Myocardial perfusion and function in dogs with moderate coronary stenosis

MRI studies of first-pass contrast enhancement with polylysine-Gd-DTPA and myocardial tagging using spatial modulation of magnetization (SPAMM) were performed to assess the feasibility of a combined regional myocardial blood flow and 2D deformation exam. Instrumented closed-chest dogs were imaged at a baseline control state (Cntl) followed by two interventions: moderate coronary stenosis (St) achieved by partial occlusion of the left anterior descending (LAD) and moderate coronary stenosis with dobutamine loading (StD). Hypoperfusion of the anterior region (ANT) of the myocardium (LAD distribution) relative to the posterior wall (POS) based on the upslope of the signal intensity time curve from the contrast-enhanced MR images was demonstrated only with dobutamine loading (ANT:POS Cntl=1.077 ± 0.15 versus ANT:POS StD=0.477 ± 0.11, P<0.03) and was confirmed with radio-labeled microspheres measurements (ANT:POS Cntl=1.18 ± 0.2 ml/min/g versus ANT:POS StD=0.44 ± 0.1 ml/min/g; P<0.002). Significant changes in regional myocardial shortening were only seen in the StD state (P<0.02); the anterior region showed impaired myocardial shortening with dobutamine loading (P=NS), whereas the nonaffected POS region showed a marked increase in shortening when compared with Cntl (Cntl=0.964 ± 0.02 versus StD=0.884 ± 0.03; P<0.001). These results demonstrate that an integrated quantitative assessment of regional myocardial function and semiquantitative assessment of myocardial blood flow can be performed noninvasively with ultrafast MRI.     

Current concepts in the treatment of disorders of micturition

Disorders of micturition may be divided into disturbances of the storage function of the bladder, and disturbances of the emptying function. The main symptoms of disturbances of storage function are frequency, urgency and incontinence. Hyperactivity of the bladder may lead to urge incontinence, and incompetence of the urethral closure mechanism to stress incontinence. There are many drugs available for treating bladder hyperactivity, but their efficacy as judged from controlled clinical trials (when available) is often limited. Bladder contraction in man is mediated by stimulation of muscarinic receptors, and when given parenterally anticholinergic drugs have been shown to depress bladder hyperactivity irrespective of the underlying cause. Clinically, however, treatment of urge incontinence with anticholinergic drugs is often unsatisfactory. Lack of effect of oral treatment and systemic side effects limit the use of available agents. Drugs with "mixed" actions (anticholinergic and 'direct' muscle effects), for example oxybutynin and terodiline, have well-documented efficacy in bladder hyperactivity. Side effects are common with oxybutynin; terodiline seems to be well tolerated. The aim of drug treatment of stress incontinence is to increase outflow resistance. Although there is only limited possibility of improving the condition with drugs, beneficial effects can be obtained in some patients by use of orally active alpha-adrenoceptor agonists (e.g. phenylpropanolamine) and/or oestrogens. The main symptom of disturbed bladder emptying is urinary retention. Drug therapy is aimed at improving the contractile activity of the detrusor or reducing urethral outflow resistance. Drugs used for improving bladder contractility include parasympathomimetic agents, e.g. bethanechol or carbachol, and intravesical instillation of prostaglandins. Although the efficacy of both types of treatment is open to question, bethanechol seems to be widely used. Increased outflow resistance may be seen in patients with parasympathetic decentralization of the lower urinary tract or in patients with benign prostatic hypertrophy. These patients may respond favourably to alpha-adrenoceptor blockers such as phenoxybenzamine or prazosin.     

Factors influencing the likelihood of successful decisions to treat dentin caries from bitewing radiographs

The purpose of this study was to describe the role played by the ability to estimate caries depth in successfully deciding to treat dentin caries when making use of bitewing radiographs as a diagnostic test. A 10% random sample (n = 444) of Dutch dental practitioners was sent a two-wave questionnaire concerning radiographic caries diagnosis and restorative treatment decision making. The second wave consisted of simulated bitewing radiographs of 105 tooth surfaces with and without dentin caries according to two measuring standards: (a) a micro-radiographic "gold" standard and (b) a norm of expert observers. The dentists were asked to diagnose caries at 4 depths of penetration using a 5-point certainty scoring system to measure diagnostic ability; and to make a treatment decision for each surface. The overall response was 61% (273). A regression analysis was carried out using the chance per dentist of correctly deciding to treat dentin caries as the dependent variable. The degree of agreement with the experts' diagnosis of radiographic caries depth was used to create variables measuring diagnostic ability. Five significant (P less than 0.05) variables explained 60% (R2 = 0.60) of the variation in decision making. The best diagnostic ability variable explained 47% of the variation while the treatment criterion reportedly used explained 3%. We conclude that the ability of practitioners to interpret radiographs plays a major role in treatment decision making and that their reported treatment decision making criteria should not be taken at face value.     

Fifty years of research onN-acetyl-2-aminofluorene,one of the most versatile compounds in experimental cancer research

Summary It is just about 50 years since the publication of the report on the toxicity and carcinogenicity of the potent carcinogenN-acetyl-2-aminofluorene (AAF). In 1940 very few reports on the carcinogenic activity of chemical compounds in experimental animals were available. The discovery of pure chemicals as carcinogens, such as AAF, azo dyes and benzo[a]pyrene, provided cancer researchers with a number of tools whereby the progressive changes involved in the induction of cancer could be studied in experimental systems. Contrary to the results with other carcinogens then known, AAF induced numerous types of tumors, but not at the site of application. This finding stimulated a great deal of interest in its use as an experimental carcinogen to study its metabolic fate and mechanism of action. During the following years an ever increasing number of reports appeared on the carcinogenicity of AAF in various species, on its metabolic fate, on the interaction of reactive metabolites with nucleic acids and proteins, and on its mutagenic activity. Particularly studies on the metabolism of AAF and the interaction with nucleic acids have contributed appreciably to our understanding of the mechanism of action of aromatic amines and also of other chemical carcinogens. It can be expected that AAF and its derivatives will continue to be used for specific applications in experimental cancer research. One of the most recent achievements is the preparation of site-specific AAF- and aminofluorene-modified DNA sequences for mutagenesis studies.Abbreviation AAF N-acetyl-2-aminofluorenem The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author The Editors     

Visual half-field tests of lateralized letter presentations: differences between preliterate and literate children

In the present study, hemispheric differences in global and analytic processing were investigated in preliterate and literate children, using the "dual-letter" matching task paradigm (Navon, 1977). The stimuli consisted of lateralized visual presentations of large uppercase letters made up of small uppercase letters. The task of the subject was to decide on each trial if the large or small letters were the same or not. Vocal reaction time (VRT) and error-frequency were used as dependent measures. In Experiment 1, 28 right-handed 8-years old children participated. The children were split into a preliterate and a literate group depending on teachers evaluations, and on scores on a reading test. The results showed longer VRTs for the preliterate children when the stimuli were initially presented to the right hemisphere and especially when the subjects were required to match the small letters. These results were followed up in Experiment 2, where the preliterate subjects were split into "fast" and "slow" readers. The results showed that the "slow" readers were more impaired in processing the letter stimuli when the stimuli were initially presented to the right hemisphere. It is concluded that hemispheric asymmetry for letter processing interacts with the development of normal reading ability in children.     

Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer

Human papilloma virus (HPV) type 16 infections of the genital tract are associated with the development of cervical cancer (CxCa) in women. HPV16-derived oncoproteins E6 and E7 are expressed constitutively in these lesions and might therefore be attractive candidates for T-cell-mediated adoptive immunotherapy. However, the low precursor frequency of HPV16E7-specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer. To overcome this problem, we have isolated T cell receptor (TCR) genes from four different HPV16E7-specific healthy donor and patient-derived human cytotoxic T lymphocyte (CTL) clones. We examined whether genetic engineering of peripheral blood-derived CD8+ T cells in order to express HPV16E711-20-specific TCRs is feasible for adoptive transfer purposes. Reporter cells (Jurkat/MA) carrying a transgenic TCR were shown to bind relevant but not irrelevant tetramers. Moreover, these TCR-transgenic Jurkat/MA cells showed reactivity towards relevant target cells, indicating proper functional activity of the TCRs isolated from already available T cell clones. We next introduced an HPV16E711-20-specific TCR into blood-derived, CD8+ recipient T cells. Transgenic CTL clones stained positive for tetramers presenting the relevant HPV16E711-20 epitope and biological activity of the TCR in transduced CTL was confirmed by lytic activity and by interferon (IFN)-gamma secretion upon antigen-specific stimulation. Importantly, we show recognition of the endogenously processed and HLA-A2 presented HPV16E711-20 CTL epitope by A9-TCR-transgenic T cells. Collectively, our data indicate that HPV16E7 TCR gene transfer is feasible as an alternative strategy to generate human HPV16E7-specific T cells for the treatment of patients suffering from cervical cancer and other HPV16-induced malignancies.     

Follicular lymphoma cell lines,an in vitro model for antigenic selection and cytokine-mediated growth regulation of germinal centre B cells

In the periphery, B cells differentiate in germinal centres (GCs) of secondary lymphoid organs. Isolated GC cells die quickly in vitro by apoptosis. Therefore, cell lines originating from follicular lymphomas, which are the malignant counterparts of GC B cells, would provide a stable in vitro model to study the immunobiology of GC B cells. We have established three novel human follicular lymphoma cell lines that were characterized with special reference to immunophenotypic features, response to B-cell receptor (BCR) triggering, response to cytokines and cytokine mRNA expression. One of the cell lines, HF-1A3, has a phenotype of a centrocyte. It expresses surface immunoglobulin G (sIgG) and dies by apoptosis following BCR cross-linking. Co-stimulation with interleukin-6 (IL-6), IL-15 or interferon-gamma (IFN-gamma) rescues HF-1A3 cells from BCR-induced apoptosis. The second cell line, HF-28, also represents phenotypically an IgG+ centrocyte. Ligation of its BCR leads to the cell-cycle arrest at G1 instead of apoptosis. HF-28 cells express both CD45RA and RO isoforms, which is unusual in B lymphocytes apart from plasma cells, thus suggesting a transition to plasma cell phenotype. The third cell line, HF-4.9, which phenotypically represents an sIgM+ centroblast, responds by proliferation to BCR cross-linking. These cell lines offer a unique in vitro model to study antigenic selection and cytokine-mediated growth regulation of human GC B cells.     

Dynamic graciloplasty for urinary incontinence: the potential for sequential closed-loop stimulation

Muscle tissue transplantation applied to regain or dynamically assist contractile functions is known as 'dynamic myoplasty'. Success rates of clinical applications are unpredictable, because of lack of endurance, ischemic lesions, abundant scar formation and inadequate performance of tasks due to lack of refined control. Electrical stimulation is used to control dynamic myoplasties and should be improved to reduce some of these drawbacks. Sequential segmental neuromuscular stimulation improves the endurance and closed-loop control offers refinement in rate of contraction of the muscle, while function-controlling stimulator algorithms present the possibility of performing more complex tasks. An acute feasibility study was performed in anaesthetised dogs combining these techniques. Electrically stimulated gracilis-based neo-sphincters were compared to native sphincters with regard to their ability to maintain continence. Measurements were made during fast bladder pressure changes, static high bladder pressure and slow filling of the bladder, mimicking among others posture changes, lifting heavy objects and diuresis. In general, neo-sphincter and native sphincter performance showed no significant difference during these measurements. However, during high bladder pressures reaching 40 cm H(2)O the neo-sphincters maintained positive pressure gradients, whereas most native sphincters relaxed. During slow filling of the bladder the neo-sphincters maintained a controlled positive pressure gradient for a prolonged time without any form of training. Furthermore, the accuracy of these maintained pressure gradients proved to be within the limits set up by the native sphincters. Refinements using more complicated self-learning function-controlling algorithms proved to be effective also and are briefly discussed. In conclusion, a combination of sequential stimulation, closed-loop control and function-controlling algorithms proved feasible in this dynamic graciloplasty-model. Neo-sphincters were created, which would probably provide an acceptable performance, when the stimulation system could be implanted and further tested. Sizing this technique down to implantable proportions seems to be justified and will enable exploration of the possible benefits.