Multiple Clinical Presentations of Lymphoproliferative Disorders in Pediatric Liver Transplant Recipients: A Single-Center Experience

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naive prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Oral manifestations of inflammatory bowel disease: a review based on the observation of six cases

Inflammatory bowel disease (IBD) comprises two chronic, tissue-destructive, clinical entities: Crohn`s disease (CD) and ulcerative colitis (UC), both immunologically based. Bowel symptoms are predominant, but extra-intestinal complications may occur, including involvement of the oral cavity. Oral involvement during IBD includes several types of lesions: the most common are aphthae; uncommon lesions include, among others, pyostomatitis vegetans and granulomatous lesions of CD. Starting with a presentation of six patients with oral manifestations, which were crucial for the final diagnosis of IBD, a review on the subject is presented. Oral involvement in IBD may be previous or simultaneous to the gastrointestinal symptoms. However, in the majority of cases, bowel disease precedes the onset of oral lesions by months or years. In many patients, the intestinal symptoms may be minimal and can go undetected; thus, most authors believe that the bowel must be thoroughly examined in all patients with suspected IBD even in the absence of specific symptoms. Usually, the clinical course of oral lesions is parallel to the activity of IBD; therefore, oral manifestations are a good cutaneous marker of IBD.

Percutaneous vertebroplasty for multiple myeloma of the cervical spine

Spinal involvement is a common presentation of multiple myeloma (MM); however, the cervical spine is the least common site of myelomatous involvement. Few studies evaluate the results of percutaneous vertebroplasty (PV) in the treatment of MM of the spine. The purpose of this series is to report on the use of PV in the treatment of MM of the cervical spine and to review the literature. From January 1994 to October 2007, four patients (three men and one woman; mean age, 45 years) who underwent five PV for painful MM in the cervical spine were retrospectively reviewed. The pain was estimated by the patient on a verbal analogic scale. Clinical follow-up was available for all patients (mean, 27.5 months; range, 1-96 months). The mean volume of cement injected per vertebral body was 2.3 +/- 0.8 mL (range, 1.0-4.0 mL) with a mean vertebral filling of 55.0 +/- 12.0% (range, 40.0-75.0%). Analgesic efficacy was achieved in all patients. One patient had a spinal instability due to a progression of spinal deformity noted on follow-up radiographs, without clinical symptoms. Cement leakage was detected in three (60%) of the five treated vertebrae. There was no clinical complication. The present series suggests that PV for MM of the cervical spine is safe and effective for pain control; nonetheless, the detrimental impact of the disease on bone quality should prompt close radiological follow-up after PV owing to the risk of spinal instability.

Two cases of Kallmann syndrome associated with empty sella

Kallmann syndrome (KS) is a developmental disease characterized by the association of isolated hypogonadotropic hypogonadism and anosmia/hyposmia. We report an unusual presentation of two females with KS and empty sella. These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases. Sequencing of FGFR1 gene, recently implicated in autosomal form of KS, was performed and one splicing mutation (IVS14 + 1G > A) was identified in one patient.

Angiogenic non-Hodgkin T/natural killer (NK)-cell lymphoma: Report of three cases

Angiogenic T/natural killer (NK)-cell lymphoma is a non-Hodgkin lymphoma characterized by necrosis and vascular destruction that is strongly associated with Epstein-Barr virus and AIDS. Early diagnosis is essential to improve the chances of patient survival, but severe local inflammatory infiltrate impairs histologic diagnosis by obscuring neoplastic cells. The most common markers are CD2, CD56, cytoplasmic CD3, and CD43 EBV We describe 3 cases of angiogenic T/NK-cell lymphoma that show the diverse Presentation of the same disease. Patient I was HIV positive and had nasal obstruction, facial edema, and ulceration of the nasal mucosa. Patient 2 had fever, a sore throat, and weight loss. Patient 3 had facial edema, fever, proptosis, and rapid development Of neurologic alterations. Several biopsies were needed for histologic confirmation in these patients, despite positivity for the CD3 and CD56 markers.

Advantages and Pitfalls of the Polymerase Chain Reaction in the Diagnosis of Esophageal Ulcers in AIDS Patients

HIV-1-infected patients frequently have opportunistic esophageal infections which, when associated with severe immunodeficiency, can be attributed to unusual pathogens. The clinical presentation of several esophageal diseases is similar and the best method for a specific diagnosis of these patients has not been well defined. To evaluate the role of the polymerase chain reaction (PCR) in the etiologic definition of esophageal ulcers in HIV-1-infected patients, 96 esophageal biopsies from 79 HIV-1-infected patients were processed by PCR using specific primers for cytomegalovirus (CMV), herpes virus (HSV), human papilloma virus (HPV), HIV-1, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Treponema pallidum, and Haemophilus ducreyi. The PCR results were compared to the histopathologic results. Seventy-nine patients were studied (mean age: 34 years; 62% men; median CD4 + T cell = 103.59 cells/mu l (range 1-795.2 cells/mu l). The most common endoscopic findings were as follows: esophageal candidiasis (37.1%), esophageal ulcers (24.7%), esophagitis (11.2%), and lugol-negative areas (10.1%). The histopathologic findings in the esophageal ulcers (22 biopsies) were non-specific inflammation (31.8%), HSV (36.4%), Candida (13.6%), CMV (13.6%), or HPV disease (4.5%). In the esophageal ulcer biopsies, the PCR results were negative in 27.6% of cases, and positive for HIV (65.5%), CMV (31%), HPV (20.7%), HSV (10.3%), and H. ducreyi (6.9%). The histopathologic examination did not identify a pathogen or identified only Candida in 15 biopsies of esophageal ulcers. PCR was positive in ten (66.7%) and negative in five (33.3%) of these biopsies (idiopathic ulcers). PCR detected: HIV (53.3%), CMV (20%), HPV (13.3%), and H. ducreyi (6,7%). PCR detected more etiologic agents in esophageal ulcers than histopathology and was able to detect unusual pathogens. On the other hand, sometimes more than one pathogen was detected in the esophageal ulcers, making it difficult to reach an accurate diagnosis. This finding indicates the need for more studies to evaluate the benefit of this method in the routine evaluation of esophageal ulcer biopsies in HIV-1-infected patients.

NO EVIDENCE OF PATHOLOGICAL AUTOIMMUNITY FOLLOWING MYCOBACTERIUM LEPRAE HEAT-SHOCK PROTEIN 65-DNA VACCINATION IN MICE

Heat-shock proteins (HSPs) are currently one of the most promising targets for the development of immunotherapy against tumours and autoimmune disorders. This protein family has the capacity to activate or modulate the function of different immune system cells. They induce the activation of monocytes, macrophages and dendritic cells, and contribute to cross-priming, an important mechanism of presentation of exogenous antigen in the context of MHC class I molecules, These various immunological properties of HSP have encouraged their use in several clinical trials. Nevertheless, an important issue regarding these proteins is whether the high homology among HSPs across different species may trigger the breakdown of immune tolerance and induce autoimmune diseases. We have developed a DNA vaccine codifying the Mycobacterium leprae Hsp65 (DNAhsp65), which showed to be highly immunogenic and protective against experimental tuberculosis. Here, we address the question of whether DNAhsp65 immunization could induce pathological autoimmunity in mice. Our results show that DNAhsp65 vaccination induced antibodies that can recognize the human Hsp60 but did not induce harmful effects in 16 different organs analysed by histopathology up to 210 days after vaccination. We also showed that anti-DNA antibodies were not elicited after DNA vaccination. The results are important for the development of both HSP and DNA-based immunomodulatory agents.

Gingival and bone necrosis caused by accidental sodium hypochlorite injection instead of anaesthetic solution

Aim To report clinical complications (pain, necrotic gingival tissue and bone sequestration) resulting from accidental injection of sodium hypochlorite. Summary Root canal treatment is a routine clinical procedure with few reported complications. Sodium hypochlorite (NaOCl) is commonly used as an irrigant during the procedure because of its tissue-dissolving, antibacterial and lubricating properties. This paper presents a case in which accidental injection of sodium hypochlorite into the lingual gingiva of a female patient caused gingival and bone necrosis. Surgical intervention was required. Key learning points Sodium hypochlorite is dangerous if injected into the tissues. The presentation of sodium hypochlorite in glass, anaesthetic type cartridges is potentially dangerous, and should be condemned. All healthcare workers should check carefully the contents of any syringe before injecting into patients.

Targeting of EBNA1 for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+T cell recognition

Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) includes a unique glycine-alanine repeat domain that inhibits the endogenous presentation of cytotoxic T lymphocyte (CTL) epitopes through the class I pathway by blocking proteasome-dependent degradation of this antigen. This immune evasion mechanism has been implicated in the pathogenesis of EBV-associated diseases. Here, we show that cotranslational ubiquitination combined with N-end rule targeting enhances the intracellular degradation of EBNA1, thus resulting in a dramatic reduction in the half-life of the antigen. Using DNA expression vectors encoding different forms of ubiquitinated EBNA1 for in vivo studies revealed that this rapid degradation, remarkably, leads to induction of a very strong CTL response to an EBNA1-specific CTL epitope. Furthermore, this targeting also restored the endogenous processing of HLA class I-restricted CTL epitopes within EBNA1 for immune recognition by human EBV-specific CTLs. These observations provide, for the first time, evidence that the glycine-alanine repeat-mediated proteasomal block on EBNA1 can be reversed by specifically targeting this antigen for rapid degradation resulting in enhanced CD8+ T cell-mediated recognition in vitro and in vivo.

Tolerance or immunity to a tumor antigen expressed in somatic cells can be determined by systemic proinflammatory signals at the time of first antigen exposure

Mice transgenic for the E7 tumor Ag of human papillomavirus type 16, driven from a keratin 14 promoter, express E7 in keratinocytes but not dendritic cells. Grafted E7-transgenic skin is not rejected by E7-immunized mice that reject E7-transduced transplantable tumors. Rejection of recently transplanted E7-transgenic skin grafts, but not of control nontransgenic grafts or of established E7-transgenic grafts, is induced by systemic administration of live or killed Listeria monocytogenes or of endotoxin. Graft recipients that reject an E7 graft reject a subsequent E7 graft more rapidly and without further L. monocytogenes exposure, whereas recipients of an E7 graft given without L. monocytogenes do not reject a second graft, even if given with L. monocytogenes. Thus, cross-presentation of E7 from keratinocytes to the adaptive immune system occurs with or without a proinflammatory stimulus, but proinflammatory stimuli at the time of first cross-presentation of Ag can determine the nature of the immune response to the Ag. Furthermore, immune effector mechanisms responsible for rejection of epithelium expressing a tumor Ag in keratinocytes are different from those that reject an E7-expressing transplantable tumor. These observations have implications for immunotherapy for epithelial cancers.

The social construction of PETE in higher education: Toward a research agenda

The focus of this paper is the social construction of physical education teacher education (PETE) and its fate within the broader process of curriculum change in the physical activity field. Our task is to map the dimensions of a research program centered on the social construction of the physical activity field and PETE in higher education. Debates in the pages of Quest and elsewhere over the past two decades have highlighted not only the contentious nature of PETE practices and structures but also that PETE is changing. This paper offers one way of making sense of the ongoing process of contestation and struggle through the presentation of a theoretical framework. This framework, primarily drawing upon the work of Lave and Wenger (1991) and Bernstein (1990, 1996), is described before it is used to study the social construction of PETE in Australia. We assess the progress that has been made in developing this research program, and the questions already evident for further developments of a program of study of the physical activity field in higher education.

Delineation of sulphide ore-zones by borehole radar tomography at Hellyer Mine, Australia

Velocity and absorption tomograms are the two most common forms of presentation of radar tomographic data. However, mining personnel, geophysicists included, are often unfamiliar with radar velocity and absorption. In this paper, general formulae are introduced, relating velocity and attenuation coefficient to conductivity and dielectric constant. The formulae are valid for lossy media as well as high-resistivity materials. The transformation of velocity and absorption to conductivity and dielectric constant is illustrated via application of the formulae to radar tomograms from the Hellyer zinc-lead-silver mine, Tasmania, Australia. The resulting conductivity and dielectric constant tomograms constructed at Hellyer demonstrated the potential of radar tomography to delineate sulphide ore zones. (C) 2001 Elsevier Science B.V. All rights reserved.

Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Orthographic/phonological facilitation of naming responses in the picture-word task: An event-related fMRI study using overt vocal responding

In the picture-word interference task, naming responses are facilitated when a distractor word is orthographically and phonologically related to the depicted object as compared to an unrelated word. We used event-related functional magnetic resonance imaging (fMRI) to investigate the cerebral hemodynamic responses associated with this priming effect. Serial (or independent-stage) and interactive models of word production that explicitly account for picture-word interference effects assume that the locus of the effect is at the level of retrieving phonological codes, a role attributed recently to the left posterior superior temporal cortex (Wernicke's area). This assumption was tested by randomly presenting participants with trials from orthographically related and unrelated distractor conditions and acquiring image volumes coincident with the estimated peak hemodynamic response for each trial. Overt naming responses occurred in the absence of scanner noise, allowing reaction time data to be recorded. Analysis of this data confirmed the priming effect. Analysis of the fMRI data revealed blood oxygen level-dependent signal decreases in Wernicke's area and the right anterior temporal cortex, whereas signal increases were observed in the anterior cingulate, the right orbitomedial prefrontal, somatosensory, and inferior parietal cortices, and the occipital lobe. The results are interpreted as supporting the locus for the facilitation effect as assumed by both classes of theoretical model of word production. In addition, our results raise the possibilities that, counterintuitively, picture-word interference might be increased by the presentation of orthographically related distractors, due to competition introduced by activation of phonologically related word forms, and that this competition requires inhibitory processes to be resolved. The priming effect is therefore viewed as being sufficient to offset the increased interference. We conclude that information from functional imaging studies might be useful for constraining theoretical models of word production. (C) 2002 Elsevier Science (USA).

Secondary structure of the third extracellular loop responsible for ligand selectivity of a mammalian gonadotropin-releasing hormone receptor

The extracellular loop 3 (ECL3) of the mammalian gonadotropin-releasing hormone receptor (GnRH-R) contains an acidic amino acid (Glu(301) in the mouse GnRH-R,) that confers agonist selectivity for Are in mammalian GnRH. It is proposed that a specific conformation of ECL3 is necessary to orientate the carboxyl side chain of the acidic residue for interaction with Arg(8) of GnRH, which is supported by decreased affinity for Arg(8) GnRH but not Gln(8) GnRH when an adjacent Pro is mutated to Ala. To probe the structural contribution of the loop domain to the proposed presentation of the carboxyl side chain, we synthesized a model peptide (CGPEMLNRVSEPGC) representing residues 293-302 of mouse ECL3, where Cys and Gly residues are added symmetrically at the N and C termini, respectively, allowing the introduction of a disulfide bridge to simulate the distances at which the ECL3 is tethered to the transmembrane domains 6 and 7 of the receptor. The ability of the ECL3 peptide to bind GnRH with low affinity was demonstrated by its inhibition of GnRH stimulation of inositol phosphate production in cells expressing the GnRH-R. The CD bands of the ECL3 peptides exhibited a superposition of predominantly unordered structure and partial contributions from beta-sheet structure. Likewise, the analysis of the amide I and amide III bands from micro-Raman and FT Raman experiments revealed mainly unordered conformations of the cyclic and of the linear peptide. NMR data demonstrated the presence of a beta-hairpin among an ensemble of largely disordered structures in the cyclic peptide. The location of the turn linking the two strands of the hairpin was assigned to the three central residues L-296, N-297, and R-298. A small population of structured species among an ensemble of predominantly random coil conformation suggests that the unliganded receptor represents a variety of structural conformers, some of which have the potential to make contacts with the ligand. We propose a mechanism of receptor activation whereby binding of the agonist to the inactive receptor state induces and stabilizes a particular structural state of the loop domain, leading to further conformational rearrangements across the transmembrane domain and signal propagating interaction with G proteins. Interaction of the Glu(301) of the receptor with Arg(8) of GnRH induces a folded configuration of the ligand. Our proposal thus suggests that conformational changes of both ligand and receptor result from this interaction.