Activation of NK cell cytotoxicity

Natural killer (NK) cells are innate effector lymphocytes necessary for defence against stressed, microbe-infected, or malignant cells. NK cells kill target cells by either of two major mechanisms that require direct contact between NK cells and target cells. In the first pathway, cytoplasmic granule toxins, predominantly a membrane-disrupting protein known as perforin, and a family of structurally related serine C, proteases (granzymes) with various substrate specificities, are secreted by exocytosis and together induce apoptosis of the target cell. The granule-exocytosis pathway potently activates cell-death mechanisms that operate through the activation of apoptotic cysteine proteases (caspases), but can also cause cell death in the absence of activated caspases. The second pathway involves the engagement of death receptors (e.g. Fas/CD95) on target cells by their cognate ligands (e.g. FasL on NK cells, resulting in classical caspase-dependent apoptosis. The comparative role of these pathways in the pathophysiology of many diseases is being dissected by analyses of gene-targeted mice that lack these molecules, and humans who have genetic mutations affecting these pathways. We are also now learning that the effector function of NK cells is controlled by interactions involving specific NK cell receptors and their cognate ligands, either on target cells, or other cells of the immune system. This review will discuss the functional importance of NK cell cytotoxicity and the receptor/ligand interactions that control these processes. (C) 2004 Elsevier Ltd. All rights reserved.

Improved VDC casting of aluminium alloys through an understanding of the surface properties of the molten metal

Vertical direct chill (VDC) casting of aluminium alloys is a mature process that has evolved over many decades through gradual change to both equipment design and casting practice. Today, air-pressurised, continuous lubrication, hot top mould systems with advanced station automation are selected as the process of choice for producing extrusion billet. Specific sets of operating parameters are employed on these stations for each alloy and size combination to produce optimal billet quality. The designs and parameters are largely derived from past experience and accumulated know-how. Recent experimental work at the University of Queensland has concentrated on understanding the way in which the surface properties of liquid aluminium alloys, e.g., surface tension, wetting angle and oxide skin strength, influence the size and shape of the naturally-stab le meniscus for a given alloy, temperature and atmosphere. The wide range of alloy-and condition-dependent values measured has led to the consideration of how these properties impact the stability of the enforced molten metal meniscus within the hot top mould cavity. The actual shape and position of the enforced meniscus is controlled by parameters such as the upstream conduction distance (UCD) from sub-mould cooling and the molten metal head. The degree of deviation of this actual meniscus from the predicted stable meniscus is considered to be a key driver in surface defect formation. This paper reports on liquid alloy property results and proposes how this knowledge might be used to better design VDC mould systems and casting practices.

Synthesis of alpha-aspartyl-containing cyclic peptides

alpha-Aspartyl-containing cyclic pentapeptides were synthesised in high yields using a strategy that maintained fluorenylmethyl protection on the aspartic acid side chain during chain assembly, resin cleavage and cyclisation of the linear precursors. Tetra-n-butylammonium fluoride treatment of the fluorenylmethyl-protected cyclic peptides catalysed imide formation, whereas piperidine-induced deprotection resulted in good yields of the target cyclic peptides.

The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

Background The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA.CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. Trial design TRA.CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least I year. The TRA.CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. Conclusion TRA.CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies. (Am Heart J 2009; 158:327-34.)

PCR-mediated detection of acidophilic, bioleaching-associated bacteria

The detection of acidophilic microorganisms from mining environments by culture methods is time consuming and unreliable. Several PCR approaches were developed to amplify small-subunit rRNA sequences from the DNA of six bacterial phylotypes associated with acidic mining environments, permitting the detection of the target DNA at concentrations as low as 10 fg.

INTENSITY-MODULATED AND 3D-CONFORMAL RADIOTHERAPY FOR WHOLE-VENTRICULAR IRRADIATION AS COMPARED WITH CONVENTIONAL WHOLE-BRAIN IRRADIATION IN THE MANAGEMENT OF LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS

Purpose: To compare the sparing potential of cerebral hemispheres with intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for whole-ventricular irradiation (WVI) and conventional whole-brain irradiation (WBI) in the management of localized central nervous system germ cell tumors (CNSGCTs). Methods and Materials: Ten cases of patients with localized CNSGCTs and submitted to WVI by use of IMRT with or without a ""boost"" to the primary lesion were selected. For comparison purposes, similar treatment plans were produced by use of 3D-CRT (WVI with or without boost) and WBI (opposed lateral fields with or without boost), and cerebral hemisphere sparing was evaluated at dose levels ranging from 2 Gy to 40 Gy. Results: The median prescription dose for WVI was 30.6 Gy (range, 25.2-37.5 Gy), and that for the boost was 16.5 Gy (range, 0-23.4 Gy). Mean irradiated cerebral hemisphere volumes were lower for WVI with IMRT than for 3D-CRT and were lower for WVI with 3D-CRT than for WBI. Intensity-modulated radiotherapy was associated with the lowest irradiated volumes, with reductions of 7.5%, 12.2%, and 9.0% at dose levels., compared with 3D-CRT. Intensity-modulated radiotherapy provided of 20, 30, and 40 Gy, respectively statistically significant reductions of median irradiated volumes at all dose levels (p = 0.002 or less). However, estimated radiation doses to peripheral areas of the body were 1.9 times higher with IMRT than with 3D-CRT. Conclusions: Although IMRT is associated with increased radiation doses to peripheral areas of the body, its use can spare a significant amount of normal central nervous system tissue compared with 3D-CRT or WBI in the setting of CNSGCT treatment. (C) 2010 Elsevier Inc.

Hodgkin`s Lymphoma Presenting as Dominant Gastric Lesion in Immunocompetent Patients: Report of 5 Cases With EBV Analysis

Primary Hodgkin`s lymphoma (HL) of the stomach is an extremely rare entity. Most cases of gastric involvement by HL are observed in the setting of disseminated disease. The nonspecific nature of the symptoms and endoscopic findings, which include a large malignant-looking ulcer and mass or wall thickening, together with the considerable histological overlap between HLs and some non-HLs or undifferentiated carcinoma, make the surgical resection diagnosis extremely difficult. An accurate diagnosis is important as treatment and outcome differ significantly for these neoplasms. In small endoscopic gastric biopsies and even in postoperative specimens, the precise histological diagnosis of HL is particularly challenging. Here, the authors report 5 cases of 2 women and 3 men aged 22 to 68, with gastric involvement by classic HLs-3 primary gastric HLs and 2 as part of widespread disease. All 5 patients presented with digestive symptoms. At endoscopy, the lesions presented as ulcerated and elevated lesions, with or without mucosal thickening. Four patients were misdiagnosed in the preoperative biopsy or in the gastrectomy specimen. Association with Epstein-Barr virus (EBV) was detected in 4 cases, with a predominance of subtype A EBV. These cases illustrate the significant difficulties, both clinical and pathological, in achieving the diagnosis of HL involving the stomach in immunocompetent patients.

Diabetes, hyperglycemia and the management of cerebrovascular disease

Purpose of review Hyperglycemia is frequent in patients with cerebrovascular disease. This review article aims to summarize the recent evidence from observational studies that examined the adverse cerebrovascular effects of dysglycemic states as well as interventional studies assessing intensive management strategies for hyperglycemia. Recent findings In recent years, diabetes, prediabetic states and insulin resistance and their association with cerebrovascular disease were an important focus of research. The cerebrovascular consequences of these metabolic abnormalities were found to extend beyond ischemic stroke to covert brain infarcts, other structural brain changes and to cognitive impairment with and without dementia. Interventional studies did not reveal that more intensive management of chronic hyperglycemia and of hyperglycemia in the setting of acute stroke improves outcome. There is clear evidence, however, that the overall management of multiple risk factors and behavior modification in patients with dysglycemia may reduce the burden of cerebrovascular disease. Summary Observational studies reveal the growing burden and adverse cerebrovascular effects of dysglycemic states. Currently available interventional studies assessing more intensive strategies for the management of hyperglycemia did not prove, however, to be effective. We discuss the current evidence, pathophysiological considerations and management implications.

Final height of adults with childhood-onset steroid-responsive idiopathic nephrotic syndrome

The aim of this study was to evaluate the final stature of adults with childhood-onset steroid-responsive idiopathic nephrotic syndrome (INS) and the influence of disease-related issues on the achievement of their target heights. We analyzed 60 (41 male) patients and/or their records, with a minimum age of 19 years or at a Tanner`s pubertal stage 4 for boys or status postmenarche for girls, and normal glomerular filtration rate. Mean age at first and last consultation was 5.3 +/- 2.4 years and 20.5 +/- 3.1 years, respectively. Mean follow-up period was 15.10 years. Mean cumulative dose of prednisone was 1254 +/- 831.40 mg/kg. Mean initial and final height Z scores (HtZ) were, respectively, -0.60 +/- 1.0 and -0.64 +/- 0.92 (p = 0.72). The final HtZ showed a significant correlation only with the initial HtZ and the target HtZ (THZ). Six patients achieved a final HtZ below -2, which in male patients correlated strongly to the initial HtZ and THZ. A strong correlation was demonstrated between final HtZ, initial HtZ, and THZ. INS-related issues did not prevent the final stature to reach the predicted target height.

Failure of Imiquimod 5% Cream to Prevent Recurrence of Surgically Excised Trunk Keloids

Keloids are characterized by benign proliferation of fibroblasts in the setting of an altered cytokine profile, with a high recurrence rate after surgical treatment. Imiquimod is a topically applied immune-response modifier. Recently, auxiliary therapy using imiquimod 5% cream to prevent keloid recurrence after excisional surgery was reported to have had good results. To evaluate the efficacy of topical imiquimod 5% cream applied after surgical excision and primary closure of trunk keloids in the prevention of recurrence. Nine patients with a keloid lesion on the trunk were treated with surgical excision and primary closure. Daily application of imiquimod 5% cream for 8 weeks was initiated the night of surgery. The patients were evaluated 2, 4, 8, 12, and 20 weeks after. Keloid recurrence occurred in eight patients, seven of them 12 weeks after surgery. We lost track of one patient. The results of this study suggest that imiquimod 5% cream is not effective in preventing recurrence of trunk keloids after surgical excision. Although this is a small case series, results strongly discourage other studies using imiquimod 5% cream in the prevention of surgically excised trunk keloids. The authors have indicated no significant interest with commercial supporters.

3.0-T MRI evaluation of patients with chronic liver diseases: initial observations

Purpose: To describe the use of 3.0-T magnetic resonance imaging (MRI) for the evaluation of chronic liver diseases. Materials and Methods: Two groups of patients who had chronic liver diseases and underwent 3.0-T MRI for evaluation of the liver were included in the study. The first group of patients included 66 consecutive patients (33 male, 33 female; mean age +/- standard deviation, 56 +/- 11). The second group of patients included 30 consecutive patients (18 males, 12 females; mean age +/- standard deviation, 53 +/- 10) in whom Variable-Rate Selective Excitation (VERSE) pulses and improved adjustments procedure were used during the acquisitions. Imaging findings of chronic liver diseases, predetermined artifacts and image quality of all individual sequences in the first group and predetermined artifacts and image quality of T2-weighted sequences in the second group were reviewed retrospectively and independently by two reviewers. chi-Square tests were used to compare the findings between two groups of patients and individual sequences. Kappa statistics were used to determine the extent of agreement between the reviewers. Results: Fifteen dysplastic nodules in 6 of 66 (9%) patients and 12 hepatocellular carcinomas in 11 of 66 (17%) patients were detected. Excluding motion artifacts, three-dimensional (313) T1-weighted gradient-echo (GE) sequence was the least affected sequence by the artifacts. Image quality of T1-weighted 3D-GE sequences was excellent in 43 of 66 (65%) patients. In-phase and out-of-phase T1-weighted spoiled GE (SGE) images were fair in 62 of 66 (94%) and 61 of 66 (92%) patients, respectively. The image quality of short tau inversion recovery (STIR) and half-Fourier rapid acquisition with relaxation enhancement (RARE) sequences were fair in 31 of 66 (47%) and 53 of 66 (80%) patients. STIR and half-Fourier RARE sequences in the second group demonstrated significantly better image quality (P=.03 and P<.0001). Conclusion: 3.0-T MRI allows the acquisition of very high quality postgadolinium 3D-GE sequence, which permitted the detection and characterization of lesions in the setting of chronic liver diseases. The use of VERSE pulses and improved adjustments procedure improved the image quality of T2-weighted sequences. In-phase/out-of-phase SGE sequences are at present of fair quality. (C) 2008 Elsevier Inc. All rights reserved.

Insights on calcium-independent phospholipid membrane damage by Lys49-PLA(2) using tryptophan scanning mutagenesis of bothropstoxin-I from Bothrops jararacussu

Bothropstoxin-I (BthTx-I) is a homodimerie Lys49-PLA(2) from the venom of the snake Bothrops jararacussu, which lacks hydrolytic activity against phospholipid substrates, yet permeabilizes membranes by a Ca2+- independent mechanism. The interaction of the BthTx-I with model membranes has been studied by intrinsic tryptophan fluorescence emission (ITFE) spectroscopy. Nine separate mutants have been created each with a unique tryptophan residue located at a different position in the interfacial recognition site (IRS) of the protein. The rapid and efficient Ca2+-independent membrane damage against unilamellar liposomes composed of DPPC/DMPA in a 9:1 molar ratio was unaffected by these substitutions. Binding studies revealed low protein affinity for these liposomes and no changes were observed in the ITFE properties. In contrast, the binding of all mutants to DPPC/DMPA liposomes in a 1:1 molar ratio was stronger, and was correlated with altered ITFE properties. The blue-shifted emission spectra and increased emission intensity of mutants at positions 31, 67 and 115-117 in the interface recognition surface of the protein suggest these regions are partially inserted into the membrane. These results are consistent with a model for the Ca2+-independent membrane damaging mechanism that involves a transient interaction of the protein with the outer phospholipid leaflet of the target membrane. (C) 2007 Elsevier Masson SAS. All rights reserved.

The preparation of reach to grasp movements in adults with Down syndrome

The aim of this study was to determine the extent to which adults with Down syndrome (DS) are able to utilise advance information to prepare reach to grasp movements. The study comprised ten adults with DS; ten children matched to an individual in the group with DS on the basis of their intellectual ability, and twelve adult controls. The participants used their right hand to reach out and grasp illuminated perspex blocks. Four target blocks were positioned on a table surface, two to each side of the midsagittal plane. In the complete precue condition, participants were provided with information specifying the location of the target. In the partial precue condition, participants were given advance information indicating the location of the object relative to the midsagittal plane (left or right). In the null condition, advance information concerning the position of the target object was entirely ambiguous. It was found that both reaction times and movement times were greater for the participants with DS than for the adults without DS. The reaction times exhibited by individuals with DS in the complete precue condition were lower than those observed in the null condition, indicating that they had utilised advance information to prepare their movements. In the group with DS, when advance information specified only the location of the target object relative to the midline, reaction times were equivalent to those obtained when ambiguous information was given. In contrast, the adults without DS exhibited reaction times that were lower in both the complete and partial precue conditions when compared to the null condition. The pattern of results exhibited by the children was similar to that of the adults without DS. The movement times exhibited by all groups were not influenced by the precue condition. In summary, our findings indicate that individuals with DS are able to use advance information if it specifies precisely the location of the target object in order to prepare a reach to grasp movement. The group with DS were unable, however, to obtain the normal advantage of advance information specifying only one dimension of the movement goal (i.e., the position of an object relative to the body midline). (C) 2001 Elsevier Science B.V. All rights reserved.

The effect of obstacle position on reach-to-grasp movements

Numerous everyday tasks require the nervous system to program a prehensile movement towards a target object positioned in a cluttered environment. Adult humans are extremely proficient in avoiding contact with any non-target objects (obstacles) whilst carrying out such movements. A number of recent studies have highlighted the importance of considering the control of reach-to-grasp (prehension) movements in the presence of such obstacles. The current study was constructed with the aim of beginning the task of studying the relative impact on prehension as the position of obstacles is varied within the workspace. The experimental design ensured that the obstacles were positioned within the workspace in locations where they did not interfere physically with the path taken by the hand when no obstacle was present. In all positions, the presence of an obstacle caused the hand to slow down and the maximum grip aperture to decrease. Nonetheless, the effect of the obstacle varied according to its position within the workspace. In the situation where an obstacle was located a small distance to the right of a target object, the obstacle showed a large effect on maximum grip aperture but a relatively small effect on movement time. In contrast, an object positioned in front and to the right of a target object had a large effect on movement speed but a relatively small effect on maximum grip aperture. It was found that the presence of two obstacles caused the system to decrease further the movement speed and maximum grip aperture. The position of the two obstacles dictated the extent to which their presence affected the movement parameters. These results show that the antic ipated likelihood of a collision with potential obstacles affects the planning of movement duration and maximum grip aperture in prehension.

Tracks of Change - the changing value commitments of non-profit organisations

If nonprofit organisations are moving towards more market oriented ways of operating, is this changing the traditional meanings and value of commitments associated with their activities? This article discusses the findings of a research project conducted by the University of Queensland into the impact that changes in government policies are having on the community services sector, in particular disability services. The values and belief systems traditionally associated with the sector were found to be fundamentally unaltered.