affects the biotransformation rate, scope for induction, and metabolite profile of benzo[a]pyrene in rainbow trout. | The metabolic conversion of benzo[a]pyrene (B[a]P) by rainbow trout (Oncorhynchus mykiss) hepatocytes was not significantly different between any group of fed fish (fed one of three isoenergetic diets that varied in protein and lipid content at full satiation levels or half rations), however at 12 weeks, fasted fish exhibited significantly reduced B[a]P biotransformation rates (by 58%). Alterations in metabolite profiles were also seen: fasted fish produced significantly more Phase I metabolites, higher levels of both glucuronide and sulphate conjugates, and lower levels of presumptive glutathione conjugates, compared to fed fish. When fish were fasted, higher proportions of phenols were produced, with lower proportions of quinones, triols and tetrols. Inducing metabolism (using beta-naphthoflavone) increased metabolic scope for B[a]P by 2-fold, regardless of each diet's baseline metabolic rate. However, the balance between Phase I and II reactions was altered with induction and fasting: higher proportions of Phase I metabolites were found, with lower glutathione conjugates and higher proportions of triols/tetrols. Fasting-mediated reductions in glutathione conjugation, and increased induction of oxidation vs. conjugating enzymes, can explain altered metabolite profiles. These results suggest that in contaminated habitats, where pollution-induced reductions in food quantity or quality are combined with the presence of toxic compounds and inducers, detoxification rates can be diminished. | 18,922,589 |
Effects of low intensity exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance and type 2 diabetes mellitus. | This study was designed to evaluate effects of exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The subjects consisted of overweight subjects with normal glucose tolerance (NGT, n=10), IGT (n=10) and DM (n=10) (age: 51.1+/-8.2, 56.3+/-8.8 and 58.5+/-6.2 years, respectively). All of these patients performed exercise therapy at lactate threshold intensity for 12 weeks. Before intervention, area under the glucose curve (AUC(PG)) was higher in DM, IGT and NGT groups, and area under the insulin curve (AUC(IRI)) and the early phase insulin secretion as calculated by insulinogenic index was higher in the NGT group than in either the IGT or DM groups (p<0.05). After exercise therapy, the insulin sensitivity, AUC(PG) and AUC(IRI) improved in three groups (p<0.05, respectively). The insulinogenic index increased in IGT and DM groups (p<0.05, respectively), but the changes in the insulinogenic index showed no significant differences between IGT and DM groups. These results suggest that the ss-cell function in subjects with IGT and DM could therefore improve after exercise therapy. Moreover, AUC(PG), AUC(IRI) and insulin sensitivity were also improved no relation to NGT, IGT and DM. | 18,922,594 |
The association of plasma fibrinogen concentration with diabetic microvascular complications in young adults with early-onset of type 2 diabetes. | Diabetic nephropathy is an important risk factor for cardiovascular diseases (CVD). The underlying etiology is not fully understood but may be related to changes in inflammatory and hemostatic markers with kidney disease. We investigated the associations of the markers with microvascular complications in Pima Indians (PI) with early-onset type 2 diabetes (T2DM). C-reactive protein, interleukine-6, fibrinogen, D-dimer, plasmin-antiplasmin complex and plasminogen activator inhibitor-1 were measured in 104 PI (age: 32+/-4 y) with diabetes and 59 (32+/-4 y) with fasting glucose <110 mg/dl and 2-h glucose <140 mg/dl. Urine albumin to creatinine ratio (ACR) was used as marker of nephropathy. Severity of retinopathy was classified in the worse eye by direct ophthalmoscopy as none, background and proliferative. Of these markers, only fibrinogen was associated with ACR (r=0.25, p<0.01). After adjustment for age, sex, percentage Pima heritage, smoking status, diabetes duration, blood pressure and use of aspirin, antihypertensive and antihyperglycemic agents, general linear models (with natural log-transformed values of fibrinogen and ACR as dependent and independent variables, respectively) revealed that a one percent increase in ACR would yield a 0.02% increase in the fibrinogen (beta=0.02, p<0.05). Plasma fibrinogen was also significantly increased with severity of diabetic retinopathy (p<0.05). Increased plasma fibrinogen concentration was associated with diabetic microvascular disease, in particular with nephropathy. This may help to explain the etiologic link between nephropathy and CVD. | 18,922,595 |
Sirt1 increases skeletal muscle precursor cell proliferation. | It is important to understand the mechanisms that control muscle precursor cell (MPC) proliferation for the development of countermeasures to offset the deleterious effects of the aging-related loss of skeletal muscle mass (and myonuclei) and the impaired ability of old muscle to regrow and regenerate. Over-expression of the NAD+-dependent histone deacetylase Sirt1 increased MPC proliferation and cell cycle progression as evidenced by increased 5-bromo-2'-deoxyuridine (BrdU) incorporation, an increase in cell number, proliferating cell nuclear antigen expression, and the phosphorylation of retinoblastoma protein. Associated with the Sirt1-mediated increase in MPC cycle progression were the bidirectional decreases and increases in the expression of the cyclin-dependent kinase inhibitors p21(Waf/Cip1) and p27(Kip1), respectively. Based upon our recent observation that lowering oxygen (O2) in culture from ambient (20%) to estimated physiological levels (5%) increased MPC proliferation, we next measured Sirt1 protein at 5% and 20% O2. Interestingly, in addition to increased proliferation in MPCs cultured at 5% O2, Sirt1 expression increased, compared to 20% O2. Using O2 levels as a platform to modulate basal Sirt1 protein, activation of Sirt1 activity with resveratrol in 20% O2 increased MPC proliferation while inhibition of Sirt1 with nicotinamide in 5% O2 lowered proliferation. For the first time, Sirt1 has been shown to increase MPC proliferation. These findings could have clinical significance since MPC proliferation has important implications in regulating skeletal muscle growth, maintenance, and repair, and the aging-related loss of skeletal muscle mass. | 18,922,599 |
Expanding the scope of practice for enrolled nurses working in an Australian rural health service - implications for job satisfaction. | Career opportunities have been limited for enrolled nurses (ENs) working in small, rural health services. Medication endorsement offers ENs expanded scope of practice which may lead to improved job satisfaction. This small study compared job satisfaction between a group of ENs with recent medication endorsement and a group who elected not to undertake the course in a small, isolated health service. A questionnaire was designed to measure job satisfaction containing the measure of job satisfaction (MJS) scale and other information regarding the course in medication administration. Interviews were also conducted with medication endorsed nurses to gain a greater understanding about the course and their expanded scope of practice. Medication endorsed nurses were newer to nursing and their current job, and reported higher job satisfaction on all five factors. Non-medication endorsed nurses cited lack of confidence and ability as key reasons for not undertaking the course while medication endorsed nurses reported professional and personal reasons for expanding their scope of practice. Most enjoyed the responsibility and reported satisfaction from distributing medications and responding to pain while one viewed it as added work. The findings from this small study suggest that providing local education will improve job satisfaction of ENs. | 18,922,605 |
Dentine bonding after CPP-ACP paste treatment with and without conditioning. | To evaluate microshear bond strength (MSBS) to dentine following application of a casein phosphopeptide amorphous calcium phosphate paste (Tooth Mousse (TM)), and the effect of smear layer removal before paste application and preconditioning. Specimens of polished human dentine were divided into two groups: 1, smear layer retained; 2, smear layer removed using 15% EDTA for 90 s. In each group, half the specimens were left untreated and half treated with TM for 60 min daily x 7 days. Each subgroup was divided into three further subgroups for conditioning (Primer only; 30-40% phosphoric acid (PA)+primer; 20% polyacrylic acid (CC)+primer). Two self-etching/priming adhesives (Clearfil SE Bond (CSE) and G-Bond (GB)) were used for bonding resin composite to superficial/deep dentine and after 24h, stressed in shear until failure. Maximum loads at failure and bond failure modes were recorded. Group means were compared using one-way ANOVA and Tukey's post hoc test at alpha=0.05. TM did not significantly affect MSBS in group 1. In group 2, there was a statistically significant increase in MSBS for CSE on deep dentine (P=0.002) and a reduction for GB (P=0.013) on superficial dentine. PA conditioning did not significantly affect MSBS for CSE and GB while CC significantly reduced MSBS for GB. TM application did not reduce MSBS for CSE but significantly reduced MSBS for GB when the smear layer was removed before paste treatment. Preconditioning did not improve or worsen dentine MSBS for CSE or GB with/without TM, except when CC was used with GB. | 18,922,613 |
Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma. | Multiple myeloma (MM) is presently an incurable malignant plasma cell tumor. The objective of this study was to investigate expression of the interferon regulatory factor family (IRF1-9) and the potential role of DNA methylation in silencing IRF genes in MM cell lines and purified MM cells from patients. Using a panel of 13 human MM cell lines and purified CD138+ cells from nine MM patients, expression of IRF genes was investigated by quantitative reverse transcriptase polymerase chain reaction and Western blot. DNA methylation of the interferon consensus sequence-binding protein (ICSBP/IRF8) gene was measured using pyrosequencing, and the effect of promoter methylation on expression was analyzed by in vitro methylation of a cloned ICSBP/IRF8 promoter, and treatment of MM cells with 5-aza-2'-deoxycytidine (DAC). Eight of thirteen of the MM cell lines were found to lack ICSBP/IRF8 expression, associated with hypermethylation of the CpG island in the ICSBP/IRF8 promoter. We also found that ICSBP/IRF8 was significantly underexpressed in primary MM cells, whereas the ICSBP/IRF8 promoter was methylated in only one of nine of primary purified CD138+ MM samples. DAC-mediated demethylation restored endogenous ICSBP/IRF8 expression, whereas in vitro methylation silenced the promoter. Expression of the ICSBP/IRF8 gene is silenced in a majority of MM cell lines and primary CD138+ MM cells. DNA methylation of the ICSBP/IRF8 gene is a frequent event in MM cell lines, but silencing is also observed in the absence of methylation. These results suggest that silencing of ICSBP/IRF8 expression, by DNA methylation or other epigenetic mechanisms, may be associated with the malignant phenotype of MM. | 18,922,617 |
Magnetic resonance imaging of melanoma metastases in a clinical relevant human melanoma xenograft scid mouse model. | This study aimed to analyse (i) the metastatic behaviour of human melanoma FEMX-1 cells in scid mice after surgical excision of the PT and (ii) to evaluate the feasibility of magnetic resonance imaging (MRI) for the detection of melanoma metastases. Histology proved both high specificity (95%), and high sensitivity of MRI detection of melanoma metastasis. CEACAM1, L1, and HPA-binding site expression, all markers predicting metastasis in clinical studies, were preserved in the metastatic nodules. Thus, our xenograft model closely resembles the clinical situation of post-operative development of distant organ metastasis and demonstrates that MRI is a sensitive and highly qualified technology for intra-vital monitoring of melanoma progression. | 18,922,631 |
Acute death in heartworm-infected cats: unraveling the puzzle. | Although the acute death syndrome in feline heartworm disease is widely recognized, its pathogenesis remains a mystery. The most widely held hypothesis is that an acute anaphylactic reaction, perhaps precipitated by the death of the parasite, is the underlying cause. This study investigated the role of the physical form of antigen (Ag) in the ensuing reaction when Dirofilaria immitis-sensitized cats are challenged by intravenous (IV) administration of heartworm Ag. Healthy D. immitis-naive cats (n = 23) were sensitized using subcutaneous injections of adjuvanted D. immitis Ag administered weekly for 6 weeks. After sensitization, cats (n = 20) were anaesthetized and challenged with IV D. immitis Ag in various forms or with IV sterile 0.9% saline (n = 3). Systolic blood pressure, respiratory rate, degree of dyspnea, blood oxygen saturation, and heart rate were measured immediately before and at 10-15 min intervals after challenge until terminal apnea occurred or until euthanasia at 140 min after challenge. Blood samples were collected for complete blood count and measurements of serum serotonin immediately before and at 10, 20, and 35 min after challenge. Clinical observations were recorded as they occurred, or at 10-15 minute intervals, whichever was the more frequent. The most severe post-challenge reactions occurred in cats challenged with Ag from dead worms, live worms, and 20 ng/mL Ag. Dyspnea increased significantly after challenge in all three groups (p < 0.001; p = 0.04, and p = 0.002, respectively), and blood oxygen saturation dropped post-challenge in the Dead Worm (p < 0.001) and the 20 ng/mL Ag (p = 0.002) groups. In the 20 ng/mL Ag group, systolic blood pressure decreased (p <0.05) and respiratory rate increased (p < 0.05) post-challenge. Clinical observations included dyspnea, gastrointestinal signs (retching, defecation, or flatulence), urination, and less commonly, hemorrhage from the nostrils or anus, or cutaneous swelling (general or specifically facial). The 20 ng/mL Ag group had the highest rate of clinical signs, followed by the Dead Worm group. The most common and reliable hematologic change associated with severe clinical effects of D. immitis Ag challenge was increased hematocrit, which was statistically higher after challenge than at baseline in the Dead Worm group (p = 0.012). The model demonstrated that the physical form of heartworm Ag used for IV challenge in D. immitis-sensitized cats is an important factor for determining the characteristics of the post-challenge reaction, and the amount of exposed internal filarial Ag presented to the feline immune system may influence the severity of the response to challenge. | 18,922,636 |
Aichi cancer center initial experience of intensity modulated radiation therapy for nasopharyngeal cancer using helical tomotherapy. | To assess the feasibility of helical tomotherapy (HT) for patients with nasopharyngeal carcinoma. From June 2006 to June 2007, 20 patients with nasopharyngeal carcinoma were treated with HT with (n = 18) or without (n = 2) systemic chemotherapy. The primary tumor and involved lymph node (PTV1) were prescribed 70 Gy and the prophylactic region 54 Gy at D95, respectively. The majority of patients received 2 Gy per fraction for PTV1 in 35 fractions. Parotid function was evaluated using quantitative scintigraphy at pretreatment, and posttreatment at 3 months and 1 year later. The median patient age was 53 years, ranging from 15 to 83. Our cohort included 5, 8, 4, 2, and 1 patients with disease Stages IIB, III, IVA, IVB, and IVC, respectively. Histopathological record revealed two for World Health Organization Type I and 18 for Type 2 or 3. The median duration time for treatment preparation was 9.5 days, and all plans were thought to be acceptable regarding dose constraints of both the planning target volume and organ at risk. All patients completed their treatment procedure of intensity-modulated radiation therapy (IMRT). All patients achieved clinical remission after IMRT. The majority of patients had Grade 3 or higher toxicity of skin, mucosa, and neutropenia. At the median follow-up of 10.9 months, two patients recurred, and one patient died from cardiac disease. Parotid gland function at 1 year after completion of IMRT was significantly improved compared with that at 3 months. HT was clinically effective in terms of IMRT planning and utility for patients with nasopharyngeal cancer. | 18,922,651 |
There is no correlation between erectile dysfunction and dose to penile bulb and neurovascular bundles following real-time low-dose-rate prostate brachytherapy. | We evaluated the relationship between the onset of erectile dysfunction and dose to the penile bulb and neurovascular bundles (NVBs) after real-time ultrasound-guided prostate brachytherapy. One hundred forty-seven patients who underwent prostate brachytherapy met the following eligibility criteria: (1) treatment with 125I brachytherapy to a prescribed dose of 160 Gy with or without hormones without supplemental external beam radiation therapy, (2) identification as potent before the time of implantation based on a score of 2 or higher on the physician-assigned Mount Sinai Erectile Function Score and a score of 16 or higher on the abbreviated International Index of Erectile Function patient assessment, and (3) minimum follow-up of 12 months. Median follow-up was 25.7 months (range, 12-47 months). The 3-year actuarial rate of impotence was 23% (34 of 147 patients). An additional 43% of potent patients (49 of 113 patients) were using a potency aid at last follow-up. The penile bulb volume receiving 100% of the prescription dose (V(100)) ranged from 0-0.05 cc (median, 0 cc), with a dose to the hottest 5% (D(5)) range of 12.5-97.9 Gy (median, 40.8 Gy). There was no correlation between penile bulb D(5) or V(100) and postimplantation impotency on actuarial analysis. For the combined right and left NVB structures, V(100) range was 0.3-5.1 cc (median, 1.8 cc), and V(150) range was 0-1.5 cc (median, 0.31 cc). There was no association between NVB V(100) or V(150) and postimplantation impotency on actuarial analysis. Penile bulb doses are low after real-time ultrasound-guided prostate brachytherapy. We found no correlation between dose to either the penile bulb or NVBs and the development of postimplantation impotency. | 18,922,652 |
Effects of a short-term exposure to alcohol in rats on FAAH enzyme and CB1 receptor in different brain areas. | Acute alcohol exposure in rats (8% ethanol in the liquid diet for a period of 24 h) is associated with a decrease in the levels of endocannabinoids (anandamide and 2-arachidonoyl-glycerol) as well as in various N-acylethanolamines, in different brain regions. In the present study, we wanted to further explore: (i) whether these decreases might be caused by an increase in fatty acid amide hydrolase (FAAH), the enzyme involved in the degradation of N-acylethanolamines including anandamide, and (ii) whether the changes in endocannabinoid levels are accompanied by parallel changes in the major cannabinoid receptor type, the CB(1) receptor, activated by these ligands in the brain. Our data proved that FAAH activity did not increase in any of the four regions analyzed, even it was reduced in the hypothalamus and the prefrontal cortex. Paradoxically, FAAH levels increased in the hypothalamus and, to a lesser extent, in the prefrontal cortex and the amygdala, but not in the caudate-putamen. By contrast, the levels of CB(1) receptors were markedly reduced in the amygdala and prefrontal cortex of these rats, although no changes were seen in the hypothalamus and the caudate-putamen. These results suggest that reductions in the levels of endocannabinoids and related N-acylethanolamines caused by acute alcohol exposure are not originated by an enhanced degradation by FAAH enzyme, but they are associated with low levels of the receptors activated by these ligands, although this parallelism did not occur in all brain regions analyzed. In any case, these observations would support the notion of a general reduction in the activity of the cannabinoid signaling system by acute alcohol exposure. | 18,922,654 |
Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis. | The expression of nerve growth factor (NGF) is known to increase in the skin of patients with atopic dermatitis (AD) and is related to disease aggravation. In the present study, we measured skin NGF levels in AD patients and determined whether they correlate to AD severity as well as treatment effects. NGF in the horny layer (horn NGF) of skin lesions found on the cubital fossa of AD patients was collected via tape stripping and measured using ELISA before and after 2 and 4 weeks following initiation of treatments. Itching and eruptions on the lesions were also evaluated. Peripheral blood eosinophil count, serum LDH level and total serum IgE level were also examined. The level of NGF was significantly higher in AD patients than in healthy controls, and correlated with the severity of itch, erythema, scale/xerosis, eosinophil count, and LDH level. The NGF level decreased significantly at 2 and 4 weeks of treatment with olopatadine, a histamine H(1) receptor antagonist, and/or topical steroid. The reduction in NGF correlated with the decrease in the severity of itching and erythema, papule, scale/xerosis and lichenification of the lesion, eosinophil count, and LDH level. In psoriatic lesional skin with itch, the horn NGF was significantly higher than in non-lesional skin of psoriasis, but the value was lower than NGF in atopic skin. The level of horn NGF was found to reflect the severity of itching and eruptions in AD. Therefore, quantification of NGF in the samples collected directly from the horny layer appears to be useful in assessing severity and therapeutic effects in AD. | 18,922,683 |
Biomolecular solid state NMR with magic-angle spinning at 25K. | A magic-angle spinning (MAS) probe has been constructed which allows the sample to be cooled with helium, while the MAS bearing and drive gases are nitrogen. The sample can be cooled to 25K using roughly 3 L/h of liquid helium, while the 4-mm diameter rotor spins at 6.7 kHz with good stability (+/-5 Hz) for many hours. Proton decoupling fields up to at least 130 kHz can be applied. This helium-cooled MAS probe enables a variety of one-dimensional and two-dimensional NMR experiments on biomolecular solids and other materials at low temperatures, with signal-to-noise proportional to 1/T. We show examples of low-temperature (13)C NMR data for two biomolecular samples, namely the peptide Abeta(14-23) in the form of amyloid fibrils and the protein HP35 in frozen glycerol/water solution. Issues related to temperature calibration, spin-lattice relaxation at low temperatures, paramagnetic doping of frozen solutions, and (13)C MAS NMR linewidths are discussed. | 18,922,715 |
No relationship between mean plasma glucose and glycated haemoglobin in patients with cystic fibrosis-related diabetes. | Cystic fibrosis-related diabetes (CFRD) prevalence has increased dramatically with the improved life expectancy of patients with cystic fibrosis (CF). Glycated haemoglobin (HbA(1c)) is an important tool for monitoring blood glucose control but, unlike in type 1 and type 2 diabetes, a correlation between HbA(1c), fructosamine and mean plasma glucose has not been clearly established in CF. This study aimed to examine the relationship between mean plasma glucose and HbA(1c) or fructosamine in stable patients with CFRD. Fifteen type 1 diabetes and 13 CFRD patients (HbA(1c)<9.0%; no anaemia), matched for age and body mass index (BMI), provided 72 capillary blood glucose profiles taken 3days/month for three months. At the end of this time, HbA(1c) and fructosamine were measured. Mean plasma glucose was estimated using the Diabetes Control and Complications Trial (DCCT) conversion formula, and linear regressions carried out to establish its relationship with HbA(1c) and fructosamine. In type 1 diabetes patients, mean plasma glucose correlated significantly with HbA(1c) (r=0.68; P=0.005). In CFRD patients, no correlation was found between mean plasma glucose and HbA(1c) (r=0.24; P=0.460). Also, no association was found between mean plasma glucose, representing the month before blood sampling, and fructosamine in either group. Unlike in type 1 diabetes, HbA(1c) did not correlate with mean plasma glucose in CFRD subjects. Thus, having a normal HbA(1c) may not be sufficient to indicate a low risk of diabetes complications in CFRD. Further studies are required to explain such a discrepancy. | 18,922,724 |
Intrasyrinx hemorrhage associated with hemangioblastoma in epiconus. | Hemangioblastomas in the central nervous system are highly vascular lesions, but have low risk of hemorrhage. In spinal lesions, there are a few rare cases of intramedullary hemorrhages associated with hemangioblastoma, and their prognoses were very severe. This is the first case of an intrasyrinx hemorrhage associated with hemangioblastoma in epiconus. We report this rare case and discuss the clinical manifestations of intrasyrinx hemorrhage caused by hemangioblastoma in epiconus. A case report. This case report presents a 45-year-old woman with intrasyrinx hemorrhage caused by hemangioblastoma in epiconus. The patient presented with a sudden onset of burning bilateral leg pain and rectal/bladder dysfunction, indicating conus medullaris syndrome. Initial magnetic resonance imaging revealed an intramedullary nodular lesion in the epiconus and holocord syringomyelia. However, follow-up magnetic resonance imaging showed intramedullary hemorrhage. The patient underwent surgery, and an intrasyrinx hematoma was evacuated and the tumor was completely removed. Histological diagnosis was hemangioblastoma. Three months after surgery, the patient recovered from neurological deficits. We present this rare case, and emphasize hemangioblastoma as the differential diagnosis in hemorrhagic spinal lesion. | 18,922,743 |
Simultaneous analysis of THC and its metabolites in blood using liquid chromatography-tandem mass spectrometry. | Cannabis is considered to be the most widely abused illicit drug in Europe. Consequently, sensitive and specific analytical methods are needed for forensic purposes and for cannabinoid pharmacokinetic and pharmacodynamic studies. A simple, rapid and highly sensitive and specific method for the extraction and quantification of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy- Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy- Delta(9)-tetrahydrocannabinol (THC-COOH) in blood is presented. The method was fully validated according to international guidelines and comprises simultaneous liquid-liquid extraction (LLE) of the three analytes with hexane:ethyl acetate (90:10, v/v) into a single eluant followed by separation and quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chromatographic separation was achieved using a XBridge C(18) column eluted isocratically with methanol:0.1% formic acid (80:20, v/v). Selectivity of the method was achieved by a combination of retention time, and two precursor-product ion transitions. The use of the LLE was demonstrated to be highly effective and led to significant decreases in the interferences present in the matrix. Validation of the method was performed using 250 microL of blood. The method was linear over the range investigated (0.5-40 microg/L for THC, 1-40 microg/L for 11-OH-THC, and 2-160 microg/L for THC-COOH) with excellent intra-assay and inter-assay precision; relative standard deviations (RSDs) were <12% for THC and 11-OH-THC and <8% for THC-COOH for certified quality control samples. The lower limit of quantification was fixed at the lowest calibrator in the linearity experiments. No instability was observed after repeated freezing and thawing or in processed samples. The method was subsequently applied to 63 authentic blood samples obtained from toxicology cases. The validation and actual sample analysis results show that this method is rugged, precise, accurate, and well suited for routine analysis. | 18,922,747 |
Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits. | White-matter damage is a leading cause of neurological handicap. Although hypoxia-ischemia and excitotoxicity are major pathogenic factors, a role for genetic influences was suggested recently. Thus, protracted gestational hypoxia was associated with white-matter damage (WMD) in rat pups but not in mouse pups. Indeed, microglial activation and vessel-wall density on postnatal days (P)1 and P10 were found increased in both mouse and rat pups, but cell death, astrogliosis, and myelination were only significantly altered in hypoxic rat pups. We investigated whether this species-related difference was ascribable to effects of antenatal hypoxia on the expression of glutamate receptor subunits by using immunocytochemistry, PCR, and excitotoxic double hit insult. Quantitative PCR in hypoxic mouse pups on P1 showed 2- to 4-fold down-regulation of the AMPA-receptor subunits -1, 2, and -4; of the kainate-receptor subunit GluR7; and of the metabotropic receptor subunits mGluR1, -2, -3, -5, and -7. None of the glutamate-receptor subunits was down-regulated in the hypoxic rat pups. NR2B was the only NMDA-receptor subunit that was down-regulated in hypoxic mice but not in hypoxic rat on P1. Ifenprodil administration to induce functional inhibition of NMDA containing NR2B-subunit receptors prevented hypoxia-induced myelination delay in rat pups. Intracerebral injection of a glutamate agonist produced a larger decrease in ibotenate-induced excitotoxic lesions in hypoxic mouse pups than in normoxic mouse pups. Gestational hypoxia may regulate the expression of specific glutamate-receptor subunits in fetal mice but not in fetal rats. Therefore, genetic factors may influence the susceptibility of rodents to WMD. | 18,922,769 |
A host dicer is required for defective viral RNA production and recombinant virus vector RNA instability for a positive sense RNA virus. | Defective interfering (DI) RNAs, helper virus-dependent deletion mutant RNAs derived from the parental viral genomic RNA during replication, have been described for most RNA virus taxonomic groups. We now report that DI RNA production in the chestnut blight fungus, Cryphonectria parasitica, persistently infected by virulence-attenuating positive sense RNA hypoviruses, depends on one of two host dicer genes, dcl-2. We further report that nonviral sequences that are rapidly deleted from recombinant hypovirus RNA virus vectors in wild-type and dicer gene dcl-1 deletion mutant strains are stably maintained and expressed in the Deltadcl-2 mutant strain. These results establish a requirement for dcl-2, the C. parasitica dicer gene responsible for antiviral defense and generation of virus-derived small interfering RNAs, in DI RNA production and recombinant virus vector RNA instability. | 18,922,782 |
Oct25 represses transcription of nodal/activin target genes by interaction with signal transducers during Xenopus gastrulation. | The balance between differentiation signals and signals maintaining the undifferentiated state of embryonic cells ensures proper formation of germ layers. The nodal/activin pathway represents one of the major signaling chains responsible for the differentiation of embryonic cells into mesodermal and endodermal germ layers, while Oct4 is one of the major players in the maintenance of an undifferentiated state. Here we show that Oct25, an Oct4 homologue in Xenopus, antagonizes the activity of nodal/activin signaling by inhibiting the transcription of its target genes, Gsc and Mix2. The inhibitory effect is achieved by forming repression complexes on the promoters of Gsc and Mix2 between Oct25 and the signal transducers of the nodal/activin pathway, WBSCR11, FAST1, and Smad2. We have analyzed the significance of the Oct binding site for its inhibitory effect within the Gsc promoter. Albeit VP16-Oct25 fusion protein demonstrated a stimulating effect and EVE-Oct25 revealed a repression effect on an artificial reporter that is composed of eight repeats of Oct binding motifs, both fusions, like wild-type Oct25, inhibited mesendoderm formation and the activity of Gsc and Mix2 promoters. These results suggest that the regulatory effect of Oct25 on the expression of Gsc and Mix2 is mediated by specific protein/protein interactions. Furthermore, we demonstrate that histone deacetylase activities are not required for the inhibitory effect of Oct25. Our results provide a novel view in that Oct25 controls the nodal/activin pathway and thus maintains the undifferentiated state of embryonic cells in preventing them from premature differentiation. | 18,922,797 |
Reconstructing tumor-wise protein expression in tissue microarray studies using a Bayesian cell mixture model. | Tissue microarrays (TMAs) quantify tissue-specific protein expression of cancer biomarkers via high-density immuno-histochemical staining assays. Standard analysis approach estimates a sample mean expression in the tumor, ignoring the complex tissue-specific staining patterns observed on tissue arrays. In this article, a cell mixture model (CMM) is proposed to reconstruct tumor expression patterns in TMA experiments. The concept is to assemble the whole-tumor expression pattern by aggregating over the subpopulation of tissue specimens sampled by needle biopsies. The expression pattern in each individual tissue element is assumed to be a zero-augmented Gamma distribution to assimilate the non-staining areas and the staining areas. A hierarchical Bayes model is imposed to borrow strength across tissue specimens and across tumors. A joint model is presented to link the CMM expression model with a survival model for censored failure time observations. The implementation involves imputation steps within each Markov chain Monte Carlo iteration and Monte Carlo integration technique. The model-based approach provides estimates for various tumor expression characteristics including the percentage of staining, mean intensity of staining and a composite meanstaining to associate with patient survival outcome. R package to fit CMM model is available at http://www.mskcc.org/mskcc/html/85130.cfm | 18,922,808 |
Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth. | A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant approximately 50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy(-1) (equivalent to an excess absolute risk coefficient of about 3% Gy(-1)), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia. | 18,922,822 |
Current and emerging strategies for the management of acute myeloid leukemia in the elderly. | Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemias diagnosed in adults. The elderly are disproportionately affected by AML, as 35% of newly diagnosed patients are aged >or=75 and the median age at diagnosis is 67. Elderly individuals also respond less well to standard chemotherapy than do younger individuals, as reflected by lower complete remission and relapse-free survival rates in major clinical trials. A higher prevalence of comorbid conditions as well as the unique biological features of elderly AML patients account for the relatively poor response to therapy observed in this population. Compared with AML in younger individuals, for example, AML in the elderly more often emerges from a preceding myelodysplastic syndrome and is more frequently associated with poor-prognosis karyotypes such as 5q- or 7q-. The introduction of novel therapies over the past decade has already altered the treatment paradigm of elderly individuals with AML. The first of these to emerge was gemtuzumab ozogamicin. Other agents are currently under evaluation in clinical trials, including inhibitors of multidrug resistance, farnesyltransferase inhibitors, novel nucleoside analogues, and inhibitors of the FMS-like tyrosine kinase-3. This review describes the biological features of AML in the elderly and summarizes both the current and emerging strategies for the treatment of this disease in older individuals. | 18,922,830 |
Switching first-line disease-modifying therapy after failure: impact on the course of relapsing-remitting multiple sclerosis. | Options for non-responders to relapsing-remitting multiple sclerosis (RRMS) first-line disease-modifying therapies (DMT) are limited. We explored whether switching first-line DMT is effective. Patients with RRMS who first received interferon-beta (IFNB) or glatiramer acetate (GA) were classified in three categories: DMT change because of suboptimal response, DMT change because of other reasons, and no DMT change during follow-up. Outcomes included annualized relapse rate (ARR) and relapse-free proportions. We identified 597 patients who initiated first-line DMT. For patients who did not change DMT (n = 240), pre-DMT and on-DMT median ARR were 0.50 and 0 (P < 0.0001). At 24 months, 76% (95%CI = 69-81%) of patients who did not change DMT were relapse-free. Of the 155 who switched because of suboptimal response, 101 switched to another first-line DMT. Median ARR pre-DMT, on first DMT and second DMT were: 0.50, 0.55, and 0.25 for switchers from IFNB to GA (IFNB/GA, n = 12) (pre-DMT versus first DMT: P = 0.92; first versus second DMT: P = 0.31); 0.90, 0.50, and 0 for switchers from GA to IFNB (GA/IFNB, n = 18; P = 0.19; P = 0.01); 0.50, 0.68, and 0 for switchers from an IFNB to another IFNB (IFNB/IFNB', n = 71; P = 0.34; P = 0.02). Estimated relapse-free proportion after 24 months of treatment was 42% (95%CI=15-66%) during the period on IFNB versus 53% (95%CI = 17-80%) on GA for IFNB/GA (P = 0.21); 12% (95%CI = 0-40%) on GA versus 87% (95%CI = 59-97%) on IFNB for GA/IFNB (P = 0.001); and 41% (95%CI = 29-52%) on initial IFNB versus 67% (95%CI = 53-79%) on subsequent IFNB for IFNB/IFNB' (P = 0.0001). Switching first-line DMT in patients with RRMS failing initial therapy may be effective in many cases. | 18,922,831 |
Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA). | We examined copy number changes in the genomes of B cells from 58 patients with chronic lymphocytic leukemia (CLL) by using representational oligonucleotide microarray analysis (ROMA), a form of comparative genomic hybridization (CGH), at a resolution exceeding previously published studies. We observed at least 1 genomic lesion in each CLL sample and considerable variation in the number of abnormalities from case to case. Virtually all abnormalities previously reported also were observed here, most of which were indeed highly recurrent. We observed the boundaries of known events with greater clarity and identified previously undescribed lesions, some of which were recurrent. We profiled the genomes of CLL cells separated by the surface marker CD38 and found evidence of distinct subclones of CLL within the same patient. We discuss the potential applications of high-resolution CGH analysis in a clinical setting. | 18,922,857 |
Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. | Inactivation of the transforming growth factor beta (TGFbeta) tumor suppressor pathway is a main step in the development of a variety of human tumors. The miR-106b-25 and miR-17-92 clusters are emerging as key modulators of TGFbeta signaling in gastrointestinal and other tumors, interfering with cell cycle arrest and apoptosis when overexpressed in cancer cells. Genetic ablation of these microRNAs (miRNAs) reveals their physiologic role in the control of liver and central nervous system apoptosis, supporting the notion that miRNA-based homeostatic mechanisms can be usurped by cancer cells to resist TGFbeta tumor suppression. | 18,922,889 |
Utilization of pathway signatures to reveal distinct types of B lymphoma in the Emicro-myc model and human diffuse large B-cell lymphoma. | The Emu-myc transgenic mouse has provided a valuable model for the study of B-cell lymphoma. Making use of gene expression analysis and, in particular, expression signatures of cell signaling pathway activation, we now show that several forms of B lymphoma can be identified in the Emu-myc mice associated with time of tumor onset. Furthermore, one form of Emu-myc tumor with pre-B character is shown to resemble human Burkitt lymphoma, whereas others exhibit more differentiated B-cell characteristics and show similarity with human diffuse large B-cell lymphoma in the pattern of gene expression, as well as oncogenic pathway activation. Importantly, we show that signatures of oncogenic pathway activity provide further dissection of the spectrum of diffuse large B-cell lymphoma, identifying a subset of patients who have very poor prognosis and could benefit from more aggressive or novel therapeutic strategies. Taken together, these studies provide insight into the complexity of the oncogenic process and a novel strategy for dissecting the heterogeneity of B lymphoma. | 18,922,927 |
Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. | An extraordinary new technique using hyperpolarized (13)C-labeled pyruvate and taking advantage of increased glycolysis in cancer has the potential to improve the way magnetic resonance imaging is used for detection and characterization of prostate cancer. The aim of this study was to quantify, for the first time, differences in hyperpolarized [1-(13)C] pyruvate and its metabolic products between the various histologic grades of prostate cancer using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Fast spectroscopic imaging techniques were used to image lactate, alanine, and total hyperpolarized carbon (THC = lactate + pyruvate + alanine) from the entire abdomen of normal mice and TRAMP mice with low- and high-grade prostate tumors in 14 s. Within 1 week, the mice were dissected and the tumors were histologically analyzed. Hyperpolarized lactate SNR levels significantly increased (P < 0.05) with cancer development and progression (41 +/- 11, 74 +/- 17, and 154 +/- 24 in normal prostates, low-grade primary tumors, and high-grade primary tumors, respectively) and had a correlation coefficient of 0.95 with the histologic grade. In addition, there was minimal overlap in the lactate levels between the three groups with only one of the seven normal prostates overlapping with the low-grade primary tumors. The amount of THC, a possible measure of substrate uptake, and hyperpolarized alanine also increased with tumor grade but showed more overlap between the groups. In summary, elevated hyperpolarized lactate and potentially THC and alanine are noninvasive biomarkers of prostate cancer presence and histologic grade that could be used in future three-dimensional (13)C spectroscopic imaging studies of prostate cancer patients. | 18,922,937 |
NADPH oxidase contributes to renal damage and dysfunction in Dahl salt-sensitive hypertension. | The goal of this study was to test the hypothesis that NADPH oxidase contributes importantly to renal cortical oxidative stress and inflammation, as well as renal damage and dysfunction, and increases in arterial pressure. Fifty-four 7- to 8-wk-old Dahl salt-sensitive (S) or R/Rapp strain rats were maintained for 5 wk on a high sodium (8%) or high sodium + apocynin (1.5 mmol/l in drinking water). Arterial and venous catheters were implanted on day 21. By day 35 in the high-Na S rats, mRNA expression of renal cortical gp91phox, p22phox, p47phox, and p67phox NADPH subunits in S rats increased markedly, and treatment of high-Na S rats with the NADPH oxidase inhibitor apocynin resulted in significant decreases in mRNA expression of these NADPH oxidase subunits. At the same time, in apocynin-treated S rats 1) renal cortical GSH/GSSG ratio increased, 2) renal cortical O2(.-) release and NADPH oxidase activity decreased, and 3) renal glomerular and interstitial damage markedly fell. Apocynin also decreased renal cortical monocyte/macrophage infiltration, and apocynin, but not the xanthine oxidase inhibitor allopurinol, attenuated decreases in renal hemodynamics and lowered arterial pressure. These data suggest that NADPH oxidase plays an important role in causing renal cortical oxidative stress and inflammation, which lead to decreases in renal hemodynamics, renal cortical damage, and increases in arterial pressure. | 18,922,960 |
Validation, performance under field conditions, and cost-effectiveness of Capillus HIV-1/HIV-2 and determine HIV-1/2 rapid human immunodeficiency virus antibody assays using sequential and parallel testing algorithms in Tanzania. | Rapid human immunodeficiency virus (HIV) antibody tests support the effort to expand access to HIV testing and counseling services in remote, rural, and poor parts of the world. We validated the Capillus HIV-1/HIV-2 (Trinity Biotech PLC, Bray, County Wicklow, Ireland) and Determine HIV-1/2 (Abbott Laboratories, Abbott Park, IL) rapid tests in a reference laboratory using patient samples from Tanzania and evaluated the performance of the tests under field conditions in northern Tanzania. We used the resulting data to study sequential and parallel testing algorithms. In the validation study, sensitivity, specificity, the predictive value of a positive test (PV(+)), and the predictive value of a negative test (PV(-)) were all 100% for Capillus and Determine. In the field evaluation among 12,737 clients, sensitivity, specificity, PV(+), and PV(-) were 99.7%, 99.8%, 98.7%, and 99.9%, respectively, for Capillus and 99.6%, 99.9%, 99.5%, and 99.9%, respectively, for Determine. A sequential testing algorithm that did not confirm a negative initial Capillus result with a Determine result cost $7.77 per HIV diagnosis but missed 0.3% of HIV infections. A sequential testing algorithm that did not confirm a negative initial Determine result with a Capillus result cost $7.64 per HIV diagnosis but missed 0.4% of HIV infections. A parallel testing algorithm cost $13.46 per HIV diagnosis but detected more HIV-infected clients. | 18,923,015 |
Loss of inhibitory neuron AMPA receptors contributes to ataxia and epilepsy in stargazer mice. | Stargazer mice are characterized by ataxia and seizures, which resemble the human disorder absence epilepsy. Stargazin, the protein mutated in stargazer mice, promotes the expression and function of neuronal AMPA receptors (AMPARs). However, it is unclear how decreased expression of excitatory AMPARs generates stargazer seizures, given that seizures often result from increased neuronal excitability. Additionally, although stargazer ataxia has been attributed to loss of AMPARs from cerebellar granule cells, other cerebellar neurons have not been examined. To examine the role of AMPAR dysfunction in these behavioral phenotypes, electrophysiological recordings were used to probe AMPAR regulation in relevant brain regions. We found that both cerebellar Purkinje cells and inhibitory thalamic reticular nucleus neurons have strongly reduced synaptic AMPAR function in stargazer mice. Together, our data suggest that impaired AMPAR regulation in multiple neuron populations may contribute to the behavioral phenotypes of absence seizures and ataxia seen in stargazer mice and imply that an understanding of human genetic disorders will require knowledge of both the genes that are mutated as well as their precise cellular expression pattern. | 18,923,036 |
Expression of active p21-activated kinase-1 induces Ca2+ flux modification with altered regulatory protein phosphorylation in cardiac myocytes. | p21-Activated kinase-1 (Pak1) is a serine-threonine kinase that associates with and activates protein phosphatase 2A in adult ventricular myocytes and, thereby, induces increased Ca2+ sensitivity of skinned-fiber tension development mediated by dephosphorylation of myofilament proteins (Ke Y, Wang L, Pyle WG, de Tombe PP, Solaro RJ. Circ Res 94: 194-200, 2004). We test the hypothesis that activation of Pak1 also moderates cardiac contractility through regulation of intracellular Ca2+ fluxes. We found no difference in field-stimulated intracellular Ca2+ concentration ([Ca2+]i) transient amplitude and extent of cell shortening between myocytes expressing constitutively active Pak1 (CA-Pak1) and controls expressing LacZ; however, time to peak shortening was significantly faster and rate of [Ca2+]i decay and time of relengthening were slower. Neither caffeine-releasable sarcoplasmic reticulum (SR) Ca2+ content nor fractional release was different in CA-Pak1 myocytes compared with controls. Isoproterenol application revealed a significantly blunted increase in [Ca2+]i transient amplitude, as well as a slowed rate of [Ca2+]i decay, increased SR Ca2+ content, and increased cell shortening, in CA-Pak1 myocytes. We found no significant change in phospholamban phosphorylation at Ser16 or Thr17 in CA-Pak1 myocytes. Analysis of cardiac troponin I revealed a significant reduction in phosphorylated species that are primarily attributable to Ser(23/24) in CA-Pak1 myocytes. Nonstimulated, spontaneous SR Ca2+ release sparks were significantly smaller in amplitude in CA-Pak1 than LacZ myocytes. Propagation of spontaneous Ca2+ waves resulting from SR Ca2+ overload was significantly slower in CA-Pak1 myocytes. Our data indicate that CA-Pak1 expression has significant effects on ventricular myocyte contractility through altered myofilament Ca2+ sensitivity and modification of the [Ca2+]i transient. | 18,923,061 |
DNA helicases Sgs1 and BLM promote DNA double-strand break resection. | A key cellular response to DNA double-strand breaks (DSBs) is 5'-to-3' DSB resection by nucleases to generate regions of ssDNA that then trigger cell cycle checkpoint signaling and DSB repair by homologous recombination (HR). Here, we reveal that in the absence of exonuclease Exo1 activity, deletion or mutation of the Saccharomyces cerevisiae RecQ-family helicase, Sgs1, causes pronounced hypersensitivity to DSB-inducing agents. Moreover, we establish that this reflects severely compromised DSB resection, deficient DNA damage signaling, and strongly impaired HR-mediated repair. Furthermore, we show that the mammalian Sgs1 ortholog, BLM--whose deficiency causes cancer predisposition and infertility in people--also functions in parallel with Exo1 to promote DSB resection, DSB signaling and resistance to DSB-generating agents. Collectively, these data establish evolutionarily conserved roles for the BLM and Sgs1 helicases in DSB processing, signaling, and repair. | 18,923,075 |
Economic outcomes of a dental electronic patient record. | The implementation of an electronic patient record (EPR) in many sectors of health care has been suggested to have positive relationships with both quality of care and improved pedagogy, although evaluation of actual results has been somewhat disillusioning. Evidence-based dentistry clearly suggests the need for tools and systems to improve care, and an EPR is a critical tool that has been widely proposed in recent years. In dental schools, EPR systems are increasingly being adopted, despite obstacles such as high costs, time constraints necessary for process workflow change, and overall project complexity. The increasing movement towards cost-effectiveness analyses in health and medicine suggests that the EPR should generally cover expenses, or produce total benefits greater than its combined costs, to ensure that resources are being utilized efficiently. To test the underlying economics of an EPR, we utilized a pre-post research design with a probability-based economic simulation model to analyze changes in performance and costs in one dental school. Our findings suggest that the economics are positive, but only when student fees are treated as an incremental revenue source. In addition, other performance indicators appeared to have significant changes, although most were not comprehensively measured pre-implementation, making it difficult to truly understand the performance differential-such pre-measurement of expected benefits is a key lesson learned. This article also provides recommendations for dental clinics and universities that are about to embark on this endeavor. | 18,923,100 |
The IKK-neutralizing compound Bay11 kills supereffector CD8 T cells by altering caspase-dependent activation-induced cell death. | Antigen with dual costimulation through CD137 and CD134 induces powerful CD8 T cell responses. These effector T cells are endowed with an intrinsic survival program resulting in their accumulation in vivo, but the signaling components required for survival are unknown. We tested a cadre of pathway inhibitors and found one preclinical compound, Bay11-7082 (Bay11), which prevented survival. Even the gammac cytokine family members IL-2, -4, -7, and -15 could not block death, nor could pretreatment with IL-7. We found that dual costimulation caused loading of phosphorylated IkappaBalpha (p-IkappaBalpha) and high basal levels of NF-kappaB activity in the effector CD8 T cells. Bay11 trumped both events by reducing the presence of p-IkappaBalpha and ensuing NF-kappaB activity. Not all pathways were impacted to this degree, however, as mitogen-mediated ERK phosphorylation was evident during NF-kappaB inhibition. Nonetheless, Bay11 blocked TCR-stimulated cytokine synthesis by rapidly accentuating activation-induced cell death through elicitation of a caspase-independent pathway. Thus, in effector CD8 T cells, Bay11 forces a dominant caspase-independent death signal that cannot be overcome by an intrinsic survival program nor by survival-inducing cytokines. Therefore, Bay11 may be a useful tool to deliberately kill death-resistant effector T cells for therapeutic benefit. | 18,923,104 |
The association between perceived discrimination and obesity in a population-based multiracial and multiethnic adult sample. | We examined whether perceived chronic discrimination was related to excess body fat accumulation in a random, multiethnic, population-based sample of US adults. We used multivariate multinomial logistic regression and logistic regression analyses to examine the relationship between interpersonal experiences of perceived chronic discrimination and body mass index and high-risk waist circumference. Consistent with other studies, our analyses showed that perceived unfair treatment was associated with increased abdominal obesity. Compared with Irish, Jewish, Polish, and Italian Whites who did not experience perceived chronic discrimination, Irish, Jewish, Polish, and Italian Whites who perceived chronic discrimination were 2 to 6 times more likely to have a high-risk waist circumference. No significant relationship between perceived discrimination and the obesity measures was found among the other Whites, Blacks, or Hispanics. These findings are not completely unsupported. White ethnic groups including Polish, Italians, Jews, and Irish have historically been discriminated against in the United States, and other recent research suggests that they experience higher levels of perceived discrimination than do other Whites and that these experiences adversely affect their health. | 18,923,119 |
Regulation of kinetochore recruitment of two essential mitotic spindle checkpoint proteins by Mps1 phosphorylation. | Mps1 is a protein kinase that plays essential roles in spindle checkpoint signaling. Unattached kinetochores or lack of tension triggers recruitment of several key spindle checkpoint proteins to the kinetochore, which delays anaphase onset until proper attachment or tension is reestablished. Mps1 acts upstream in the spindle checkpoint signaling cascade, and kinetochore targeting of Mps1 is required for subsequent recruitment of Mad1 and Mad2 to the kinetochore. The mechanisms that govern recruitment of Mps1 or other checkpoint proteins to the kinetochore upon spindle checkpoint activation are incompletely understood. Here, we demonstrate that phosphorylation of Mps1 at T12 and S15 is required for Mps1 recruitment to the kinetochore. Mps1 kinetochore recruitment requires its kinase activity and autophosphorylation at T12 and S15. Mutation of T12 and S15 severely impairs its kinetochore association and markedly reduces recruitment of Mad2 to the kinetochore. Our studies underscore the importance of Mps1 autophosphorylation in kinetochore targeting and spindle checkpoint signaling. | 18,923,149 |
Long-term effects of delayed fatherhood in mice on postnatal development and behavioral traits of offspring. | This study aims to analyze, in mice, the long-term effects of delayed fatherhood on postnatal development, spontaneous motor activity, and learning capacity of offspring. Hybrid parental-generation (F(0)) males, at the age of 12, 70, 100, and 120 wk, were individually housed with a randomly selected 12-wk-old hybrid female. The resulting first-generation (F(1)) offspring were tested for several developmental and behavioral variables. Cumulative percentage of F(1) pups that attained immediate righting in the 120-wk group was lower than that found in the 12-, 70-, and 100-wk groups. Furthermore, the postnatal day of attaining immediate righting was higher in pups from the 120-wk group when compared to pups from the other age-groups. At the age of 20 wk, F(1) offspring from the 120-wk group displayed lower counts of motor activity than offspring from the 12-, 70-, and 100-wk groups. One week later, a higher percentage of offspring from the 100- and 120-wk groups entered the dark compartment during the retention trial of the passive-avoidance test when compared to offspring from the 12-wk group. Offspring from the 120-wk group exhibited also lower step-through latency in the retention trial than offspring from the 12-, 70-, and 100-wk groups. These results show that advanced paternal age at conception has long-term effects on preweaning development, spontaneous motor activity, and reduced passive-avoidance learning capacity of mouse offspring. | 18,923,158 |
Chronic-intermittent cold stress in rats induces selective ovarian insulin resistance. | In rat ovary chronic cold stress increases sympathetic nerve activity, modifies follicular development, and initiates a polycystic condition. To see whether there is a relationship between the previously described changes in follicular development and metabolic changes similar to those in women with polycystic ovary, we have studied the effect of chronic cold stress (4 degrees C for 3 h/day, Monday to Friday, for 4 wk) on insulin sensitivity and the effect of insulin on sympathetic ovarian activity. Although cold-stressed rats ate more than the controls, they did not gain more weight. Insulin sensitivity, determined by hyperinsulinemic-euglycemic clamp, was significantly increased in the stressed animals. Insulin in vitro increased the basal release of norepinephrine from the ovaries of control rats but not from those of stressed rats, suggesting a local neural resistance to insulin in stressed rats. The levels of mRNA and protein for IRS1 and SLC2A4 (also known as GLUT4), molecules involved in insulin signaling, decreased significantly in the ovaries but not in the muscle of stressed rats. This decrease was preferentially located in theca-interstitial cells compared with granulosa cells, indicating that theca cells (the only cells directly innervated by sympathetic nerves) are responsible for the ovarian insulin resistance found in stressed rats. These findings suggest that ovarian insulin resistance produced by chronic stress could be in part responsible for the development of the polycystic condition induced by stress. | 18,923,160 |
Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? | Except in rare cases, the stomach can withstand exposure to highly concentrated hydrochloric acid, refluxed bile salts, alcohol, and foodstuffs with a wide range of temperatures and osmolarity. This is attributed to a number of physiological responses by the mucosal lining to potentially harmful luminal agents, and to an ability to rapidly repair damage when it does occur. Since the discovery in 1971 that prostaglandin synthesis could be blocked by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), there has been great interest in the contribution of prostaglandins to gastric mucosal defense. Prostaglandins modulate virtually every aspect of mucosal defense, and the importance of this contribution is evident by the increased susceptibility of the stomach to injury following ingestion of an NSAID. With chronic ingestion of these drugs, the development of ulcers in the stomach is a significant clinical concern. Research over the past two decades has helped to identify some of the key events triggered by NSAIDs that contribute to ulcer formation and/or impair ulcer healing. Recent research has also highlighted the fact that the protective functions of prostaglandins in the stomach can be carried out by other mediators, in particular the gaseous mediators nitric oxide and hydrogen sulfide. Better understanding of the mechanisms through which the stomach is able to resist injury in the presence of luminal irritants is helping to drive the development of safer anti-inflammatory drugs, and therapies to accelerate and improve the quality of ulcer healing. | 18,923,189 |
Combining results from lectin affinity chromatography and glycocapture approaches substantially improves the coverage of the glycoproteome. | Identification of glycosylated proteins, especially those in the plasma membrane, has the potential of defining diagnostic biomarkers and therapeutic targets as well as increasing our understanding of changes occurring in the glycoproteome during normal differentiation and disease processes. Although many cellular proteins are glycosylated they are rarely identified by mass spectrometric analysis (e.g. shotgun proteomics) of total cell lysates. Therefore, methods that specifically target glycoproteins are necessary to facilitate their isolation from total cell lysates prior to their identification by mass spectrometry-based analysis. To enrich for plasma membrane glycoproteins the methods must selectively target characteristics associated with proteins within this compartment. We demonstrate that the application of two methods, one that uses periodate to label glycoproteins of intact cells and a hydrazide resin to capture the labeled glycoproteins and another that targets glycoproteins with sialic acid residues using lectin affinity chromatography, in conjunction with liquid chromatography-tandem mass spectrometry is effective for plasma membrane glycoprotein identification. We demonstrate that this combination of methods dramatically increases coverage of the plasma membrane proteome (more than one-half of the membrane glycoproteins were identified by the two methods uniquely) and also results in the identification of a large number of secreted glycoproteins. Our approach avoids the need for subcellular fractionation and utilizes a simple detergent lysis step that effectively solubilizes membrane glycoproteins. The plasma membrane localization of a subset of proteins identified was validated, and the dynamics of their expression in HeLa cells was evaluated during the cell cycle. Results obtained from the cell cycle studies demonstrate that plasma membrane protein expression can change up to 4-fold as cells transit the cell cycle and demonstrate the need to consider such changes when carrying out quantitative proteomics comparison of cell lines. | 18,923,192 |
An integral conservative gridding--algorithm using Hermitian curve interpolation. | The problem of re-sampling spatially distributed data organized into regular or irregular grids to finer or coarser resolution is a common task in data processing. This procedure is known as 'gridding' or 're-binning'. Depending on the quantity the data represents, the gridding-algorithm has to meet different requirements. For example, histogrammed physical quantities such as mass or energy have to be re-binned in order to conserve the overall integral. Moreover, if the quantity is positive definite, negative sampling values should be avoided. The gridding process requires a re-distribution of the original data set to a user-requested grid according to a distribution function. The distribution function can be determined on the basis of the given data by interpolation methods. In general, accurate interpolation with respect to multiple boundary conditions of heavily fluctuating data requires polynomial interpolation functions of second or even higher order. However, this may result in unrealistic deviations (overshoots or undershoots) of the interpolation function from the data. Accordingly, the re-sampled data may overestimate or underestimate the given data by a significant amount. The gridding-algorithm presented in this work was developed in order to overcome these problems. Instead of a straightforward interpolation of the given data using high-order polynomials, a parametrized Hermitian interpolation curve was used to approximate the integrated data set. A single parameter is determined by which the user can control the behavior of the interpolation function, i.e. the amount of overshoot and undershoot. Furthermore, it is shown how the algorithm can be extended to multidimensional grids. The algorithm was compared to commonly used gridding-algorithms using linear and cubic interpolation functions. It is shown that such interpolation functions may overestimate or underestimate the source data by about 10-20%, while the new algorithm can be tuned to significantly reduce these interpolation errors. The accuracy of the new algorithm was tested on a series of x-ray CT-images (head and neck, lung, pelvis). The new algorithm significantly improves the accuracy of the sampled images in terms of the mean square error and a quality index introduced by Wang and Bovik (2002 IEEE Signal Process. Lett. 9 81-4). | 18,923,199 |
Treatment seeking behavior for urinary incontinence among north Indian women. | Urinary incontinence is a common but neglected problem of women. To ascertain the treatment seeking behavior of north Indian women having urinary incontinence (UI). Two residential colonies of Chandigarh. Cross-sectional face-to-face interview based study. This study was conducted by a trained nurse during April 2005-July 2005 among women aged 18 years and above. Women with UI were identified in a screening survey. They were interviewed individually regarding their treatment seeking behavior and socio-demographic data. Percentage, mean, standard deviation, chi-square test. Of the 220 enlisted incontinent women 20% (44) women consulted some health agency. Only 8.6% (19) women had heard about pelvic floor muscle exercises. Seventy-two percent (158) cases had UI for more than one year. The most common reason quoted for not seeking treatment was, 'UI was considered as 'normal', 'did not take it seriously' and 'shyness.' Many (153;70%) women reported that UI affected their daily routine as well as social activities like shopping and visiting friends. Urinary incontinence seriously affected the quality of life of women. Still, consultation rate for UI was low in the north Indian women. | 18,923,213 |
Comparison of oral ketamine and oral midazolam as sedative agents in pediatric dentistry. | The safe and effective treatment of uncooperative or combative preschool children with extensive dental needs is one of pediatric dentist's ongoing challenges. The traditional methods of behavior management are no longer acceptable to parents as they are not ready to spare more time for dental treatment of their children. Keeping this in mind, the present study was designed and carried out to evaluate the sedative effects of oral ketamine and oral midazolam prior to general anesthesia. Twenty uncooperative children in the age-group of 2-6 years were selected after thorough medical examination and investigations. Informed consent was obtained from the parent. This was a randomized double-blind study. An anesthesiologist administered either 0.5 mg/kg midazolam or 5 mg/kg ketamine orally. The heart rate, respiratory rate, and oxygen saturation were recorded at regular intervals. The sedation and anxiolysis scores were also recorded. The parents were asked to answer a questionnaire at the follow-up session the next day on the surgical experience of the parent and the child and side effects experienced, if any. When the data was subjected to statistical analysis, it was observed that both drugs resulted in adequate sedation at the end of 30 min, with oral midazolam providing significantly better anxiolysis. The heart rate and respiratory rate were marginally higher with oral ketamine. The questionnaire revealed a better response with oral midazolam; side effects were more prominent with oral ketamine. | 18,923,220 |
Cemento-ossifying fibroma--a rare case. | The concept of 'fibro-osseous lesions' of bone has evolved over the last several decades and now includes two major entities: fibrous dysplasia and ossifying fibroma, as well as the other less common lesions such as florid osseous dysplasia, periapical dysplasia, focal sclerosing osteomyelitis, proliferative periostitis of garrie, and ostitis deformans. The cemento-ossifying fibroma is a central neoplasm of bone as well as periodontium which has caused considerable controversy because of confusion regarding terminology and the criteria for its diagnosis. The cemento-ossifying fibroma is odontogenic in origin, whereas ossifying fibroma is of bony origin. This article reports a rare case of an 11-year-old male who came to us with the history of swelling in the maxillary anterior region causing difficulty in closing of mouth as well as in mastication. | 18,923,226 |
Device-based nonspecific immunomodulation therapy (Celacade), and its potential role in the treatment of chronic heart failure. | Chronic heart failure (CHF) remains a leading cause of mortality and morbidity, despite the use of optimal standard-of-care medical therapies. Although the role of the immune system in the pathogenesis and progression of CHF has been well-appreciated, attempts to modify specific systemic immune mediators have been unsuccessful. Building on the modest successes of more broad-spectrum immune therapies, Celacade therapy was developed, a device that induces apoptosis in an ex vivo blood sample. Upon reinjection into the body, the treated blood sample has been shown to have an anti-inflammatory effect. Celacade has been successful in several animal models of disease where inflammation plays an important pathogenic role. Two phase III clinical trials of Celacade have been undertaken. A trial on the use of Celacade in peripheral arterial disease with intermittent claudication was terminated early due to a lack of clinical effect, and a larger trial of Celacade treatment in CHF (ACCLAIM) was completed in 2006. ACCLAIM did not reach the primary end point for the overall study population; however, the study results demonstrated a reduced risk of death or first cardiovascular hospitalization by 39% in patients with New York Heart Association class II CHF and a 26% reduction in patients with class II, III, and IV disease who had no prior history of myocardial infarction. Celacade has been approved for treatment of CHF in these groups of patients in the European Union, and an FDA-mandated confirmatory study of Celacade for possible approval in the United States is in progress. | 18,923,231 |
Prasugrel: a new antiplatelet drug for the prevention and treatment of cardiovascular disease. | Prasugrel, trade name Effient, is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration. It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic P2Y12 receptor on the platelet surface. Prasugrel has been shown to be a potent antiplatelet agent with a faster, more consistent, and greater inhibition of platelet aggregation compared with clopidogrel. It is debatable, however, how effectively these pharmacologic benefits will translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events, including stent thrombosis, with prasugrel, but with an increased risk of major bleeding. The exact role of prasugrel in the management of ischemic heart disease is still being defined, but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent. | 18,923,235 |
Effects of facetectomy and crosslink augmentation on motion segment flexibility in posterior lumbar interbody fusion. | Biomechanical assessment using calf lumbar motion segments. To determine whether facetectomy affects the primary stability of posterior lumbar interbody fusion. To improve visualization and access to the disc space, the facet joints frequently are removed. Previous biomechanical studies have indicated a fundamental role for the facet joints in maintaining spinal segment stability. Single motion segments from calf lumbar spines were tested for pure-moment flexibility in flexion-extension (FE), lateral bending (LB), and axial rotation (AR). After testing intact, an interbody cage and pedicle screw system were implanted. Next, a bilateral facetectomy was performed, and finally a crosslink was added. Flexibility testing was repeated at each stage of implantation. Data are reported for range of motion (ROM), neutral zone (NZ), and a new compliance parameter (COM), based on the slopes of the moment-angle curve in the neutral and elastic regions. With posterior lumbar interbody fusion implantation, ROM in FE was reduced 82% +/- 4% (mean +/- standard deviation) and NZ 78% +/- 7% over intact (P < 0.015: Wilcoxon). Reduction in LB was slightly more, whereas reduction in AR was considerably less and did not achieve statistical significance for NZ. After facetectomy, ROM in FE increased 0.3 degrees (P < 0.05), on average, and NZ did not change. In LB neither changed significantly. In AR, ROM increased 0.6 degrees (P < 0.05), and NZ increased 0.2 degrees (P < 0.05). The addition of a crosslink changed ROM and NZ less than 0.1 degrees in FE and LB, whereas in AR it restored half of the stability lost due to facetectomy in ROM (P < 0.05), and had a similar trendwise effect on NZ. The new compliance measure, COM, was found to agree with the direction of change in ROM more consistently than did NZ. Facetectomy causes a nominal increase in ROM and NZ in FE and LB, which are not affected by the addition of a crosslink. Although the effect of facetectomy is greater in AR-and crosslink has a measurable restoring effect-all differences are within a few tenths of a degree under this loading paradigm. Thus, the clinical utility of adding a crosslink may not be justified based on these small biomechanical changes. COM can serve as a complement to ROM and NZ, or even as a surrogate when its 2 components are reported together, as it shows strong agreement with ROM, effectively distinguishes between lax and elastic region behaviors, and provides a measure of flexibility independent of the load range. | 18,923,306 |
Innovative management of anal fistula by the use of the anal fistula plug: hype or help? | Impressed by the initial success rates of 80% of the anal fistula plug for the closure of cryptoglandular and Crohn's associated anorectal fistulas, preliminary results from centers world-wide showed a healing rates between 24% and 88%. When compared to traditional flap repair for closing high anorectal fistulas, impairement of continence may be decreased using the plug procedure. Analyzing the different experiences of the plug procedure ranging from promising to disappointing results, a variety of issues such as bowel preparation, treatment of fistula tract, closure of the internal opening, and postoperative management have to be considered. Furthermore, the ''ideal'' indication has still to be defined. At the moment, all results which have been published only provide short-term results, and the question whether the plug procedure is appropriate and effective in Crohn's disease cannot be answered definitely. Finally, the question how to proceed in patients with plug dislodgement or failure remains unclear. In general, the introduction of the plug has accelerated a ''new'' discussion on the optimal treatment of complex fistulas. Further analysis is needed to explain the definite role of this innovative technique in comparison to traditional surgical techniques. | 18,923,352 |
Delayed presentation of diaphragmatic rupture as intra-thoracic gastric volvulus. | Diaphragmatic injuries are quite rare and result from either blunt or penetrating trauma. They are not always recognized at the time of injury and there is often a delay between the trauma and the diagnosis The diagnosis is confirmed by chest X-ray, USG, CT Scan and barium studies This case report discusses the delayed presentation of diaphragmatic rupture as an intrathoracic gastric volvulus observed in a 36-year-old man. | 18,923,354 |
Focus on urinary bladder cancer markers: a review. | Finding and development of new bladder cancer markers is still a very dynamic field. Because of the mass of all these markers it is impossible to report all of them. This paper reviews the role of bladder cancer markers in diagnosis and highlights the most important biomarkers studied and reported recently. A medline based literature search was performed to examine the field of bladder cancer markers. Major topics focus on selected bladder cancer markers from nearly all categories of the wide field of bladder cancer markers: Hematuria, FISH, FGFR3, SURVIVIN, u-PAR, TP53 mutation, HER-2/neu, TPA, NMP22, CK-19, CK-20, CYFRA 21-1. The use and clinical importance as diagnostic help are discussed. In this review a highlight to some of the most important markers was made. Further determination of recurrence and progression marker will contribute to establish better treatments for the individual patient. Molecular staging of urological tumors will allow selecting cases that will require systemic treatment. It is necessary and important to integrate under the same objectives basic and clinical research. | 18,923,360 |
Management of early-invasive high-grade transitional cell carcinoma of the bladder. | The decision in favor or against an early cystectomy in patients with initial pT1G3 urothelial carcinoma of the bladder (UCBC) is challenging. In the present review the authors dwell on the key issues in the controversial discussion about optimal management of so called ''early invasive'' UCBC. The quality of transurethral resection of the bladder tumor (TURBT) as diagnostic and therapeutic method plays an important role. Histopathological assessment delivers crucial risk factors for stratification. Last but not least life quality under different therapeutic regimes should be comprised in the decision process. | 18,923,363 |
High prevalence of neuropathy in patients with impaired 60-minute oral glucose tolerance test but normal fasting and 120-minute glucose levels. | The aim of this study was to define the prevalence of neuropathy in patients with impaired 60-min oral glucose tolerance test (OGTT) but normal fasting and 120-min glucose levels and to evaluate risk factors for polyneuropathy and glucose intolerance. The hospital files of 320 patients (56.5+/-11.9 years, 73.1% female), who had both electrodiagnostic test for sensory symptoms (nerve conduction studies and needle electromyography) and OGTT in maximum 6 months apart, were studied in this retrospective design study. Serum glucose levels at fasting and 0-, 30-, 60-, 90- and 120-min of OGTT and some biochemical parameters were recorded. Fifteen percent of patients had diabetes mellitus (DM) and 10.9% and 5.6% had impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Twenty-one patients (6.6%) had only impaired 60-min blood glucose levels. Polyneuropathy was found in 44.4%, 28.5%, and 50.0% of patients with IGT, IFG and DM respectively. The prevalence of polyneuropathy was significantly higher in patients with impaired 60-min than OGTT normal subjects (52.4% vs 21.7% p=0.003). Fasting blood glucose, HDL, LDL and TSH levels, age, glucose intolerance low serum folic acid and significantly increased polyneuropathy risk. Age, weight, body mass index, high fasting, 30, 60-, 90-, 120-min serum glucose, insulin and HgA1c levels were risk factors for glucose intolerance. Since the prevalence of neuropathy in patients with impaired 60-min glucose levels is high, it would be valuable to look at 60-min glucose levels to detect abnormal glucose metabolism and the neuropathy earlier in the course. | 18,923,366 |
Bending properties of nickel-titanium instruments: a comparative study. | The aim of the present study was to evaluate the bending properties of twisted file instruments, and compare them with other commercially available nickel-titanium (NiTi) instruments (Mtwo and Hero) manufactured with traditional methods. Despite NiTi superelastic properties, flexibility of NiTi instruments is limited by size and taper. A new manufacturing process involving twisting of a ground blank combined with heat treatment has been developed by SybronEndo, aiming to produce a NiTI rotary file with superior flexibility: the Twisted File (TF). Experimental procedures strictly followed the testing methodology described in ISO 3630-1. Bending moment was measured when the instrument attained a 45 degrees bend. Data were collected and statistically analyzed. Results showed that TF were the most flexible instruments, with a significant improvement in flexibility (P< 0.05). ranging from 100% to 250% over the other tested instruments. Even if flexibility is also influenced by instruments design, such a great improvement is mainly related to the new TF manufacturing process. The flexibility is influenced by instruments design, such a great improvement is mainly related to the new manufacturing process developed by SybronEndo, which seems to play a major role in increasing the flexibility of TF instruments. | 18,923,374 |
Apocynin attenuates tubular apoptosis and tubulointerstitial fibrosis in transgenic mice independent of hypertension. | Angiotensin II stimulates the formation of reactive oxygen species by increased NADPH oxidase activity, which contributes to proapoptotic and profibrotic mechanisms critical in renal injury. Here we determine if apocynin, an inhibitor of NADPH oxidase, interferes with the action of the intrarenal renin-angiotensin system to minimize the progression of renal disease. Transgenic mice that overexpress rat angiotensinogen in their proximal tubule cells were given either apocynin, perindopril, or hydralazine while untreated or apocynin-treated non-transgenic littermates served as controls. Untreated transgenic mice had significant elevations of their systolic blood pressure, albuminuria, reactive oxygen species production, NADPH oxidase activity, tubular apoptosis, active caspase-3, Bax, transforming growth factor-beta1, plasminogen activator inhibitor-1, extracellular matrix proteins, collagen type IV, and phosphorylated p47phox expression compared to untreated non-transgenic mice. Apocynin and perindopril blunted these changes; however, apocynin had no effect on the systolic blood pressure whereas hydralazine prevented hypertension and tubulointerstitial fibrosis but not proximal tubule cell apoptosis. Our study shows that the intrarenal renin-angiotensin system stimulates proximal tubule cell apoptosis and tubulointerstitial fibrosis, in part, by enhanced NADPH oxidase activity and reactive oxygen species generation independent of systemic hypertension. | 18,923,387 |
Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose. | Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k(e)), elimination half-lives (t(1/2)), and maximum concentration of adducts (C(max)) of the subjects. The mean (+/-SD)k(e) and half-life were 0.486 +/- 0.084 days(-1) and 1.47+/- 0.30 days, respectively, and the C(max) was 1.2 (+/-2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC(max), adduct T(max), Rumack-Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity. | 18,923,390 |
The Phaeodactylum genome reveals the evolutionary history of diatom genomes. | Diatoms are photosynthetic secondary endosymbionts found throughout marine and freshwater environments, and are believed to be responsible for around one-fifth of the primary productivity on Earth. The genome sequence of the marine centric diatom Thalassiosira pseudonana was recently reported, revealing a wealth of information about diatom biology. Here we report the complete genome sequence of the pennate diatom Phaeodactylum tricornutum and compare it with that of T. pseudonana to clarify evolutionary origins, functional significance and ubiquity of these features throughout diatoms. In spite of the fact that the pennate and centric lineages have only been diverging for 90 million years, their genome structures are dramatically different and a substantial fraction of genes ( approximately 40%) are not shared by these representatives of the two lineages. Analysis of molecular divergence compared with yeasts and metazoans reveals rapid rates of gene diversification in diatoms. Contributing factors include selective gene family expansions, differential losses and gains of genes and introns, and differential mobilization of transposable elements. Most significantly, we document the presence of hundreds of genes from bacteria. More than 300 of these gene transfers are found in both diatoms, attesting to their ancient origins, and many are likely to provide novel possibilities for metabolite management and for perception of environmental signals. These findings go a long way towards explaining the incredible diversity and success of the diatoms in contemporary oceans. | 18,923,393 |
EFC/F-BAR proteins and the N-WASP-WIP complex induce membrane curvature-dependent actin polymerization. | Extended Fer-CIP4 homology (EFC)/FCH-BAR (F-BAR) domains generate and bind to tubular membrane structures of defined diameters that are involved in the formation and fission of endocytotic vesicles. Formin-binding protein 17 (FBP17) and Toca-1 contain EFC/F-BAR domains and bind to neural Wiskott-Aldrich syndrome protein (N-WASP), which links phosphatidylinositol (4,5)-bisphosphate (PIP(2)) and the Rho family GTPase Cdc42 to the Arp2/3 complex. The N-WASP-WASP-interacting protein (WIP) complex, a predominant form of N-WASP in cells, is known to be activated by Toca-1 and Cdc42. Here, we show that N-WASP-WIP complex-mediated actin polymerization is activated by phosphatidylserine-containing membranes depending on membrane curvature in the presence of Toca-1 or FBP17 and in the absence of Cdc42 and PIP(2). Cdc42 further promoted the activation of actin polymerization by N-WASP-WIP. Toca-1 or FBP17 recruited N-WASP-WIP to the membrane. Conserved acidic residues near the SH3 domain of Toca-1 and FBP17 positioned the N-WASP-WIP to be spatially close to the membrane for activation of actin polymerization. Therefore, curvature-dependent actin polymerization is stimulated by spatially appropriate interactions of EFC/F-BAR proteins and the N-WASP-WIP complex with the membrane. | 18,923,421 |
Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing. | Dystrophia myotonica type 1 (DM1), the most common muscular dystrophy in adults, results from expansion of a CTG repeat in the 3'-untranslated region of the dystrophia myotonica protein kinase gene (DMPK). Correction of the mutant DMPK transcript is a potential therapeutic strategy in DM1. We investigated the efficacy of artificial trans-splicing molecules (ATMs) to target and correct DMPK transcripts. ATMs designed to target intron 14 of DMPK pre-mRNA transcripts were tested for their ability to trans-splice the transcripts of a DMPK mini-gene construct and the endogenous DMPK transcripts of human myosarcoma cells (CCL-136). On agarose gel electrophoresis analysis, six of eight ATMs showed trans-splicing efficacy when applied to DMPK mini-gene construct transcripts, of which three were able to trans-splice endogenous DMPK pre-mRNA transcripts in myosarcoma cells, with trans-splicing efficiency ranging from 1.81 to 7.41%. These findings confirm that artificial trans-splicing can repair DMPK pre-mRNA and provide proof-of-principle evidence for this approach as potential therapeutic strategy for DM1. | 18,923,454 |
Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. | Failure of normal brain development leads to mental retardation or autism in about 3% of children. Many genes integral to pathways by which synaptic modification and the remodelling of neuronal networks mediate cognitive and social development have been identified, usually through loss of function. Evidence is accumulating, however, that either loss or gain of molecular functions can be deleterious to the nervous system. Copy-number variation, regulation of gene expression by non-coding RNAs and epigenetic changes are all mechanisms by which altered gene dosage can cause the failure of neuronal homeostasis. | 18,923,513 |
Pairs of cooperating cleaner fish provide better service quality than singletons. | Service providers may vary service quality depending on whether they work alone or provide the service simultaneously with a partner. The latter case resembles a prisoner's dilemma, in which one provider may try to reap the benefits of the interaction without providing the service. Here we present a game-theory model based on the marginal value theorem, which predicts that as long as the client determines the duration, and the providers cooperate towards mutual gain, service quality will increase in the pair situation. This prediction is consistent with field observations and with an experiment on cleaning mutualism, in which stable male-female pairs of the cleaner wrasse Labroides dimidiatus repeatedly inspect client fish jointly. Cleaners cooperate by eating ectoparasites off clients but actually prefer to cheat and eat client mucus. Because clients often leave in response to such cheating, the benefits of cheating can be gained by only one cleaner during a pair inspection. In both data sets, the increased service quality during pair inspection was mainly due to the smaller females behaving significantly more cooperatively than their larger male partners. In contrast, during solitary inspections, cleaning behaviour was very similar between the sexes. Our study highlights the importance of incorporating interactions between service providers to make more quantitative predictions about cooperation between species. | 18,923,522 |
Activating mutations in ALK provide a therapeutic target in neuroblastoma. | Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease. | 18,923,525 |
Development and annotation of perennial Triticeae ESTs and SSR markers. | Triticeae contains hundreds of species of both annual and perennial types. Although substantial genomic tools are available for annual Triticeae cereals such as wheat and barley, the perennial Triticeae lack sufficient genomic resources for genetic mapping or diversity research. To increase the amount of sequence information available in the perennial Triticeae, three expressed sequence tag (EST) libraries were developed and annotated for Pseudoroegneria spicata, a mixture of both Elymus wawawaiensis and E. lanceolatus, and a Leymus cinereus x L. triticoides interspecific hybrid. The ESTs were combined into unigene sets of 8 780 unigenes for P. spicata, 11 281 unigenes for Leymus, and 7 212 unigenes for Elymus. Unigenes were annotated based on putative orthology to genes from rice, wheat, barley, other Poaceae, Arabidopsis, and the non-redundant database of the NCBI. Simple sequence repeat (SSR) markers were developed, tested for amplification and polymorphism, and aligned to the rice genome. Leymus EST markers homologous to rice chromosome 2 genes were syntenous on Leymus homeologous groups 6a and 6b (previously 1b), demonstrating promise for in silico comparative mapping. All ESTs and SSR markers are available on an EST information management and annotation database (http://titan.biotec.uiuc.edu/triticeae/). | 18,923,529 |
New resources for studying the rose flowering process. | Knowledge of the flowering process - an important trait in ornamental plants such as roses - is necessary for efficient control of flowering. This study was carried out to develop and characterize new resources to gain further insight into floral control in rose. We studied floral initiation in a nonrecurrent blooming rose (hybrid of Rosa wichurana) and a recurrent blooming rose (Rosa hybrida Black Baccara. In Black Baccara, floral initiation took place rapidly after bud burst, whereas in the greenhouse R. wichurana remained vegetative. During floral initiation, the apex enlarged and domed quickly and concomitantly. This is the first description of this transition between the vegetative and floral bud stages in rose. From these vegetative and pre-floral tissues, two cDNA libraries were constructed and 5,000 ESTs sequenced. By collecting our ESTs and those available in public databases, we developed a comprehensive database representing approximately 5,000 unique sequences after clustering. By screening this database for candidate genes involved in the flowering process, we identified 13 genes potentially involved in gibberellic acid signalling, photoperiod pathways, and floral development. Based on expression data, we put forward different hypotheses on the control of flowering in rose (photoperiod control and involvement of gibberellins) relative to what is already known in Arabidopsis. | 18,923,534 |
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