Plasma cell depletion with bortezomib in the treatment of refractory N-methyl-d-aspartate (NMDA) receptor antibody encephalitis. Rational developments in neuroimmunological treatment.

BACKGROUND AND PURPOSE: The aim was to assess the therapeutic potential of bortezomib in the treatment of refractory N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis and its potential in other immune-mediated, B-cell-driven neurological diseases. METHODS: Two cases of severe NMDAR antibody encephalitis, resistant to first and second line therapy with steroids, intravenous immunoglobulins, plasma exchange, cyclophosphamide and rituximab, were treated with four and five cycles of 1.3 mg/m2 bortezomib at 350 and 330 days following initial presentation. RESULTS: Both patients showed significant clinical improvement with reductions of NMDAR antibody titres following bortezomib treatment. This is the first case in the literature where the NMDAR antibody level was undetectable following treatment with bortezomib. CONCLUSION: Bortezomib's unique ability to target long-lived autoreactive plasma cells appears to be a useful adjunct to standard second line immunosuppressive therapy in treatment-refractory NMDAR antibody encephalitis. The drug's pharmacodynamics, cell targeting and mechanism of action are reviewed, and it is postulated that bortezomib may be useful in a host of B-cell-driven neuroimmunological diseases.

Carotid atherosclerotic calcification does not result in high signal intensity in MR imaging of intraplaque hemorrhage.

BACKGROUND AND PURPOSE: Calcium can potentially shorten T1, generating high signal intensity in GREs. Because IPH appears as high signal intensity in MRIPH and the surface effects of calcium can potentially shorten T1 of surrounding water protons, the purpose of this study was to evaluate whether the high signal intensity seen on MRIPH could be attributed solely to IPH and not calcification. MATERIALS AND METHODS: Eleven patients undergoing carotid endarterectomy were imaged by using MRIPH. Calcification was assessed by scanning respective endarterectomy specimens with a tabletop MicroCT. MRIPH/MicroCT correlation used an 8-segment template. Two readers evaluated images from both modalities. Agreement between MRIPH/MicroCT was measured by calculating Cohen κ. RESULTS: High signal intensity was seen in 58.8% and 68.9% (readers 1 and 2, respectively) of MRIPH segments, whereas calcification was seen in 44.7% and 32.1% (readers 1 and 2, respectively) of MicroCT segments. High signal intensity seen by MRIPH showed very good but inverse agreement to calcification (κ = -0.90; P < .0001, 95% CI, -0.93 to -0.86, reader 1; and κ = -0.74; P < .0001; 95% CI, -0.81 to -0.69, reader 2). Most interesting, high signal intensity demonstrated excellent agreement with lack of calcification on MicroCT (κ = 0.92; P < .0001; 95% CI, 0.89-0.94, reader 1; and κ = 0.97; P < .0001; 95% CI, 0.96-0.99, reader 2). In a very small number of segments, high signal intensity was seen in MRIPH, and calcification was seen on MicroCT; however, these represented a very small proportion of segments with high signal intensity (5.9% and 1.6%, readers 1 and 2, respectively). CONCLUSIONS: High signal intensity, therefore, reliably identified IPH, known to describe complicated plaque, rather than calcification, which is increasingly recognized as identifying more stable vascular disease.

Antibodies to endothelial cells identify myocardial damage and predict development of coronary artery disease in patients with transplanted hearts.

BACKGROUND: Transplant-induced coronary artery disease is a leading cause of graft failure in cardiac allograft recipients after the first year of transplantation, but there presently is no test to identify patients at high risk for developing the disease. Our research is focused on development of a predictive test to identify patients at high risk of developing the disease. METHODS: Sixty-eight cardiac allograft recipients transplanted and followed at Methodist Hospital between 1982 and 1996 were studied. Serial annual angiograms were used to diagnose coronary artery disease, and serial endomyocardial biopsies were used to detect cellular infiltrates and microvascular disease. Biopsy-matched serum samples were used for cardiac troponin-T determinations as measures of myocardial damage, and serum antibodies to endothelial cells were determined by using flow cytometry, enzyme-linked immunosorbent assay and immunoblotting techniques. The endothelial antibody data were evaluated statistically for associations with angiographic changes, biopsy findings and biochemical evidence of myocardial damage. FINDINGS: Antibodies to endothelial cells were identified by all three techniques, and significant associations were found for the amount of antibody identified by Western immunoblotting with histological rejection grades in biopsies, which were confirmed immunocytochemically as macrophages (p<0.01) and T lymphocytes (P = 0.03). These antibodies also associated significantly with vascular antithrombin depletion (p = 0.02), biochemical evidence of myocardial damage (p = 0.005) and subsequent development of coronary artery disease (p = 0.03). INTERPRETATION: The significant association of anti-endothelial antibodies with cellular infiltrates, depletion of vascular antithrombin and myocardial damage suggests a role for antibody in the development of transplant-induced arteriopathy. The significant association of antiendothelial antibodies with the future development of coronary artery disease further suggests that assessment of these antibodies may provide a non-invasive test to predict the development of transplant-induced coronary artery disease.

A new enzyme-linked immunosorbent assay to measure anti-endothelial antibodies after cardiac transplantation demonstrates greater inhibition of antibody formation by tacrolimus compared with cyclosporine.

BACKGROUND: Chronic rejection or transplant-associated coronary artery disease (TxCAD) is the most serious complication after human cardiac transplantation. Previous studies, using Western blotting, have shown formation of antibodies against endothelial antigens of 56 and 58 kDa, which are associated with early TxCAD. These antigens were later identified as being vimentin and its breakdown products. The aims of the present study were to devise a robust assay for detection of anti-vimentin antibodies and to compare antibody formation in patients taking different immunosuppressive drugs. METHODS: 106 sequential serum samples from 19 patients taking tacrolimus and 68 sera from 12 patients taking cyclosporine were examined by enzyme-linked immunosorbent assay (ELISA) for anti-vimentin antibodies and Western blotting for reactivity against bands at 56/58 kDa. Serum samples were taken before transplantation and at 1, 3, 6, 9, and 12 months. RESULTS: The vimentin ELISA produced significantly higher numbers of positive episodes per patient (3.92+/-1.08) compared with use of Western blotting (2.54+/-0.52). Serum from patients taking tacrolimus contained significantly less antibodies measured by ELISA (15.8%) or Western blotting (6.5%) than sera from patients taking cyclosporine (46.8% for ELISA; P=0.001 and 21% by Western blotting, P=0.01). Intravascular ultrasound performed on six patients at 12 months showed a correlation between anti-vimentin antibody formation and detection of early coronary disease. CONCLUSIONS: The results demonstrate first, that differences in antibody profiles produced by different immunosuppressive drugs, and second, that detection of anti-vimentin antibodies may be a noninvasive method of detecting disease activity in transplanted vessels.

Donor ACE gene polymorphism: a genetic risk factor for accelerated coronary sclerosis following cardiac transplantation.

AIMS: To investigate the role of angiotensin converting enzyme (ACE) (I/D) gene polymorphism in the development of coronary sclerosis after cardiac transplantation. METHODS AND RESULTS: Eighty cardiac transplant recipients (44 transplant associated coronary artery disease; 36 non-transplant associated coronary artery disease) and their donors were genotyped by polymerase chain reaction. The allele frequencies of the recipients in the transplant associated coronary artery disease and non-transplant associated coronary artery disease groups (I = 0.47 and 0.48, D = 0.53 and 0.52, respectively) did not differ significantly between the groups. However, there was a negative association between the frequency of the I allele in the donor and the development of transplant associated coronary artery disease. The D allele in the donor population of the non-transplant associated coronary artery disease group had a significantly (P < 0.01) lower frequency (0.35) than either the transplant associated coronary artery disease group (0.53) or that of the general population (0.57). Other factors analysed were recipient family history, cholesterol levels, age, sex and body mass index, donor age and acute rejection, of which the significant (P < 0.05) factors were acute rejection and sex of the recipient. CONCLUSION: These results suggest that the ACE genotype of the donor organ may be an additional risk factor for the development of coronary artery disease following cardiac transplantation and that tissue rather than circulating ACE could be implicated in the pathogenesis of this disease.

The medical device directives and their impact on the development and manufacturing of medical implants.

The introduction of a legal framework for the supply of medical implants is discussed with reference to the Active Implantable Medical Device Directive and the Medical Device Directive. The definitions of medical device and manufacturer are discussed. The application of the Directives to device/drug combinations is considered. All implants must meet certain essential requirements to ensure that they do not harm the patient, clinician or any third party. For most implants this will be indicated on the product or its packaging by CE; marking involving an independent organization called a Notified Body; the latter are appointed by the Competent Authority of the Member State. Devices are classified in proportion to the risk associated with them. The steps needed to be taken by manufacturers are outlined and the verification options discussed. The role of standards and the new approach to writing them in Europe is presented. After placing a product on the market, the manufacturer must set up a system of post-market surveillance, including a vigilance procedure, in order to monitor product performance. Individual Member States can exercise the safeguard clause when a product appears to have had the CE marking incorrectly applied.

A method of two-dimensional mapping of cortical perfusion by cylindrical transformation of HMPAO SPET data.

In order to synthesize three-dimensional information on relative regional blood flow (rCBF) from the cortical grey matter in 99Tcm-hexamethylpropyleneamine oxime (HMPAO) single photon emission tomographic (SPET) images into a single two-dimensional 'cortical peel' (CP) image, we developed a program that performs cylindrical transformation of SPET data. A sub-routine of this program performs measurements of cortex-to-cerebellum rCBF ratios for 54 cortical regions in the CP image. This program was used to establish a normative database derived from 30 young normal control subjects aged 28.7 +/- 6.9 years. The database was then used to express cortex-to-cerebellum rCBF ratios in four colour-coded ranges of normal standard deviation of the mean rCBF ratio across the cortical regions in the CP image. This CP method was implemented for 30 clinical HMPAO SPET studies in patients (n = 30, aged 71.8 +/- 4.2 years) with suspected dementia as well as several studies in aged healthy subjects (n = 8, aged 67 +/- 9.8 years). In 25/30 (83%) patients, all abnormalities seen on the tomographic display were evident on the corresponding CP image. No aged healthy subjects showed abnormalities on either the tomographic display or the corresponding CP image. An advantage of this technique is that the extent and severity of rCBF abnormalities are readily appreciated in one single image. This technique, in conjunction with the conventional multi-slice tomographic display, was a useful tool in identifying various patterns of rCBF abnormalities in the patients with clinically suspected dementia.

Pre-transplant anti-epithelial cell antibodies and graft failure after single lung transplantation.

Eighty-five patients undergoing single lung transplantation have been studied to determine the presence of anti-epithelial cell antibodies (AECA) prior to transplantation using the human lung carcinoma epithelial cell line A549 in a microcytotoxicity assay. In addition, 29 healthy volunteers were also assayed for the presence of AECA. Twenty-seven of the 85 recipients exhibited AECA prior to transplantation compared to none of the 29 control subjects (p = 0.0001). Actuarial graft survival at 1 year was 78% for the AECA negative group compared to 56% for AECA positive recipients (p = 0.01). No correlation was seen between the presence of AECA and graft rejection as determined by transbronchial biopsy. However, there was an association between AECA and post-transplant infection (p = NS) where 16 (64%) of the AECA positive recipients had postoperative infection episodes compared to 25 (47%) of the negative recipients. Sodium dodecylsulphate polyacrylamide gel electrophoresis and Western blotting was also performed for 68 of the recipients and antibody reactivity was detected in 22 patients compared to 26 patients exhibiting AECA detectable by microcytotoxicity. The presence of AECA demonstrable by Western blotting did not correlate with graft survival, rejection or infection. In conclusion, AECA detectable prior to single lung transplantation are associated with a decrease in graft survival and with postoperative infections.

Antiendothelial antibodies after heart transplantation: the accelerating factor in transplant-associated coronary artery disease?

Although the precise cause of transplant-associated coronary artery disease is unknown, immune mechanisms have been implicated. Using the techniques of SDS-PAGe and Western immunoblotting, we have previously shown that a strong positive correlation exists between the development of coronary artery disease and the presence of antiendothelial antibodies reactive with a doublet of polypeptides of approximately 60 and 62 kDa. We have now extended this study to investigate the temporal pattern of antiendothelial antibody formation after transplantation and its association with cellular rejection episodes. The original study used patients in whom coronary artery disease had developed early after transplantation, that is at 1 or 2 years. Here we investigate whether antiendothelial antibodies are also made in patients in whom the disease does not develop until 5 to 10 years after heart transplantation and whether the antibodies are found in patients with severe nontransplant atherosclerosis. We confirm the 60 to 62 kDa antigens are membrane bound, and recalculation of their molecular mass makes the doublet 56 and 57.5 kDa. The results show that antibodies specific for the doublet of endothelial antigens are rarely produced by patients other than those in whom rapidly progressing coronary artery disease develops early after transplantation. The antibodies are unrelated to cellular rejection episodes. We believe their production may be an accelerating factor for the rapid development of transplant-associated coronary artery disease.

Anti-endothelial antibodies and coronary artery disease after cardiac transplantation.

Accelerated coronary artery disease is the most serious complication after cardiac transplantation. The disease has a multifactorial aetiology, with little agreement about the relative importance of the various risk factors. We have investigated the frequency of anti-endothelial antibodies against human umbilical vein endothelial cells by one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis and western blotting. Peptide-specific anti-endothelial antibodies were found in 15/21 heart transplant recipients with accelerated coronary artery disease, and 1/20 transplant patients who had not developed the disease. Positive immunofluorescence of patients' serum on frozen sections of coronary vessels confirmed the endothelial specificity of antibodies. These results provide evidence of an immune aetiology for transplant-associated coronary artery disease and could have important implications for its diagnosis and therapy.

Low interrater agreement on the semantic base of textual material.

The present paper describes three experiments which were conducted to determine whether independent raters could agree upon the semantic base of textual materials. These experiments were occasioned by an earlier experiment in which the investigators reported success in increasing the ability of students to extract the semantic base from textual materials. The present paper reports our unsuccessful attempts to obtain an acceptable level of agreement among independent raters about what constituted the semantic base of a number of texts. The paper concludes by raising some doubts about the strategy of extending behavior-analytic research to verbal behavior by combining behavior-change procedures with cognitive constructs.

An evaluation of planned early postnatal transfer home with nursing support.

A community-based programme of planned early postnatal transfer home with the continuity of hospital nursing care was instituted in a defined geographic area of the western suburbs of Sydney in 1983. Mothers were offered the option of discharge in 24-48 hours after delivery, with home visits by a hospital midwife, subject to certain medical and social criteria. An evaluation of the programme in terms of morbidity, psychosocial impact on the family and costs was undertaken. For evaluation, a quasi-experimental study of parallel groups was designed in preference to randomized selection as it was believed that the personal choice would be fundamental to the success of the scheme. A contemporary control group was achieved with volunteer mothers who opted for the traditional five- to seven-day hospital stay. Studies of maternal response and the partner's response and adjustment were undertaken, including the administration of questionnaires that were designed to detect the presence of mild postnatal depression. No increased morbidity occurred in the early discharge group. The early discharge group performed more favourably on the questionnaire that was designed to measure their postpartum adjustment. Continued postnatal domiciliary surveillance reduces the risk that early neonatal pathological changes, especially jaundice, may be overlooked.

The prevalence of human isolates of Salmonella subspecies II in southern Africa.

The Salmonella Reference Centre in Johannesburg received 14059 strains of human origin between 1979 and 1984. A significant proportion (6.3%) proved to belong to subspecies II. The majority were cultured from faecal material, usually associated with symptoms related to the gastrointestinal tract. They comprised 884 isolates, represented by 203 serotypes, of which 45 were new serotypes. The poor hygienic conditions found in many rural areas, together with possible contamination of food and water by wild animals, may contribute to the greater frequency of human S.II infections and the widespread occurrence of unusual serotypes in man in this geographic region.

Radioactive tracer technique for monitoring of microleakage: an interim report.

A diffusion apparatus for the measurement and monitoring of microleakage is described. Radioactive ions are used to measure the diffusion across a section of a filled tooth. A study was made of the sealing ability of some amalgams and a composite resin filling material.