[Study of lymphocyte subsets and its activated-molecules in patients with paroxysmal nocturnal hemoglobinuria].
To investigate the relationship between subsets of lymphocytes and between its activated status and the clinical manifestations in patients with PNH, and to unfold immunological mechanism in the pathogenesis of PNH. The peripheral blood mononuclear cells (PBMNC) from 18 PNH patients and 20 controls were separated into two subpopulations using anti-CD(59) monoclonal antibody combined with goat-anti-mouse IgG immunomagnetic beads. CD(3)(+), CD(4)(+) and CD(8)(+) lymphocyte subsets were detected by flow cytometry. In 6 newly diagnosed patients, phenotypes associated with T cell activation such as CD(28)(+)/CD(4)(+) or CD(8)(+) cells, CD(8)(+) CD(38)(+) cells, and HLA-DR(+)/CD(4)(+) or CD(8)(+), and NK (CD(3)(-) CD(16)(+)) cells were detected in the peripheral blood. Patients with PNH showed significantly increased CD(3)(+) CD(8)(+)/CD(3)(+) CD(4)(+) ratio as compared with controls (1.22 +/- 0.51 vs 0.86 +/- 0.27, P < 0.05), and the CD(3)(+) CD(8)(+)/CD(3)(+) CD(4)(+) ratio in CD(59)(-) PBMC was higher than that in CD(59)(+) PBMC (2.31 +/- 1.56 vs 0.62 +/- 0.27, P < 0.05). The ratios of CD(4)(+) CD(28)(+)/CD(4)(+) markedly decreased and CD(8)(+)HLA-DR(+)/CD(8)(+) increased. Patients with PNH appear to have abnormalities in their lymphocytes. Increased ratios of CD(3)(+) CD(8)(+)/CD(3)(+) CD(4)(+) and HLA-DR(+) CD(8)(+)/CD(8)(+) lymphocytes as well as declined ratio of CD(4)(+) CD(28)(+)/CD(4)(+) lymphocytes might be involved in the pathogenesis of PNH.


[Factors associated with early sexual activity among Chilean adolescents].
Nowadays, adolescent population begins sexual activity earlier, a behavior with negative psychological ana social consequences. To determine the association between family factors and early sexual activity in adolescents of low and middle socioeconomic level. A sample of 3,210 adolescents, who confidentially requested care in a sexual and reproductive health university center, between 2000 and 2007, was analyzed. Adolescents who started sexual activity before 15 years of age, and those who started sexual activity after 15 years of age, were compared. Data was collected from structured interviews conducted at the adolescente first visit. Logistic regression was used to identify family factors associated with early sexual initiating in both, men and women. Family factors associated with early sexual activity start were not being raised by both parents, a poor parent-child relationship, a poor family communication, mothers with a history of adolescent motherhood, mothers employed outside the home and family dysfunction. Among women, the variables associated with a higher risk of early sexual debut were not married parents and history of adolescent fatherhood record among parents. Among men, these variables were permissions without restriction during the week and punishment when family rules were broken. Family factors must be considered in the design of strategies to prevent early sexual activity.


The subtypes of human immunodeficiency virus in Australia and Asia.
Worldwide, the human immunodeficiency virus exhibits a great genetic variability, with multiple circulating subtypes of the virus. This variability allows study of the movement of HIV strains within and between human populations but also has implications for diagnosis, treatment and monitoring. The type of HIV causing the epidemic in Australia is changing from being homogeneous subtype B, reflecting a greater regional diversity. In this paper the classification of HIV-1 subtypes and their distribution within the Australasian region are reviewed and the implications of these distribution patterns discussed.


Clinical trials in ALS: a review of the role of clinical and neurophysiological measurements.
We have reviewed all the published clinical trials of ALS and, from those considered sufficiently large, and containing a control group, we have evaluated their methodology with regard to statistical power. This implies a critical analysis of the endpoint measurements. We have concluded that clinical endpoints used in clinical trials of ALS have frequently been insufficiently sensitive, non-linear, or even not intuitively highly relevant to the disease. We suggest that the ALS-FRS, perhaps also MUNE and the Neurophysiological Index, may be the best measures currently available. These techniques have complementary characteristics that allow them to be used to address different aspects of the disease and its treatment in various trials designs. In the past some trials may have failed to demonstrate a treatment effect because the chosen endpoint measures and the trial design were inappropriate.


Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and -B Inhibitor.
Monoamine oxidases inhibitors (MAOIs) are effective therapeutic drugs for managing Parkinson's disease (PD) and depression. However, their irreversibility may lead to rare but serious side effects. As finding safer and reversible MAOIs is our target, we characterized the recombinant human (h) MAO-A and MAO-B inhibition potentials of two common natural isoflavones, genistein (GST) and daidzein (DZ) using luminescence assay. The results obtained showed that DZ exhibits partial to no inhibition of the isozymes examined while GST inhibited hMAO-B (IC50 of 6.81 μM), and its hMAO-A inhibition was more potent than the standard deprenyl. Furthermore, the reversibility, mode of inhibition kinetics, and tyramine oxidation of GST were examined. GST was a time-independent reversible and competitive hMAO-A and hMAO-B inhibitor with a lower K i of hMAO-B (1.45 μM) than hMAO-A (4.31 μM). GST also inhibited hMAO-B tyramine oxidation and hydrogen peroxide production more than hMAO-A. Docking studies conducted indicated that the GST reversibility and hMAO-B selectivity of inhibition may relate to C5-OH effects on its orientation and its interactions with the threonine 201 residue of the active site. It was concluded from this study that the natural product GST has competitive and reversible MAOs inhibitions and may be recommended for further investigations as a useful therapeutic agent for Parkinson's disease.


Validating tumor linkage using the NAACCR site pairs table.
The objective of this study is to illustrate use of the Site Pairs Table developed by the North American Association of Central Cancer Registries (NAACCR) Record Linkage Work Group to validate tumor linkage in a central registry database and to identify potential cases with inaccurate tumor linkage. Central registries often receive reports for patients with multiple tumors, and they receive multiple reports from different sources for the same tumor. Tumor site pairs (pairs of unique tumors for patients with multiple tumors) ought not refer to the same tumor as represented in the Site Pairs Table. Likewise, abstract pairs (pairs of abstracts relating to the same tumor) ought to be identified during the tumor linkage process as belonging to the same tumor. Three central cancer registries represented on the work group contributed data to the study. The data included cases diagnosed 1992-2003 and represented 143,288 patients with multiple tumors and 280,227 tumors with multiple abstracts. Totals of 181,118 tumor site pairs and 391,670 abstract site pairs were generated from the data and compared to the Site Pairs Table. Of the abstract site pairs 381,389 (97.4%) were found in the Site Pairs Table. One registry reviewed its portion of the 2.6% not found in the table and determined 12% of the cases were incorrectly linked and should change from one tumor to two tumors. Of the tumor site pairs, 144,793 (80%) were not found in the Site Pairs Table. Further evaluation of the remaining 20% by paired site and laterality, histology and timing showed 19.3% were considered unique tumors and 0.7% were identified as potential cases with inaccurate tumor linkage. Two registries reviewed their portion of these cases. One registry changed two tumors to one tumor on 44% of the cases they reviewed. The other registry changed two tumors to one tumor on 53% of the cases they reviewed. Analyzing site pairs within the registry database using the Site Pairs Table assists in identifying inaccurate tumor linkages as was shown in this study.


Ligand Specificity of Bean Leaf Soluble Auxin-binding Protein.
The soluble bean leaf auxin-binding protein (ABP) has a high affinity for a range of auxins including indole-3-acetic acid (IAA), alpha-napthaleneacetic acid, phenylacetic acid, 2,4,5-trichlorophenoxyacetic acid, and structurally related auxins. A large number of nonauxin compounds that are nevertheless structurally related to auxins do not displace IAA from bean ABP. Bean ABP has a high affinity for auxin transport inhibitors and antiauxins. The specificity of pea ABP for representative auxins is similar to that found for bean ABP. The bean ABP auxin binding site is similar to the corn endoplasmic reticulum auxin-binding sites in specificity for auxins and sensitivity to thiol reagents and azide. Qualitative similarities between the ligand specificity of bean ABP and the specificity of auxin-induced bean leaf hyponasty provide further evidence, albeit circumstantial, that ABP (ribulose 1,5-bisphosphate carboxylase) can bind auxins in vivo. The high incidence of ABP in bean leaves and the high affinity of this protein for auxins and auxin transport inhibitors suggest possible functions for ABP in auxin transport and/or auxin sequestration.


Characterization of the metabolic profile associated with serum 25-hydroxyvitamin D: a cross-sectional analysis in population-based data.
Numerous observational studies have observed associations between vitamin D deficiency and cardiometabolic diseases, but these findings might be confounded by obesity. A characterization of the metabolic profile associated with serum 25-hydroxyvitamin D [25(OH)D] levels, in general and stratified by abdominal obesity, may help to untangle the relationship between vitamin D, obesity and cardiometabolic health. Serum metabolomics measurements were obtained from a nuclear magnetic resonance spectroscopy (NMR)- and a mass spectrometry (MS)-based platform. The discovery was conducted in 1726 participants of the population-based KORA-F4 study, in which the associations of the concentrations of 415 metabolites with 25(OH)D levels were assessed in linear models. The results were replicated in 6759 participants (NMR) and 609 (MS) participants, respectively, of the population-based FINRISK 1997 study. Mean [standard deviation (SD)] 25(OH)D levels were 15.2 (7.5) ng/ml in KORA F4 and 13.8 (5.9) ng/ml in FINRISK 1997; 37 metabolites were associated with 25(OH)D in KORA F4 at P < 0.05/415. Of these, 30 associations were replicated in FINRISK 1997 at P < 0.05/37. Among these were constituents of (very) large very-low-density lipoprotein and small low-density lipoprotein subclasses and related measures like serum triglycerides as well as fatty acids and measures reflecting the degree of fatty acid saturation. The observed associations were independent of waist circumference and generally similar in abdominally obese and non-obese participants. Independently of abdominal obesity, higher 25(OH)D levels were associated with a metabolite profile characterized by lower concentrations of atherogenic lipids and a higher degree of fatty acid polyunsaturation. These results indicate that the relationship between vitamin D deficiency and cardiometabolic diseases is unlikely to merely reflect obesity-related pathomechanisms.


Metastatic carcinoma in the neck from an occult primary lesion.
Over an 11-year period, from January 1980 to December 1990, 23 patients with metastatic carcinoma of the neck were admitted to Addington Hospital with an unknown primary lesion. More than 50% of patients presented with disease in the N3 nodal stage. Sixteen patients had squamous cell carcinoma, 6 undifferentiated carcinoma and 1 adenocarcinoma. The diagnoses were made by means of fine-needle aspiration cytology and histological assessment of the neck nodes. Twenty-one patients were treated with radiotherapy and 2 with surgery. The primary tumour became apparent in only 4 (17%) patients, 7, 8, 9, and 12 months respectively after initial presentation. The sites were the base of tongue in 2, the pyriform fossa in 1 and the scalp in the remaining patient. The overall 3-year and 5-year survival rates were 26% and 17% respectively.


Differentially expressed transcripts and associated protein pathways in basilar artery smooth muscle cells of the high-salt intake-induced hypertensive rat.
The pathology of cerebrovascular disorders, such as hypertension, is associated with genetic changes and dysfunction of basilar artery smooth muscle cells (BASMCs). Long-term high-salt diets have been associated with the development of hypertension. However, the molecular mechanisms underlying salt-sensitive hypertension-induced BASMC modifications have not been well defined, especially at the level of variations in gene transcription. Here, we utilized high-throughput sequencing and subsequent signaling pathway analyses to find a two-fold change or greater upregulated expression of 203 transcripts and downregulated expression of 165 transcripts in BASMCs derived from rats fed a high-salt diet compared with those from control rats. These differentially expressed transcripts were enriched in pathways involved in cellular, morphological, and structural plasticity, autophagy, and endocrine regulation. These transcripts changes in the BASMCs derived from high-salt intake-induced hypertensive rats may provide critical information about multiple cellular processes and biological functions that occur during the development of cerebrovascular disorders and provide potential new targets to help control or block the development of hypertension.


A full gap above the Fermi level: the charge density wave of monolayer VS2.
In the standard model of charge density wave (CDW) transitions, the displacement along a single phonon mode lowers the total electronic energy by creating a gap at the Fermi level, making the CDW a metal-insulator transition. Here, using scanning tunneling microscopy and spectroscopy and ab initio calculations, we show that VS2 realizes a CDW which stands out of this standard model. There is a full CDW gap residing in the unoccupied states of monolayer VS2. At the Fermi level, the CDW induces a topological metal-metal (Lifshitz) transition. Non-linear coupling of transverse and longitudinal phonons is essential for the formation of the CDW and the full gap above the Fermi level. Additionally, x-ray magnetic circular dichroism reveals the absence of net magnetization in this phase, pointing to coexisting charge and spin density waves in the ground state.


Physician perceptions of pharmacist-provided medication therapy management: qualitative analysis.
To identify physician perceptions of community pharmacist-provided medication therapy management (MTM). Three focus groups consisting of family and internal medicine physicians were conducted in Pittsburgh, York, and Philadelphia, PA, using a semistructured topic guide to facilitate discussions. Each participant completed an exit survey at session conclusion. 23 physicians participated in one of three focus groups conducted in Pittsburgh (n = 9), York (n = 6), and Philadelphia (n = 8). Participants identified common medication issues in their practices: nonadherence, adverse effects, drug interactions, medication costs, and incomplete patient understanding of the medication regimen. Receipt of a complete patient medication list was reported as the greatest potential benefit of MTM. Participants believed that physicians would be better suited as MTM providers than pharmacists. Concerns identified were the mechanism of pharmacist payment, reimbursement of time spent by physicians to coordinate care, and the training/preparation of the pharmacist. The need for a trusting relationship between a patient's primary care physician and the pharmacists providing MTM was identified. This study provides information to assist pharmacists when approaching physicians to propose collaboration through MTM. Pharmacists should tell physicians that they will receive an updated patient medication list after each visit and emphasize that direct communication is essential to coordinate care.


The loss of p27 protein has an independent prognostic significance in gastric cancer.
p27 and cyclin E are regulators of the G1 to S phase transition. This study was performed to determine whether two cell cycle regulators--p27 and cyclin E--provided prognostic information in gastric cancer patients. A total of 115 gastric cancer patients were eligible for this study from Jan. 1988 through Dec. 1994, and their paraffin blocks were chosen for immunohistochemical staining against p27 and cyclin E. Consequently, 35 patients were stained positively for p27 (30.4%) and 24 for cyclin E (20.9%). A high level of p27 expression was more frequently observed in intestinal type (43.9%) than in diffuse (23.0%) (p = 0.019). Concerning patients' survival, univariate analysis showed that the depth of invasion (p = 0.043), the number of metastatic nodes (p = 0.024) and the expression of p27 (p = 0.031) were significant prognostic factors. In particular, p27 negative group showed a worse overall survival than their counterpart (42.42 +/- 9.63% Vs 26.63 +/- 4.17%). On multivariate analysis by Cox regression model, the expression of p27 (p = 0.048) and number of metastatic nodes (p = 0.026) were significant prognostic factors on overall survival. Loss of the p27 protein has independent prognostic significance in gastric carcinomas, and whether p27 negative gastric cancer requires more radical therapies can be elucidated by future clinical trials.


Promonocytic U937 subclones expressing CD4 and CXCR4 are resistant to infection with and cell-to-cell fusion by T-cell-tropic human immunodeficiency virus type 1.
Different strains of human immunodeficiency virus type 1 (HIV-1) vary markedly in the ability to infect cells of the monocyte/macrophage (M/M) lineage. M/M are generally resistant to infection with T-cell-tropic (T-tropic) strains of HIV-1. Recently, the chemokine receptors CCR5 and CXCR4 were identified as cofactors for fusion/entry of macrophage- and T-tropic strains of HIV-1, respectively. To investigate the mechanisms of resistance of M/M to T-tropic HIV-1 infection, we examined a number of subclones of the U937 promonocytic cell line. We found that certain subclones of U937 (plus clones) could, while others (minus clones) could not, support replication of T-tropic strains of HIV-1. We demonstrate that (i) both minus and plus clones support HIV-1 replication when transfected with an infectious molecular cDNA clone of a T-tropic HIV-1; (ii) minus clones do not, but plus clones do, efficiently support fusion with cells expressing HIV-1 IIIB Env; (iii) both plus and minus clones (with the exception of one clone) express physiologically functional CXCR4 protein as well as CD4 on the cell surface; (iv) introduction of CXCR4 into the CXCR4-negative clone does not restore fusogenicity with or susceptibility to T-tropic HIV-1; and (v) a ligand (stromal cell-derived factor 1) for or a monoclonal antibody (12G5) to CXCR4 does not effectively inhibit HIV-mediated cell-to-cell fusion of U937 cells. These data indicate that resistance to T-tropic HIV-1 infection of U937 minus clones occurs at fusion/ entry events and that expression of functional CXCR4 and CD4 is not a sole determinant for susceptibility to T-tropic HIV-1 infection; furthermore, they suggest that other factors are positively or negatively involved in HIV-mediated cell-to-cell fusion in U937 promonocytic cells.


Partial proteolysis of human L-type phosphofructokinase.
L (liver) type phosphofructokinase subunits purified from human leukocytes are slightly lighter than L subunits from liver and red blood cells. A mild treatment of red blood cell L4 enzyme with subtilisin converts its subunits into forms of similar molecular weight to leukocyte enzyme. From a kinetical point of view, subtilisin-treated L4 phosphofructokinase and leukocyte enzymes are characterized by a decrease of the allosteric properties as compared to non-treated red cell L4 phosphofructokinase.


Late-postnatal cannabinoid exposure persistently increases FoxP2 expression within zebra finch striatum.
Prior work has shown that cannabinoid exposure of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. We are currently working to identify physiological substrates for this altered song learning. FoxP2 is a transcription factor associated with altered vocal development in both zebra finches and humans. This protein shows a distinct pattern of expression within Area X of striatum that coincides with peak expression of CB(1) cannabinoid receptors during sensorimotor learning. Coincident expression in a brain region essential for song learning led us to test for a potential signaling interaction. We have found that cannabinoid agonists acutely increase expression of FoxP2 throughout striatum. When administered during sensorimotor song learning, cannabinoids increase basal levels of striatal FoxP2 expression in adulthood. Thus, song-altering cannabinoid treatments are associated with persistent increases in basal expression of FoxP2 in zebra finch striatum.


Current clinical application of serum biomarkers to detect and monitor ovarian cancer - update.
In recent decades many potential serum biomarkers have been assessed in the diagnosis of ovarian cancer. Except cancer antigen 125 (CA125) and human epididymis protein 4 (HE4), none of them have been applied to everyday clinical practice. Based on extensive scientific evidence, CA125 combined with HE4 to form the risk of ovarian malignancy algorithm (ROMA), have become widespread in clinical practice in the evaluation of adnexal masses. Early ovarian cancer is often asymptomatic, so it remains challenging to develop even more effective methods for early diagnosis and screening. Among others, OVA1 is tested as a potential tool to improve the stratification of the risk of ovarian cancer. Also, a lot of effort is being made to develop suitable methods to monitor ovarian cancer patients. Serum CA125 already plays an established role in monitoring the treatment (except targeted therapies) and relapse setting in ovarian cancer patients, with a more limited role in subtypes other than in high-grade serous carcinoma, and always in correlation with imaging and clinical assessment. Human epididymis protein 4 (as well as circulating tumour DNA - ctDNA) is not recommended for monitoring at that timepoint, although encouraging newly published studies might influence their role in the future.


Synganglion histology in different stages of Rhipicephalus sanguineus ticks (Acari: Ixodidae).
The present study performs a morpho-histological description of the central nervous system of Rhipicephalus sanguineus ticks in order to analyze if there are differences in this tissue among larvae, nymphs, and adults. The results showed that the central nervous system in all the life stages of R. sanguineus consists of a mass of fused nerves named synganglion. Externally, this organ does not present segmentation, consisting of a single structure located ventromedially in the third anterior of the body. This organ is externally covered by the neural lamella or neurilemma, a uniform and acellular layer. Below, there is the periganglionic membrane or perineurium, formed by glial cells, which are characterized by their elongated nuclei. The esophagus penetrates the synganglion dividing it in two regions: supraesophageal, which is the smaller of the two and consists of a protocerebrum, a single dorsal ganglion located anteriordorsally to the esophagus; and the subesophageal, which is the largest part of the synganglion, located in the posterior region and ventral to the esophagus. Internally, the synganglion is subdivided in an external cortical region-which contains the cellular body of the nervous cells-and an internal neuropile formed by a set of neural fibers and it is constituted by bilaterally symmetric ganglia, from where nerves emerge towards several parts of the body. The results here obtained showed that there are no differences in the morpho-histology of this tissue in different life stages of R. sanguineus, suggesting that the initial structure is maintained during the whole life cycle of the tick, i.e., from larval to adult stage.


Synthesis of Hydroxysumanene and Substituent Effect of Hydroxy Group on Bowl Inversion Dynamics and Electronic Structure.
Hydroxysumanene was synthesized from acylsumanenes by Baeyer-Villiger oxidation. DFT calculation predicted the higher bowl inversion energy and deeper bowl structure of hydroxysumanene than those of pristine sumanene. The bowl inversion energy of hydroxysumanene was experimentally determined by 2D-EXSY NMR measurement as 21.2 kcal/mol. The energy was larger than that of pristine sumanene (20.3 kcal/mol), which agreed with the calculation result. Electrochemical measurement indicated the higher HOMO level of hydroxysumanene than that of sumanene, which confirmed the electron-rich character of the phenolic function in the bowl skeleton.


Modified ultrafiltration: role in adult cardiac surgical haemostasis.
During cardiac surgery, cardiopulmonary bypass (CPB) leads to haemodilutional anaemia and activation of inflammatory mediators, affecting haemostasis. Modified Ultrafiltration (MUF) is being increasingly favoured for haemoconcentration without blood transfusion and reducing post operative bleeding. Aim of this study was to record the impact of modified ultrafiltration on haemoconcentration and postoperative bleeding during adult cardiac surgery. This randomized control trial included 100 patients, divided into 2 groups; MUF and control group. Serial blood samples were drawn to evaluate haematological indices. Postoperative chest drainage was recorded for 24 hours. Results were expressed in terms of percentages, means and p value (p < 0.05 was taken as significant). Four patients were excluded and 96 patients were analyzed (MUF n = 50, control n = 46). According to American society of anaesthetist (ASA) classification, MUF group was higher risk group (p = 0.02) with longer extracorporeal perfusion time (p < 0.001). Haemoconcentration was successfully achieved in MUF group (final haemoglobin = 10.7 +/- 1.25, haematocrit = 33 +/- 3.64%, p < 0.001) with lower blood loss (MUF = 395 +/- 153 ml, control = 755 +/- 435 ml, p < 0.001) and transfusion requirement (p < 0.001). Re-exploration rate was 4% and 6.5% in MUF and control group respectively (p = 0.57). Mortality in both groups was comparable (MUF = 4%, control = 4.3%, p = 0.94). Modified ultrafiltration is a safe procedure which successfully achieves haemoconcentration, lowers blood loss and transfusion requirement after cardiac surgery in adult population.


Prioritization of health care services. A progress report by the Oregon Health Services Commission.
The Oregon Health Services Commission is composed of a group of 11 consumers and health care professionals. It was appointed by the governor as required by the "Oregon Basic Health Services Act" to produce a prioritized list of health services ranked on the basis of their relative importance to populations served. Following actuarial analysis, the legislature will determine the extent to which the "list" of services can be funded to provide health care access for Medicaid recipients earning up to the 100th percentile of the federal poverty level. Prioritization will be based on a cost-benefit formula applied to each treatment/condition unit and assignment of each of these to a general category, which itself has been ranked on the basis of "public value."


Effects of speech and language treatment on recovery from aphasia.
Language recovery in aphasic patients who received one of three types of speech and language treatment was compared with that in aphasic patients who received no treatment. One hundred aphasic patients were followed from 2 to 4 weeks postonset for 1 year or until recovery, using a standardized test battery administered at systematic intervals. Both treatment methods provided by trained speech-language pathologists were efficacious, while the method provided by trained nonprofessionals approached statistical significance. Small group size prevented resolution of the question of whether one type of treatment was superior to another.


Rapid and sensitive liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of yonkenafil and its major metabolites in rat plasma.
Yonkenafil is a promising drug for treatment of male erectile dysfunction. Previous studies showed that the piperazine-N,N'-deethylation metabolite, piperazine-N-deethylation metabolite, and piperazine-N-deethylation-N,N'-deethylation metabolite were the major metabolites of yonkenafil after extensive metabolism. We developed a sensitive and selective method for the simultaneous quantification of yonkenafil and its major metabolites using high-throughput liquid chromatography with tandem mass spectrometry. Analytes and internal standard were extracted from a small quantity of plasma (50 μL) using liquid-liquid extraction with diethyl ether/dichloromethane (60:40, v/v), and the baseline separation was achieved on Zorbax SB-C18 column using ammonia/water/methanol (0.2:20:80, v/v/v) as the mobile phase. The assay was performed with an electrospray positive ionization mass spectrometry through the multiple-reaction monitoring mode within 2 min. Calibration curve of the method was linear within the range of 1.00-1000 ng/mL for all the analytes with the intra- and interday precisions of 4.0-5.2 and 4.0-5.3% for yonkenafil, 3.1-4.9 and 3.1-5.2% for the piperazine-N,N'-deethylation metabolite, 4.8-6.8 and 4.8-7.3% for the piperazine-N-deethylation metabolite, and 2.9-6.1 and 5.4-6.3% for the piperazine-N-deethylation-N,N'-deethylation metabolite, respectively. The recoveries were above 90% with low matrix effects. The validated assay was successfully applied to support a preclinical pharmacokinetic study in six rats using a single oral dose of yonkenafil (8 mg/kg).


Maternal diet high in fat reduces docosahexaenoic acid in liver lipids of newborn and sucking rat pups.
The effect of a maternal diet high in fat, similar to Western foods, and of diabetes on liver essential fatty acid composition of the mother and the newborn and sucking pups was investigated. Female Sprague-Dawley rats were fed on either a low-fat (42 g/kg) or a high-fat (329 g/kg) diet for 10 d before mating, throughout pregnancy and post-partum. On the first day of pregnancy, diabetes was induced by intravenous administration of streptozotocin in half the animals from the two diet groups. Half the pups were killed at birth, and the remaining pups and mothers at days 15 and 16 respectively. At birth, there was a significant reduction in the proportions of docosahexaenoic acid (DHA) in the liver phosphoglycerols and neutral lipids of the pups of both high-fat control and diabetic mothers compared with those of low-fat control and diabetic mothers. Diabetes decreased arachidonic (AA) and linoleic acid values in both the low- and high-fat groups at birth. The sucking pups of both the high-fat control and diabetic mothers exhibited a significant reduction in DHA and a concomitant compensatory increase in AA and a lowering in DHA-AA balance. In the mothers, the high-fat diet significantly increased the proportions of DHA in ethanolamine phosphoglycerols but had no observable effect in choline phosphoglycerols and neutral lipids. In the fetus the DHA level (g/100 g total fatty acids) was disproportionately reduced by the maternal high-fat diet. The adverse effect of the high-fat diet on the level of DHA (g/100 g total fatty acids) was greater in the neonate (and by implication the fetus) than in the sucking pups or mothers. It is concluded that a distortion of the biochemistry is induced in the offspring through a maternal high-fat diet, without genetic predisposition.


Cytokines as therapeutic drugs.
Cytokines are a growing group of proteins that are responsible for the communication of cells of the immune system, hematopoietic cells, and other cell types. They play a dominant role in various diseases, particularly in promoting and perpetuating inflammation. Cytokine production is a reaction of the body to a pathologic state to restore homeostasis. In such cases, the therapeutic intervention should support the reaction of the body by giving the cytokine itself (agonistic therapeutics). In other cases, manifestation of a disease results from an overproduction of cytokines, making cytokine antagonists desirable therapeutic drugs. Furthermore, cytokines may be good candidates as cancer therapeutics, especially to support the restoration of blood cell populations after chemotherapy or radiation.


Surface Electromyography Analysis of Three Squat Exercises.
The aim of this study was to perform an electromyography comparison of three commonly used lower limb injury prevention exercises: a single-leg squat on a bench (SLSB), a double-leg squat (DLS) and a double-leg squat on a BOSU® balance trainer (DLSB). After determining the maximum isometric voluntary contraction of the hamstring and quadriceps, eight female athletes performed 3 repetitions of each exercise, while electromyography activity of the biceps femoris (BF), semitendinosus (ST), vastus lateralis (VL) and vastus medialis (VM) was monitored. Comparisons between exercises revealed higher activation in BF (descending phase: p = 0.016, d = 1.36; ascending phase: p = 0.046, d = 1.11), ST (descending phase: p = 0.04, d = 1.87; ascending phase: p = 0.04, d = 1.87), VL (ascending phase: p = 0.04, d = 1.17) and VM (descending phase: p = 0.05, d = 1.11; ascending phase: p = 0.021, d = 1.133) muscles for the SLSB compared to the DLSQ. Furthermore, higher muscular activation of the ST (ascending phase: p = 0.01, d = 1.51; descending phase: p = 0.09, d = 0.96) and VM (ascending phase: p = 0.065, d = 1.03; descending phase: p = 0.062, d = 1.05) during the SLSB with respect to the DLSB was observed. In conclusion, the SLSB elicits higher neuromuscular activation in both hamstring and quadriceps muscles compared to the other two analysed exercises. Additionally, the higher muscle activation of both medial muscles (ST and VM) during the SLSB suggests that single leg squatting exercises may enhance lower limb medial to lateral balance, and improve knee stability in the frontal plane.


Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet.
Malignant brain tumors are a significant health problem in children and adults and are largely unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration (the Warburg effect), malignant brain cancer can be managed through changes in metabolic environment. In contrast to malignant brain tumors that are mostly dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (beta-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome, honed through millions of years of environmental forcing and variability selection, can transition from one energy state to another. We propose a different approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and less metabolically flexible tumor cells. This approach to brain cancer management is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are discussed.


Dynamic Regulation of the Nexus Between Stress Granules, Roquin, and Regnase-1 Underlies the Molecular Pathogenesis of Warfare Vesicants.
The use of chemical warfare agents is prohibited but they have been used in recent Middle Eastern conflicts. Their accidental exposure (e.g. arsenical lewisite) is also known and causes extensive painful cutaneous injury. However, their molecular pathogenesis is not understood. Here, we demonstrate that a nexus of stress granules (SGs), integrated stress, and RNA binding proteins (RBPs) Roquin and Reganse-1 play a key role. Lewisite and its prototype phenylarsine oxide (PAO) induce SG assembly in skin keratinocytes soon after exposure, which associate with various RBPs and translation-related proteins. SG disassembly was detected several hours after exposure. The dynamics of SG assembly-disassembly associates with the chemical insult and cell damage. Enhanced Roquin and Regnase-1 expression occurs when Roquin was recruited to SGs and Regnase-1 to the ribosome while in the disassembling SGs their expression is decreased with consequent induction of inflammatory mediators. SG-targeted protein translational control is regulated by the phosphorylation-dependent activation of eukaryotic initiation factors 2α (eIF2α). Treatment with integrated stress response inhibitor (ISRIB), which blocks eIF2α phosphorylation, impacted SG assembly dynamics. Topical application of ISRIB attenuated the inflammation and tissue disruption in PAO-challenged mice. Thus, the dynamic regulation of these pathways provides underpinning to cutaneous injury and identify translational therapeutic approach for these and similar debilitating chemicals.


Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes.
The proinflammatory cytokine interleukin-6 (IL-6) may modulate the onset and progression of complications of diabetes. As this cytokine increases after exercise, and many other exercise responses are altered by prior glycemic fluctuations, we hypothesized that prior hyperglycemia might exacerbate the IL-6 response to exercise. Twenty children with type 1 diabetes (12 boys/8 girls, age 12-15 yr) performed 29 exercise studies (30-min intermittent cycling at approximately 80% peak O2 uptake). Children were divided into four groups based on highest morning glycemic reading [blood glucose (BG) < 150, BG 151-200, BG 201-300, or BG > 300 mg/dl]. All exercise studies were performed in the late morning, after hyperglycemia had been corrected and steady-state conditions (plasma glucose < 120 mg/dl, basal insulin infusion) had been maintained for > or = 90 min. Blood samples for IL-6, growth factors, and counterregulatory hormones were drawn at pre-, end-, and 30 min postexercise time points. At all time points, circulating IL-6 was lowest in BG < 150 and progressively higher in the other three groups. The exercise-induced increment also followed a similar dose-response pattern (BG < 150, 0.6 +/- 0.2 ng/ml; BG 151-200, 1.2 +/- 0.8 ng/ml; BG 201-300, 2.1 +/- 1.1 ng/ml; BG > 300, 3.2 +/- 1.4 ng/ml). Other measured variables (growth hormone, IGF-I, glucagon, epinephrine, cortisol) were not influenced by prior hyperglycemia. Recent prior hyperglycemia markedly influenced baseline and exercise-induced levels of IL-6 in a group of peripubertal children with type 1 diabetes. While exercise is widely encouraged and indeed often considered part of diabetic management, our data underscore the necessity to completely understand all adaptive mechanisms associated with physical activity, particularly in the context of the developing diabetic child.


Quiescent gastric stem cells maintain the adult Drosophila stomach.
The adult Drosophila copper cell region or "stomach" is a highly acidic compartment of the midgut with pH < 3. In this region, a specialized group of acid-secreting cells similar to mammalian gastric parietal cells has been identified by a unique ultrastructure and by copper-metallothionein fluorescence. However, the homeostatic mechanism maintaining the acid-secreting "copper cells" of the adult midgut has not been examined. Here, we combine cell lineage tracing and genetic analysis to investigate the mechanism by which the gastric epithelium is maintained. Our investigation shows that a molecularly identifiable population of multipotent, self-renewing gastric stem cells (GSSCs) produces the acid-secreting copper cells, interstitial cells, and enteroendocrine cells of the stomach. Our assays demonstrate that GSSCs are largely quiescent but can be induced to regenerate the gastric epithelium in response to environmental challenge. Finally, genetic analysis reveals that adult GSSC maintenance depends on Wnt signaling. Characterization of the GSSC lineage in Drosophila, with striking similarities to mammals, will advance the study of both homeostatic and pathogenic processes in the stomach.


Plant-Oil-Based Fibre Composites for Boat Hulls.
Plant-oil-based fibre composites for boat hulls are an interesting and growing group of materials. Although many problems are to be tackled at different stages of their preparation, the green composites are already successfully commercialised. Within this paper, the most important chemical and physical characteristics of both natural fibres and sustainable resins are provided in the form of a comprehensive review. Finally, the complex issue of interactions filler-matrix is considered.


Cocaine Withdrawal Impairs mGluR5-Dependent Long-Term Depression in Nucleus Accumbens Shell Neurons of Both Direct and Indirect Pathways.
We previously reported that animals withdrawn from repeated cocaine exposure exhibited a selective deficit in the ability to elicit metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD) in the nucleus accumbens (NAc) shell. To determine whether such impairment occurs in the NAc in a cell-type-specific manner, we used bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of gene regulatory elements for the dopamine D1 receptor (Drd1) or dopamine D2 receptor (Drd2) to identify distinct subpopulations of medium spiny neurons (MSNs). We found that bath application of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) reliably induced LTD in both NAc shell and core MSNs of wild-type, hemizygous Drd1-eGFP, and Drd2-eGFP mice. Confirming our previous results, cocaine withdrawal selectively impaired DHPG-LTD in NAc shell Drd1-expressing direct and Drd2-expressing indirect pathway MSNs. We also found that the expression of DHPG-LTD in NAc MSNs was not affected by the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 1-naphthyl acetyl spermine. Furthermore, systemic administration of mGluR5-negative allosteric modulator fenobam before the daily injection of cocaine preserved mGluR5 function and significantly reduced the expression of cocaine-induced behavioral sensitization. These results reveal that withdrawal from repeated cocaine exposure may result in the impairment of NAc mGluR5-LTD in a subregion- but not cell-type-specific manner and suggests that pharmacological antagonism of mGluR5 may represent a potential strategy for reducing cocaine-induced addictive behaviors.


Spinocerebellar ataxia type 10: Frequency of epilepsy in a large sample of Brazilian patients.
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by an ATTCT repeat intronic expansion in the SCA10 gene. SCA 10 has been reported in Mexican, Brazilian, Argentinean and Venezuelan families. Its phenotype is overall characterized by cerebellar ataxia and epilepsy. Interestingly, Brazilian patients reported so far showed pure cerebellar ataxia, without epilepsy. Here, authors provide a systematic analysis of the presence, frequency and electroencephalographic presentation of epilepsy among 80 SCA10 patients from 10 Brazilian families. Overall, the frequency of epilepsy was considered rare, been found in 3.75 % of the cases while this finding in populations from other geographic areas reaches 60% of SCA10 cases.


Comparative Analysis of the Effects of Long-Term 3,5-diiodothyronine Treatment on the Murine Hepatic Proteome and Transcriptome Under Conditions of Normal Diet and High-Fat Diet.
Background: The thyroid hormone (TH) metabolite 3,5-diiodothyronine (3,5-T2) is considered as a potential drug for treatment of nonalcoholic fatty liver disease (NAFLD) based on its prominent antisteatotic effects in murine models of obesity without the detrimental thyromimetic side effects known for classical TH. To expand our understanding of its mode of action, we comprehensively characterized the effects of 3,5-T2 on hepatic gene expression in a diet-induced murine model of obesity by a combined liver proteome and transcriptome analysis. Materials and Methods: Male C57BL/6 mice fed high-fat diet (HFD) to induce NAFLD or standard diet (SD) as control were treated with 2.5 μg/g body weight 3,5-T2 or saline for 4 weeks. We performed mass spectrometry analyses and integrated those proteome data with earlier published microarray-based transcriptome data from the same animals. In addition, concentrations of several sex steroids in serum and different tissues were determined by gas chromatography-tandem mass spectrometry. Results: We observed limited concordance between transcripts and proteins exhibiting differential abundance under 3,5-T2 treatment, which was only partially explainable by methodological reasons and might, therefore, reflect noncanonical post-transcriptional events. The treatment affected the levels of more and partially different proteins under HFD as compared with SD, demonstrating response modulation by the hepatic lipid load. The hepatic physiological signatures of 3,5-T2 treatment inferable from the omics data comprised the reduction of oxidative stress and alteration of apolipoprotein profiles, both due to decreased liver fat content. In addition, induction of several classical TH target genes and genes involved in the biosynthesis of cholesterol, bile acids (BAs), and male sex steroids was observed. The latter finding was supported by hepatic sex steroid measurements. Conclusion: While confirming the beneficial hepatic liver fat reduction by 3,5-T2 treatment, our data suggest that besides the well-known induction of fatty acid oxidation the stimulation of cholesterol- and BA synthesis with subsequent excretion of the latter through bile might represent a further important mechanism in this context. The obvious intensified male sex steroid exposition of the liver in 3,5-T2-treated HFD animals can be predicted to cause enhanced hepatic "masculinization," with not yet clear but potentially detrimental physiological consequences.


The mating-type and pathogenicity locus of the fungus Ustilago hordei spans a 500-kb region.
The fungal pathogen Ustilago hordei causes the covered smut disease of barley and oats. Mating and pathogenicity in this fungus are controlled by the MAT locus, which contains two distinct gene complexes, a and b. In this study, we tagged the a and b regions with the recognition sequence for the restriction enzyme I-SceI and determined that the distance between the complexes is 500 kb in a MAT-1 strain and 430 kb in a MAT-2 strain. Characterization of the organization of the known genes within the a and b gene complexes provided evidence for nonhomology and sequence inversion between MAT-1 and MAT-2. Antibiotic-resistance markers also were used to tag the a gene complex in MAT-1 strains (phleomycin) and the b gene complex in MAT-2 strains (hygromycin). Crosses were performed with these strains and progeny resistant to both antibiotics were recovered at a very low frequency, suggesting that recombination is suppressed within the MAT region. Overall, the chromosome homologues carrying the MAT locus of U. hordei share features with primitive sex chromosomes, with the added twist that the MAT locus also controls pathogenicity.


GABA inhibits endozepine release from cultured rat astrocytes.
In the mammalian brain, the endogenous ligands for benzodiazepine receptors (also called endozepines) are predominantly synthesized by glial cells. It has recently been reported that rat astrocytes in primary culture release substantial amounts of endozepines. The aim of the present study was to investigate the possible involvement of GABA in the control of endozepine release. Exposure of cultured rat astrocytes to GABA (10(-7) to 10(-5) M) induced a dose-related inhibition of endozepine secretion. At higher doses (3 x 10(-5) to 10(-3) M), the effect of GABA gradually diminished. The inhibitory effect of GABA (10(-5) M) was mimicked by the GABA(B) receptor agonist baclofen (10(-5) M). In contrast, the GABA(A) receptor agonists 3APS and isoguvacine (10(-5) M each) did not modify endozepine release. The inhibition of endozepine secretion evoked by GABA and baclofen (10(-5) M each) was totally abrogated by the specific GABA(B) receptor antagonist phaclofen (10(-4) M). GABA and baclofen caused a significant inhibition of forskolin-evoked production of cAMP in astrocytes and this effect was abolished in the presence of phaclofen. In contrast, isoguvacine had no effect on cAMP production. Exposure of astrocytes to dbcAMP induced a time- and dose-dependent stimulation of endozepine release. These data indicate that GABA, acting through GABA(B) receptors negatively coupled to adenylyl cyclase, inhibits endozepine release from cultured rat astrocytes. The secretion of endozepines thus appears to be a valuable marker to monitor astrocyte activity.


Biomechanical Analysis of Cervical Disc Replacement and Fusion Using Single Level, Two Level, and Hybrid Constructs.
A biomechanical study comparing arthroplasty with fusion using human cadaveric C2-T1 spines. To compare the kinematics of the cervical spine after arthroplasty and fusion using single level, 2 level and hybrid constructs. Previous studies have shown that spinal levels adjacent to a fusion experience increased motion and higher stress which may lead to adjacent segment disc degeneration. Cervical arthroplasty achieves similar decompression but preserves the motion at the operated level, potentially decreasing the occurrence of adjacent segment disc degeneration. 11 specimens (C2-T1) were divided into 2 groups (BRYAN and PRESTIGE LP). The specimens were tested in the following order; intact, single level total disc replacement (TDR) at C5-C6, 2-level TDR at C5-C6-C7, fusion at C5-C6 and TDR at C6-C7 (Hybrid construct), and lastly a 2-level fusion. The intact specimens were tested up to a moment of 2.0 Nm. After each surgical intervention, the specimens were loaded until the primary motion (C2-T1) matched the motion of the respective intact state (hybrid control). An arthroplasty preserved motion at the implanted level and maintained normal motion at the nonoperative levels. Arthrodesis resulted in a significant decrease in motion at the fused level and an increase in motion at the unfused levels. In the hybrid construct, the TDR adjacent to fusion preserved motion at the arthroplasty level, thereby reducing the demand on the other levels. Cervical disc arthroplasty with both the BRYAN and PRESTIGE LP discs not only preserved the motion at the operated level, but also maintained the normal motion at the adjacent levels. Under simulated physiologic loading, the motion patterns of the spine with the BRYAN or PRESTIGE LP disc were very similar and were closer than fusion to the intact motion pattern. An adjacent segment disc replacement is biomechanically favorable to a fusion in the presence of a pre-existing fusion.


Intestinal Barrier Disturbances in Haemodialysis Patients: Mechanisms, Consequences, and Therapeutic Options.
There is accumulating evidence that the intestinal barrier and the microbiota may play a role in the systemic inflammation present in HD patients. HD patients are subject to a number of unique factors, some related to the HD process and others simply to the uraemic milieu but with common characteristic that they can both alter the intestinal barrier and the microbiota. This review is intended to provide an overview of the current methods for measuring such changes in HD patients, the mechanisms behind these changes, and potential strategies that may mitigate these modifications. Lastly, intradialytic exercise is an increasingly employed intervention in HD patients; however the potential implications that this may have for the intestinal barrier are not known; therefore future research directions are also covered.


Revamping highly weathered soils in the tropics with biochar application: What we know and what is needed.
Fast weathering of parent materials and rapid mineralization of organic matter because of prevalent climatic conditions, and subsequent development of acidity and loss/exhaustion of nutrient elements due to intensive agricultural practices have resulted in the degradation of soil fertility and productivity in the vast tropical areas of the world. There is an urgent need for rejuvenation of weathered tropical soils to improve crop productivity and sustainability. For this purpose, biochar has been found to be more effective than other organic soil amendments due to biochar's stability in soil, and thus can extend the benefits over long duration. This review synthesizes information concerning the present status of biochar application in highly weathered tropical soils highlighting promising application strategies for improving resource use efficiency in terms of economic feasibility. In this respect, biochar has been found to improve crop productivity and soil quality consistently through liming and fertilization effects in low pH and infertile soils under low-input conditions typical of weathered tropical soils. This paper identifies several advance strategies that can maximize the effectiveness of biochar application in weathered tropical soils. However, strategies for the reduction of costs of biochar production and application to increase the material's use efficiency need future development. At the same time, policy decision by linking economic benefits with social and environmental issues is necessary for successful implementation of biochar technology in weathered tropical soils. This review recommends that advanced biochar strategies hold potential for sustaining soil quality and agricultural productivity in tropical soils.


Comparing an immediate cessation versus reduction approach to smokeless tobacco cessation.
Relatively few studies have investigated pharmacological or behavioral treatment of smokeless tobacco (ST) users who do not have immediate quit plans. In this study, we compared a reduction treatment approach with an immediate cessation approach in a population of ST users who reported no immediate plans to quit. Subjects randomly assigned to the immediate cessation condition set a quit date soon after enrollment and were offered 2 weeks of nicotine patch therapy to help in their cessation efforts. Subjects assigned to the ST reduction group were provided with their choice of either 4 mg nicotine lozenge or ST brand switching to help them reduce their ST use or levels of nicotine exposure, respectively. Quit date was 6 weeks after the onset of treatment. Follow-up was at 12 weeks and 26 weeks postenrollment and 26 weeks postquit. Both 7-day point prevalence abstinence and prolonged abstinence rates following the quit date were significantly higher in the immediate cessation group versus the reduction group at 12 and 26 weeks (all p values ≤ .04) and for prolonged abstinence at 6 months postquit (p = .002). Significant reductions in ST use among nonquitters were observed for both groups (p < .0001) with no differences between groups. Our study demonstrated that immediate cessation with an established quit date resulted in greater cessation success than a gradual reduction approach among ST users who do not have an immediate quit plan but are motivated to quit.


The DNA sequences required for apolipoprotein B expression in the heart are distinct from those required for expression in the intestine.
We recently reported that the apolipoprotein B (apo-B) gene is expressed in the heart and that the heart secretes apo-B-containing lipoproteins. We have also recently demonstrated that the tissue-specific expression of the apo-B gene is complex, with apo-B gene expression in the intestine being dependent on an enhancer element located very far from the structural gene (between 54 and 62 kb 5' to exon 1). In this study, we investigated whether these distant DNA sequences control or affect the expression of the apo-B gene in the heart. To address this issue, we analysed heart apo-B gene expression in heart tissue from a series of human apo-B transgenic mice generated from human genomic DNA constructs that ranged in size from 70 to 207 kb. All of these constructs contained the coding portion of the apo-B gene, but each contained different amounts of flanking sequences (5-120 kb 5' to the gene and 1.5-35 kb 3' to the gene). Each construct conferred human apo-B gene expression in the heart, including those containing as little as 5 kb of 5'-flanking sequences or as little as 1.5 kb of 3'-flanking sequences. These data support the idea that apo-B gene expression in the heart, unlike that in the intestine, is not affected by a distant enhancer element.


Three new monoclonal antibodies that define a unique antigen associated with prolymphocytic leukemia/non-Hodgkin's lymphoma and are effectively internalized after binding to the cell surface antigen.
Prolymphocytic leukemia (PLL) is closely related to chronic lymphocytic leukemia (CLL), but present with distinctive clinical/laboratory features and associated with much worse prognosis. In this study, we generated three new IgG1-kappa monoclonal antibodies (MoAbs), termed SN8, SN8a and SN8b, by use of an unconventional approach, ie, by using an isolated B PLL antigen preparation to immunize mice. These MoAbs, particularly SN8, showed a highly selective reactivity to B PLL and B non-Hodgkin's lymphoma (NHL) among various human leukemia-lymphoma specimens tested; eg, SN8 was capable of effectively distinguishing B PLL from B CLL as well as from hairy cell leukemia (HCL) cell specimens. The cell surface antigen defined by the three MoAbs was determined to be a covalently linked heterodimeric glycoprotein complex (gp49/40) consisting of a 49,000 dalton (alpha-chain) and a 40,000-dalton component (beta-chain). Epitope comparison showed that the epitope defined by SN8 (SN8 epitope) is in close proximity to SN8a epitope but in a distant position from SN8b epitope. Western blot analysis showed that both SN8 and SN8a epitopes are on the beta-chain, but SN8b epitope was not detected on either the alpha- or the beta-chain of the reduced antigen in the same analysis. Binding of either SN8 or SN8b to the cell surface gp49/40 did not cause significant downregulation of the antigen expression whereas binding of SN8a to the antigen caused small (approximately 20%) decrease in the antigen expression. Among the various normal peripheral blood cells, only a subpopulation (6.0% to 24.2% among different specimens derived from different donors) of B cells reacted with the SN8 series MoAbs; these MoAbs showed no significant reactivity against T cells, granulocytes, monocytes, erythrocytes, and platelets. Minimal or no significant reactivity (0 to 2.6% among different specimens) was detected against normal bone marrow cells. Ricin A-chain conjugates of the three MoAbs are all strongly effective for specific killing of SN8 antigen-expressing leukemia cells in the absence of any potentiators; furthermore, the addition of 10 mmol/L NH4Cl, a potentiator, enhanced strongly the cytotoxic activities of the SN8, SN8a, and SN8b conjugates. Thus, each of the three MoAbs was effectively internalized after binding to the cell surface antigen.


Characteristics, needs, and help seeking of partner violence victims mandated to community services by courts and child protective services.
The rapid growth of a subpopulation of women victimized by intimate partner violence (IPV) garnered the attention of 2 human service agencies in 1 Southeastern United States city. These agencies noted a shift in their clientele from female IPV victims who voluntarily sought agency services to victims who were mandated to agency services by child protective services (CPS), the court system, or both. Court-referred victims had been arrested for perpetrating IPV against their male partners. CPS-referred victims were experiencing concerning levels of IPV in their families, whether or not the victim had ever perpetrated IPV. Moreover, this subpopulation of women tended to be primary caregivers of children. In response to the growth of this subpopulation, the agencies collaborated to design and implement a program targeting female IPV victims who were primary caregivers for their children and who had been mandated to the agencies' services. The research team partnered with the agencies to conduct an investigation of this community-developed program and its participants. This article presents an exploratory, descriptive study that investigates (a) the characteristics of service-mandated, parenting IPV victims; (b) the needs of service-mandated, parenting IPV victims; and (c) the types of help-seeking behavior these women had engaged in before their service referral. Study findings indicate that, although the participants showed parenting strengths and active help-seeking efforts, this sample of women was characterized by severe IPV experiences and serious mental health needs.


First results of the ITER-relevant negative ion beam test facility ELISE (invited).
An important step in the European R&D roadmap towards the neutral beam heating systems of ITER is the new test facility ELISE (Extraction from a Large Ion Source Experiment) for large-scale extraction from a half-size ITER RF source. The test facility was constructed in the last years at Max-Planck-Institut für Plasmaphysik Garching and is now operational. ELISE is gaining early experience of the performance and operation of large RF-driven negative hydrogen ion sources with plasma illumination of a source area of 1 × 0.9 m(2) and an extraction area of 0.1 m(2) using 640 apertures. First results in volume operation, i.e., without caesium seeding, are presented.


Photodynamic Therapy of Cancers With Internal Light Sources: Chemiluminescence, Bioluminescence, and Cerenkov Radiation.
Photodynamic therapy (PDT) is a promising and minimally invasive modality for the treatment of cancers. The use of a self-illuminating system as a light source provides an intriguing solution to the light penetration issues of conventional PDT, which have gained considerable research interest in the past few years. This mini review aimed to present an overview of self-illuminating PDT systems by using internal light sources (chemiluminescence, bioluminescence, and Cerenkov radiation) and to give a brief discussion on the current challenges and future perspectives.


Right Heart Catheterization: Right From the Anatomical Snuffbox.
We present two cases where a right heart catheterization was performed from the anatomical snuffbox through the distal cephalic vein along with a left heart catheterization from the distal radial artery.


Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-gamma inhibition of TGF-beta1 action.
Interferon-gamma (IFN-gamma) is a multifunctional cytokine that elicits antifibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN-gamma in modulating the fibrogenic action of transforming growth factor (TGF)-beta(1) in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN-gamma inhibited TGF-beta(1)-mediated alpha-smooth muscle actin (alpha-SMA) expression. IFN-gamma also abolished TGF-beta(1)-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF-gamma inhibits TGF-beta(1) action, the signaling pathways that are critical for mediating the antifibrotic activity of IFN-gamma were studied. Stimulation of HKC cells with IFN-gamma triggered a sustained activation of Erk-1/2 and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with an Mek1 inhibitor abolished the inhibitory effect of IFN-gamma on alpha-SMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN-gamma and suppressed TGF-beta(1)-mediated alpha-SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN-gamma to attenuate TGF-beta(1)-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN-gamma is capable of antagonizing the fibrogenic actions of TGF-beta(1) in renal tubular epithelial cells. The antifibrotic action of IFN-gamma appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.


Use of the derivatizing agent 4-aminobenzoic acid 2-(diethylamino)ethyl ester for high-sensitivity detection of oligosaccharides by electrospray ionization mass spectrometry.
A method for the high-sensitivity detection of oligosaccharides by electrospray ionization mass spectrometry (ESI-MS) is reported. The method involves the chemical derivatization with 4-aminobenzoic acid 2-(diethylamino)-ethyl ester (ABDEAE). This derivative, which contains a 2-(diethylamino)ethyl group, having a high proton affinity, enhances the ionization efficiency of analytes in the positive ESI mode. Experiments using maltohexaose as a model oligosaccharide revealed that derivatization with ABDEAE gave a remarkably large increase in molecular ion abundance. Using a mixture of acetonitrile, 2-methoxyethanol, 2-propanol, and water (1:1:1:1 v/v/v/v) as solvent for ESI, ABDEAE-derivatized maltohexaose could be detected at a level of 10 fmol. This represents a 5000-fold improvement in sensitivity over underivatized maltohexaose. ESI tandem mass spectrometry of the ABDEAE-derivatized maltohexaose provides structural information at the low-picomole level. In this spectrum, 1,5X' and 0,2A" series of sequence ions, arising from ring cleavage, were observed as the predominant ions.


Program Quality and Developmental Outcomes Related to Youth Volleyball in Ethiopia: Assessing Relationships and Variations.
This study aims to assess program quality and developmental outcomes of a youth volleyball project in one of the regional states in Ethiopia, and further examine variations between groups across gender and project site zones. We applied a cross-sectional survey design, collecting quantitative data from youth volleyball players (n = 215) with a mean age of 16.18 years (SD = 0.69) through a self-reported questionnaire. The results indicated that young players' perceptions did not vary significantly across gender, except for the mean score of the perceived experience variable for girls (M = 2.68, SD = 0.318) was significantly higher than the mean score of boys (M = 2.58, SD = 0.258). One-way (project site zone) analyses of variance (ANOVAs) identified that youth volleyball projects in the central zone were consistently rated higher than those in the western zone, except for the current practice rating. Moreover, correlation analysis results indicated the presence of a significant relationship, both within and between program quality and developmental outcome variables. Furthermore, the results of regression analysis indicated that the program quality variables together predicted each of the developmental outcomes, accounting for 18.9% to 31.7% of the variances. It is concluded that the quality of the youth volleyball program in Ethiopia varies considerably across the project site zones and the program quality variables significantly relate to the developmental outcomes measured with differential effects. The data from this study reveals several practical applications for Ethiopia and beyond in terms of guiding youth volleyball projects. Moreover, the findings of the study showed that youth sport and the manner in which it is structured and delivered to youth players influences the attainment of positive developmental outcomes. These results suggest that contextual differences really do have an effect on the quality of youth sport program processes and developmental outcomes.


Tunable dual emission in doped semiconductor nanocrystals.
Colloidal manganese-doped semiconductor nanocrystals have been developed that show pronounced intrinsic high-temperature dual emission. Photoexcitation of these nanocrystals gives rise to strongly temperature dependent luminescence involving two distinct but interconnected emissive excited states of the same doped nanocrystals. The ratio of the two intensities is independent of nonradiative effects. The temperature window over which pronounced dual emission is observed can be tuned by changing the nanocrystal energy gap during growth. This unique combination of properties makes this new class of intrinsic dual emitters attractive for ratiometric optical thermometry applications.


A validation trial of subdermal injection compared with intraparenchymal injection for sentinel lymph node biopsy in breast cancer.
Sentinel lymph node (SLN) biopsy is increasingly being used as an accurate and less morbid surrogate for axillary dissection. However, a standardized technique in the biopsy of SLNs is not used. Some authors propose subdermal injection to be as accurate as peritumoral intraparenchymal injection (IPI). Our objective is to determine whether the SLNs identified by subdermal injection truly represent SLNs and match those found with IPI. Specific end points of the study were 1) successful localization of the SLN by the IPI of isosulfan blue or the radiocolloid intradermal injection, 2) successful uptake of radiocolloid and isosulfan blue on individual SLN, and 3) determination of the frequency with which the radiocolloid injection detected the "gold standard" blue SLN. SLNs were found in 71 of 73 cases (success rate = 97%). Blue SLNs were identified in 64 patients (88%). SLNs in 61 patients (84%) were radioactive. A total of 112 SLNs were identified in 71 patients (1.6 nodes/patient). Seventy-six of 87 SLNs found with IPI were also radioactive (concordance of 87%). All SLNs harboring metastatic cancer (16 patients) were found by both techniques, being both blue and radioactive. Our results support the concept of shared lymphatic pathways in the breast with a high degree of communication between the subdermal lymphatics and the intraparenchymal lymphatics. The success in identification of the SLN is made simpler and improved by the addition of subdermal radiocolloid injection.


[Inhibition of hepatitis B virus associated DNA polymerase by antiviral agents: in vitro studies with clinical implications (author's transl)].
The complete hepatitis B virus (Dane particle) contains a circular doublestranded DNA with single stranded regions and an endogenous DNA polymerase. The HBV associated DNA polymerase closes the single stranded regions of the HBV-DNA in the presence of triphosphatase and a detergent. The DNA polymerase reaction can be inhibition by antiviral substances that exhibit different mode of actions: intercalating agents, phosphonoformiate and the triphosphates of arabinofuranosyladenine and arabinofuranosylcytosine. The value of these in vitro test for the therapy of HBsAg positive chronic liver disease is limited by the fact that is remains so far unclear whether the HBV associated DNA polymerase is a virus- or a host-coded enzyme, and whether virus- or host-coded enzymes are involved in HBV-DNA synthesis in vivo.


Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a.
To assess the tolerance, toxicity, and antitumoral activity of the weekly combination of cisplatin (CDDP) and interferon alfa-2a (IFNalpha2a) in advanced diffuse malignant mesothelioma (DMM). Twenty-six patients with DMM (23 pleural and three peritoneal), previously untreated, were enrolled onto this study between August 1991 and December 1992. All patients had measurable disease defined by computed tomographic (CT) scan and diagnostic confirmation by histopathology review panel. IFNalpha2a (3 x 10(6) IU subcutaneously on days 1 to 4) and CDDP (60 mg/m2/wk on day 2) were given weekly. Initially planned as a 5-weeks-on/3-weeks-off treatment cycle, poor patient tolerance observed in the first 12 patients treated (group A) led to schedule adaptation with a shorter treatment sequence and prolongation of the rest period (4 weeks on/4 weeks off) in the following 14 patients (group B). At least two cycles were administered to each patient in the absence of tumor progression. Twenty-six patients were assessable for toxicity and 25 for efficacy (World Health Organization [WHO] criteria). Sixty-eight cycles of IFN/CDDP were given, with a median of three cycles per patient (range, one to five). Toxicity was mainly clinical, with progressive anorexia, asthenia, and prolonged nausea/emesis; these side effects have limited treatment acceptance in many patients. Thrombocytopenia and leukopenia were rarely noted as treatment-limiting toxicities. Objective responses (all partial) were obtained in 10 patients (95% confidence interval [CI], 20% to 60%). The median response duration was 11 months (range, 6 to 18). The median time to progression (TTP) for the whole cohort was 6 months and the median survival time was 12 months (range, 5 to 32). Objective responders had a significantly longer median TTP (21 months) and survival time (25 months) than nonresponders (3 and 8 months, respectively). The results of this pilot phase I-II study show encouraging antitumor activity in this traditionally resistant tumor, even if the specific contribution of IFN remains speculative and needs further clinical research. Our ongoing program is exploring the dose-intensity impact of IFN dose within the same combination.


Comparison between Slow Components of HR and V˙O2 Kinetics: Functional Significance.
Aerobic exercise prescription is often based on a linear relationship between pulmonary oxygen consumption (V˙O2) and heart rate (HR). The aim of the present study was to test the hypothesis that during constant work rate (CWR) exercises at different intensities, the slow component of HR kinetics occurs at lower work rate and is more pronounced that the slow component of V˙O2 kinetics. Seventeen male (age, 27 ± 4 yr) subjects performed on a cycle ergometer an incremental exercise to voluntary exhaustion and several CWR exercises: 1) moderate CWR exercises, below gas exchange threshold (GET); 2) heavy CWR exercise, at 45% of the difference between GET and V˙O2 peak (Δ); 3) severe CWR exercise, at 95% of Δ; 4) "HRCLAMPED" exercise in which work rate was continuously adjusted to maintain a constant HR, slightly higher than that determined at GET. Breath-by-breath V˙O2, HR, and other variables were determined. In moderate CWR exercises, no slow component of V˙O2 kinetics was observed, whereas a slow component with a relative amplitude (with respect to the total response) of 24.8 ± 11.0% was observed for HR kinetics. During heavy CWR exercise, the relative amplitude of the HR slow component was more pronounced than that for V˙O2 (31.6 ± 11.2% and 23.3 ± 9.0%, respectively). During HRCLAMPED, the decrease in work rate (~14%) needed to maintain a constant HR was associated with a decreased V˙O2 (~10%). The HR slow component occurred at a lower work rate and was more pronounced than the V˙O2 slow component. Exercise prescriptions at specific HR values, when carried out for periods longer than a few minutes, could lead to premature fatigue.


Achievement Goals and their Underlying Goal Motivation: Does it Matter Why Sport Participants Pursue their Goals?
This study examined whether the good or bad outcomes associated with mastery-approach (MAP) and performance-approach (PAP) goals depend on the extent to which they are motivated by autonomous or controlled motivation. A sample of 515 undergraduate students who participated in sport completed measures of achievement goals, motivation of achievement goals, perceived goal attainment, sport satisfaction, and both positive and negative affect. Results of moderated regression analyses revealed that the positive relations of both MAP and PAP goals with perceived goal attainment were stronger for athletes pursuing these goals with high level of autonomous goal motivation. Also, the positive relations between PAP goals and both sport satisfaction and positive affect were stronger at high levels of autonomous goal motivation and controlled goal motivation. The shape of all these significant interactions was consistent with tenets of Self-Determination Theory as controlled goal motivation was negatively associated with positive affect and sport satisfaction and positively associated with negative affect. Overall, these findings demonstrated the importance of considering goal motivation in order to better understand the conditions under which achievement goals are associated with better experiential and performance outcomes in the lives of sport participants.


Characterizing functional stem cell-cardiomyocyte interactions.
Despite the progress in traditional pharmacological and organ transplantation therapies, heart failure still afflicts 5.3 million Americans. Since June 2000, stem cell-based approaches for the prevention and treatment of heart failure have been pursued in clinics with great excitement; however, the exact mechanisms of how transplanted cells improve heart function remain elusive. One of the main difficulties in answering these questions is the limited ability to directly access and study interactions between implanted cells and host cardiomyocytes in situ. With the growing number of candidate cell types for potential clinical use, it is becoming increasingly more important to establish standardized, well-controlled in vitro and in situ assays to compare the efficacy and safety of different stem cells in cardiac repair. This article describes recent innovative methodologies to characterize direct functional interactions between stem cells and cardiomyocytes, aimed to facilitate the rational design of future cell-based therapies for heart disease.


Modulation of voltage-gated sodium channels hyperpolarizes the voltage threshold for activation in spinal motoneurones.
Previous work has shown that motoneurone excitability is enhanced by a hyperpolarization of the membrane potential at which an action potential is initiated (V(th)) at the onset, and throughout brainstem-evoked fictive locomotion in the adult decerebrate cat and neonatal rat. Modeling work has suggested the modulation of Na(+) conductance as a putative mechanism underlying this state-dependent change in excitability. This study sought to determine whether modulation of voltage-gated sodium channels could induce V(th) hyperpolarization. Whole-cell patch-clamp recordings were made from antidromically identified lumbar spinal motoneurones in an isolated neonatal rat spinal cord preparation. Recordings were made with and without the bath application of veratridine, a plant alkaloid neurotoxin that acts as a sodium channel modulator. As seen in HEK 293 cells expressing Nav1.2 channels, veratridine-modified channels demonstrated a hyperpolarizing shift in their voltage-dependence of activation and a slowing of inactivation that resulted in an enhanced inward current in response to voltage ramp stimulations. In the native rat motoneurones, veratridine-modified sodium channels induced a hyperpolarization of V(th) in all 29 neonatal rat motoneurones examined (mean hyperpolarization: -6.6 ± 4.3 mV). V(th) hyperpolarization was not due to the effects on Ca(2+) and/or K(+) channels as blockade of these currents did not alter V(th). Veratridine also significantly increased the amplitude of persistent inward currents (PICs; mean increase: 72.5 ± 98.5 pA) evoked in response to slow depolarizing current ramps. However, the enhancement of the PIC amplitude had a slower time course than the hyperpolarization of V(th), and the PIC onset voltage could be either depolarized or hyperpolarized, suggesting that PIC facilitation did not mediate the V(th) hyperpolarization. We therefore suggest that central neuronal circuitry in mammals could affect V(th) in a mechanism similar to that of veratridine, by inducing a negative shift in the activation voltage of sodium channels. Furthermore, this shift appears to be independent of the enhancement of PICs.


Diagnosis of animal allergy.
The aims of the diagnostic evaluation are to establish the presence and severity of disease and the importance of animal exposure as the etiology of the disease. The evaluation of the importance of animals may be part of a general allergy evaluation or specifically directed toward an animal in certain cases, such as occupational exposure. The diagnostic techniques are medical history, physical examination, allergy skin tests or in vitro tests for IgE antibody and correlation of improvement in symptoms with animal avoidance.


Safety and efficacy of vernakalant for acute cardioversion of atrial fibrillation: an update.
Intravenous vernakalant has recently been approved in Europe as an atrial-selective antiarrhythmic drug for the conversion of recent-onset atrial fibrillation (AF). It inhibits atrial-selective K(+) currents (I(K,ACh) and I(Kur)) and causes rate-dependent atrial-predominant Na(+) channel block, with only a small inhibitory effect on the rapid delayed rectifier K(+) current (I(Kr)) in the ventricle. Due to its atrial-selective properties, vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, being associated with a low proarrhythmic risk for torsades de pointes arrhythmias. Five pivotal clinical trials consistently demonstrated that vernakalant rapidly terminates AF with stable maintenance of sinus rhythm for up to 24 hours. A head-to-head comparative trial showed that the 90-minute conversion rate of vernakalant was substantially higher than that of amiodarone. Initially, a longer-acting oral formulation of vernakalant was shown to be effective and safe in preventing AF recurrence after cardioversion in a Phase IIb study. However, the clinical studies testing oral vernakalant for maintenance of sinus rhythm after AF cardioversion were prematurely halted for undisclosed reasons. This review article provides an update on the safety and efficacy of intravenous vernakalant for the rapid cardioversion of AF.


Imbalances between tumor necrosis factor-alpha and its soluble receptor forms, and interleukin-1beta and interleukin-1 receptor antagonist in BAL fluid of cavitary pulmonary tuberculosis.
We investigated the possibility that the large pulmonary cavity in tuberculosis (TB) lesions might result from imbalances between tumor necrosis factor-alpha (TNF-alpha) and soluble TNF-alpha receptor forms (sTNF-RI and sTNF-RII), and interleukin-beta (IL-1beta) and IL-1 receptor antagonist (IL-1RA) in sites of local inflammation. BAL was performed in 32 patients with active pulmonary TB, and the recovered BAL fluid (BALF) was examined for concentrations of TNF-alpha and its soluble receptor forms, IL-1beta, and IL-1RA. Patients were classified into two groups: group 1, patients with a large cavity (> or = 4 cm) on chest radiographs (n = 15); and group 2, patients with a small cavity (< 4 cm; n = 3) or no cavity (n = 14) on chest radiographs. The concentrations of TNF-alpha, IL-1beta, and IL-1RA in BALF were significantly higher in group 1 patients than in group 2 patients before standardization. The difference was also statistically significant for TNF-alpha and IL-1beta after standardization with urea. Furthermore, group 1 patients had significantly higher ratios of TNF-alpha to sTNF-RI and sTNF-RII and IL-1beta to IL-1RA compared with group 2 patients. These findings suggest that the relative abundance of TNF-alpha and IL-1beta associated with imbalances of secretion of soluble TNF-alpha receptor forms and IL-1RA may have caused tissue necrosis leading to cavity formation in patients with active pulmonary TB.


[Research progress on the effects of welding fumes exposure on lung].
Welding is an important industrial activity worldwide which involving millions of practitioners. Due to the influence of welding method, welding dust concentration, ventilation, weather and other factors, the exposure of the welder is different. And resulting in different respiratory symptoms, including decreased lung function, welder's pneumoconiosis and even lung cancer, which seriously affects the life quality of the worker. Through referring to literatures, the research status of welding dust and respiratory diseases was summarized to provide direction for future research.


Experiences of cervical cancer patients in rural Ghana: An exploratory study.
Even though cervical cancer is quite a prevalent disease in Ghana, there is hardly any study on this disease. This paper sought to explore the experiences of cervical cancer patients living with the disease with emphasis on their knowledge about the disease before and after the diagnosis. Qualitative data were collected through in-depth interviews with cervical cancer patients undergoing treatment in a specialised cancer treatment health facility in rural Ghana. Cervical cancer patients had inadequate knowledge about the disease, its symptoms, risk factors, treatment and prevention prior to being diagnosed of the disease. These patients were diagnosed late because they usually sought treatment elsewhere before reporting to health facilities. They experienced physical, psychological, economic and social disruptions in their daily lives, which affected their quality of life. It is evident that lack of knowledge about cervical cancer constitutes a threat to its prevention and treatment. Intensive health education through the mass media and community health promotion outreaches can be a sure way of creating adequate knowledge about cervical cancer in Ghana. Treatment and care for cervical cancer patients should incorporate counselling sessions, which should take into consideration the different levels of disruption the women experience and the implications for their wellbeing and management of the condition.


Effect of Impeller Geometry on Lift-Off Characteristics and Rotational Attitude in a Monopivot Centrifugal Blood Pump.
The effect of the flow path geometry of the impeller on the lift-off and tilt of the rotational axis of the impeller against the hydrodynamic force was investigated in a centrifugal blood pump with an impeller supported by a single-contact pivot bearing. Four types of impeller were compared: the FR model with the flow path having both front and rear cutouts on the tip, the F model with the flow path having only a front cutout, the R model with only a rear cutout, and the N model with a straight flow path. First, the axial thrust and the movement about the pivot point, which was loaded on the surface of the impeller, were calculated using computational fluid dynamics (CFD) analysis. Next, the lift-off point and the tilt of the rotational axis of the impeller were measured experimentally. The CFD analysis showed that the axial thrust increased gently in the FR and R models as the flow rate increased, whereas it increased drastically in the F and N models. This difference in axial thrust was likely from the higher pressure caused by the smaller circumferential velocity in the gap between the top surface of the impeller and the casing in the FR and R models than in the F and N models, which was caused by the rear cutout. These results corresponded with the experimental results showing that the impellers lifted off in the F and N models as the flow rate increased, whereas it did not in the FR and R models. Conversely, the movement about the pivot point increased in the direction opposite the side with the pump outlet as the flow rate increased. However, the tilt of the rotational axis of the impeller, which oriented away from the pump outlet, was less than 0.8° in any model under any conditions, and was considered to negligibly affect the rotational attitude of the impeller. These results confirm that a rear cutout prevents lift-off of the impeller caused by a decrease in the axial thrust.


On the mechanics of the knee during the stance phase of the gait.
In this paper, we explore the mechanical behavior of the knee during the weight acceptance stage of stance during normal walking. We show that the torque/angle behavior of the knee during this stage can be approximated by a linear torsional spring. The mechanical parameters completely specifying this spring are identified, including stiffness, amount of rotation, and angle of engagement, and the effect of gait speed and body/load mass on those parameters are discussed. We discuss how the findings of this paper can be applied to the design of leg orthoses, prostheses and exoskeletons, and bipedal robots in general, allowing the implementation of human-like leg compliance during stance with a relatively simple latched-spring mechanism.


Renal function after short-term ibuprofen use in infants and children.
To test the hypothesis that short-term use of ibuprofen increases the risk of impaired renal function in children. Randomized, double-blind acetaminophen-controlled clinical trial. Children with a febrile illness were enrolled from outpatient pediatric and family medicine practices and randomly assigned to receive either acetaminophen suspension or one of two dosages of ibuprofen suspension (5 mg/kg or 10 mg/kg) for fever control. Mean blood urea nitrogen levels on admission among children admitted to hospital and assigned ibuprofen 5 mg/kg (n = 96), ibuprofen 10 mg/kg (n = 102), and acetaminophen 12 mg/kg (n = 87) were 4.1, 3.8, and 3.9 mmol/L, respectively. The corresponding creatinine levels were 43, 41, and 43 micromol/L, respectively. The prevalence of a creatinine level >62 micromol/L was 9.5% overall and did not vary by antipyretic assignment. Among 83 children hospitalized with dehydration, the mean creatinine level was 44 micromol/L, and the prevalence of an elevated creatinine was 14%; neither measure varied by antipyretic assignment. Although renal failure in children has been reported after ibuprofen use, these data suggest that for short-term use the risk of less severe renal impairment, as reflected by blood urea nitrogen and creatinine levels, is small and not significantly greater than that after acetaminophen use.


Coupling Analysis on Microstructure and Residual Stress in Selective Laser Melting (SLM) with Varying Key Process Parameters.
With the application of Selective Laser Melting (SLM) technology becoming more and more widespread, it is important to note the process parameters that have a very important effect on the forming quality. Key process parameters such as laser power (P), scan speed (s), and scanning strategy (μ) were investigated by determining the correlation between the microstructure and residual stress in this paper. A total of 10 group 316L specimens were fabricated using SLM for comprehensive analysis. The results show that the key process parameters directly affect the morphology and size of the molten pool in the SLM deposition, and the big molten pool width has a direct effect on the larger grain size and crystal orientation distribution. In addition, the larger grain size and misorientation angle also affect the size of the residual stress. Therefore, better additive manufacturing grain crystallization can be obtained by reasonably adjusting the process parameter combinations. The transfer energy density can synthesize the influence of four key process parameters (P, v, the hatching distance (δ), and the layer thickness (h)). In this study, it is proposed that the accepted energy density will reflect the influence of five key process parameters, including the scanning trajectory (μ), which can reflect the comprehensive effect of process parameters more accurately.


Comparative effects of three class I antiarrhythmic drugs on plateau and pacemaker currents of sheep cardiac Purkinje fibres.
The electrophysiological effects of three class I antiarrhythmic drugs, lignocaine, disopyramide, and penticainide, were compared in sheep cardiac Purkinje fibres. Action potential duration was shortened with all three drugs, the effect being small with disopyramide, moderate with penticainide, and greatest with lignocaine. Slowing down of the early phase of repolarisation was greatest with disopyramide, smaller with penticainide, and did not occur with lignocaine. Automaticity recorded in low potassium media was unaltered (disopyramide), depressed (penticainide), or stopped (lignocaine). Ionic currents were recorded in short fibres using the two microelectrode voltage clamp technique. The tetrodotoxin sensitive slow component of the sodium current was suppressed (lignocaine) or reduced (penticainide and disopyramide) and the instantaneous background potassium current slightly reduced (disopyramide more than penticainide), unaffected, or slightly increased (lignocaine). The three drugs depressed moderately and similarly the slow inward calcium current. The amplitude of the 4-aminopyridine sensitive transient outward potassium current was almost unaffected (lignocaine) or appreciably depressed (disopyramide more than penticainide). The pacemaker current was reduced greatly by lignocaine, moderately by penticainide, and slightly by disopyramide. Changes in ionic currents may explain the effects of the three drugs on action potential plateau and automaticity of sheep Purkinje fibres. It is concluded that the pronounced differences observed in the effects of these three class I antiarrhythmic drugs on pacemaker depolarisation and on initial repolarisation may justify a more discriminative subdivision of class I antiarrhythmic drugs.


Approaches to the prediction of language abilities in a sample of children who have developmental delays.
Prediction of the quality of language was explored using planned comparisons of three approaches, one cognitive, one neurodevelopmental, and one a combination of the two. Subjects were 37 children, ages 5-9 years, whose significant developmental delays included language and speech skills. The cognitive predictors were mental age (MA) and IQ from the Stanford-Binet Intelligence Scale. Neurodevelopmental predictors consisted of fine motor skill quotients (MQs) and dichotic speech processing scores. Chronological age (CA) was also evaluated as a predictor. A composite language ability score constituted the dependent variable. Results of regression analyses showed that CA and MQ, and MA and MQ, were nearly equal in their predictive strengths and were substantial predictors of composite language scores. Larger multiple correlations (low .8 range) were found when combinations of MA, IQ, and MQ or CA, IQ, and MQ were used as predictors. Statistical control over the 4-year age range revealed that approximately equal amounts of prediction of language scores were attributable to CA and a combination of MA, IQ, and MQ. Each of the latter variables contributed important amounts of unique variance to the language score prediction. Dichotic ear scores did not relate to cognitive or language scores and were ineffectual as predictors in regression analysis. Results indicated that children of the type studied have language and speech delays that show substantial relationships to their verbal cognitive abilities and MQs, in addition to their CAs.


Cannabis abuse and serious suicide attempts.
To compare the relationship between cannabis abuse/dependence and risk of medically serious suicide attempts in individuals making serious suicide attempts and randomly selected comparison subjects. Case-control comparison. Cases, a general hospital; controls, the local community. Cases were 302 consecutive individuals making medically serious suicide attempts; 1028 randomly selected control subjects. DSM-III-R mental disorder diagnoses; measures of socio-demographic characteristics and childhood and family experiences. Of those making serious suicide attempts, 16.2% met DSM-III-R criteria for cannabis abuse/dependence at the time of the attempt, compared with 1.9% of comparison subjects (OR = 10.3; 95%CI, 5.95-17.8, p < 0.0001). Risks of serious suicide attempt were significantly related to a series of socio-demographic and childhood characteristics, and to mental disorders that were co-morbid with cannabis abuse/dependence. When the association between cannabis abuse/dependence and suicide attempt risk was controlled for socio-demographic factors, childhood factors and concurrent psychiatric morbidity, there was a marginally significant association (OR = 2.0; 95%CI, 0.97-5.3, p < 0.06) between cannabis abuse/dependence and serious suicide attempt risk. These results suggested that much of the association between cannabis abuse/dependence and suicide attempt risk arose because: (a) individuals who develop cannabis abuse/dependency tend to come from disadvantaged socio-demographic and childhood backgrounds which, independently of cannabis abuse, are associated with higher risk of suicide attempt, or (b) because cannabis abuse/dependence is co-morbid with other mental disorders which are independently associated with suicidal behaviour. Nevertheless, the possibility remains that cannabis abuse/dependence may make an independent contribution to risk of serious suicide attempt, both directly and through the possible effects of cannabis abuse on risk of other mental disorders.