Effects of prior osteoporosis treatment on the treatment response of romosozumab followed by denosumab in patients with postmenopausal osteoporosis.

In patients with postmenopausal osteoporosis, prior osteoporosis treatment affected the bone mineral density increase of following treatment with 12 months of romosozumab, although it did not affect that of following treatment with 12 months of denosumab after romosozumab. PURPOSE: To investigate the effects of prior osteoporosis treatment on the response to treatment with romosozumab (ROMO) followed by denosumab (DMAb) in patients with postmenopausal osteoporosis. METHODS: In this prospective, observational, multicenter study, treatment-naïve patients (Naïve; n = 55) or patients previously treated with bisphosphonates (BP; n = 37), DMAb (DMAb; n = 45) or teriparatide (TPTD; n = 17) (mean age, 74.6 years; T-scores of the lumbar spine [LS] - 3.2 and total hip [TH] - 2.6) were switched to ROMO for 12 months, followed by DMAb for 12 months. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 24 months. RESULTS: A BMD increase was observed at 12 and 24 months in the following patients: Naïve (18.2% and 22.0%), BP (10.2% and 12.1%), DMAb (6.6% and 9.7%), and TPTD (10.8% and 15.0%) (P < 0.001 between the groups at both 12 and 24 months) in LS and Naïve (5.5% and 8.3%), BP (2.9% and 4.1%), DMAb (0.6% and 2.2%), and TPTD (4.3% and 5.4%) (P < 0.01 between the groups at 12 months and P < 0.001 at 24 months) in TH, respectively. The BMD increase in LS from 12 to 24 months was negatively associated with the levels of bone resorption marker at 24 months. Incidences of major fragility fractures for the respective groups were as follows: Naïve (5.5%), BP (16.2%), DMAb (11.1%), and TPTD (5.9%). CONCLUSIONS: Previous treatment affected the BMD increase of following treatment with ROMO, although it did not affect that of following treatment with DMAb after ROMO.

A multiparametric MRI-based machine learning to distinguish between uterine sarcoma and benign leiomyoma: comparison with 18F-FDG PET/CT.

AIM: To compare the performance of machine learning using multiparametric magnetic resonance imaging (mp-MRI) and positron-emission tomography (PET) to distinguish between uterine sarcoma and leiomyoma. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and informed consent was waived. Sixty-seven consecutive patients with uterine sarcoma or leiomyoma who underwent pelvic 3 T MRI and PET were included. Of 67 patients, 11 had uterine sarcomas and 56 had leiomyomas. Seven different parameters were measured in the tumours, from T2-weighted, T1-weighted, contrast-enhanced, and diffusion-weighted MRI, and PET. The areas under the receiver operating characteristic curves (AUC) with a leave-one-out cross-validation were used to compare the diagnostic performances of the univariate and multivariate logistic regression (LR) model with those of two board-certified radiologists. RESULTS: The AUCs of the univariate models using MRI parameters (0.68-0.8) were inferior to that of the maximum standardised uptake value (SUVmax) of PET (0.85); however, the AUC of the multivariate LR model (0.92) was superior to that of SUVmax, and comparable to that of the board-certified radiologists (0.97 and 0.89). CONCLUSION: The diagnostic performance of the machine learning using mp-MRI was superior to PET and comparable to that of experienced radiologists.

Value of 100 kVp scan with sinogram-affirmed iterative reconstruction algorithm on a single-source CT system during whole-body CT for radiation and contrast medium dose reduction: an intra-individual feasibility study.

AIM: To perform an intra-individual investigation of the usefulness of a contrast medium (CM) and radiation dose-reduction protocol using single-source computed tomography (CT) combined with 100 kVp and sinogram-affirmed iterative reconstruction (SAFIRE) for whole-body CT (WBCT; chest-abdomen-pelvis CT) in oncology patients. MATERIALS AND METHODS: Forty-three oncology patients who had undergone WBCT under both 120 and 100 kVp protocols at different time points (mean interscan intervals: 98 days) were included retrospectively. The CM doses for the 120 and 100 kVp protocols were 600 and 480 mg iodine/kg, respectively; 120 kVp images were reconstructed with filtered back-projection (FBP), whereas 100 kVp images were reconstructed with FBP (100 kVp-F) and the SAFIRE (100 kVp-S). The size-specific dose estimate (SSDE), iodine load and image quality of each protocol were compared. RESULTS: The SSDE and iodine load of 100 kVp protocol were 34% and 21%, respectively, lower than of 120 kVp protocol (SSDE: 10.6±1.1 versus 16.1±1.8 mGy; iodine load: 24.8±4versus 31.5±5.5 g iodine, p<0.01). Contrast enhancement, objective image noise, contrast-to-noise-ratio, and visual score of 100 kVp-S were similar to or better than of 120 kVp protocol. CONCLUSION: Compared with the 120 kVp protocol, the combined use of 100 kVp and SAFIRE in WBCT for oncology assessment with an SSCT facilitated substantial reduction in the CM and radiation dose while maintaining image quality.

Dual-layer detector CT of chest, abdomen, and pelvis with a one-third iodine dose: image quality, radiation dose, and optimal monoenergetic settings.

AIM: To compare the image quality and radiation dose of reduced iodine dose dual-layer detector (DL) computed tomography (CT) with those of a conventional 120 kVp protocol for chest-abdomen-pelvis CT (CAP-CT). MATERIALS AND METHODS: Forty patients with renal dysfunction (estimated glomerular filtrating ratio <45 ml/min/1.73 m2) underwent reduced iodine dose CAP-CT (120 kVp, 200 mg iodine/kg) on DLCT. Virtual monochromatic images (VMI) at 40-70 keV (5 keV interval) were reconstructed retrospectively. Forty matched patients who underwent conventional CAP-CT (120 kVp, 600 mg iodine/kg, iterative reconstruction) were included as controls. The size-specific dose estimate (SSDE), image noise, CT attenuation, and contrast-to-noise ratio (CNR) were compared between the protocols. Two radiologists rated image contrast, image noise, streak artefact, and diagnostic confidence on a five-point scale. RESULTS: The SSDE of the DLCT group was approximately 20% lower than that of the 120 kVp group (15.4±1.9 versus 19.4±2.3 mGy, p<0.01). DLCT-VMI provided almost constant image noise throughout the range of energies (differences of ≤13%), with the noise being equivalent or lower than 120 kVp in the abdomen. CT attenuation and CNR gradually increased as the energy decreased, with values comparable to 120 kVp being attained at around 45-50 keV. Although streak artefact was accentuated at 40-50 keV (p<0.01), the highest scores for diagnostic confidence were assigned at 40 and 45 keV, both of which were equivalent to 120 kVp (p=1.0). CONCLUSION: For CAP-CT with a one-third iodine dose, DLCT-VMI at 40-45 keV allows for a 20% reduction in radiation dose, while preserving image quality comparable to that of conventional 120 kVp protocol.

Studies on expression of aldehyde dehydrogenase in normal and cancerous tissues of thyroids.

Recently published articles have reported the controversial data regarding expression of aldehyde dehydrogenase isozyme 1A1 (ALDH1A1), a potential candidate marker for normal and cancer stem cells (CSCs), in thyroid tissues. These data prompted us to re-evaluate expression of ALDH1A1 in normal and cancerous thyroid tissues by 2 different means. The first method was immunohistochemistry with 2 different anti-ALDH1A1 antibodies from distinct companies. Following validating the integrity of these 2 antibodies by Western blotting with ALDH-expressing and nonexpressing cancer cell lines and immunohistochemistry with breast and colon tissues, we report here significant and comparable expression of ALDH1A1 in both normal and cancerous thyroid tissues with both antibodies. Next, relative expression levels of ALDH isozymes were evaluated by reverse transcription-polymerase chain reaction (RT-PCR), revealing that ALDH1A1 was the most highly expressed isozyme followed by ALDH9A1 and relative expression patterns of isozymes were very similar in normal and cancerous tissues. All these data demonstrate that thyroid cells of normal and cancer origins do express ALDH1A1 and to a lesser extent 9A1. Further study will be necessary to study functional significance of ALDH1A1 in the function and behaviors of thyroid normal and cancer stem cells.

Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse.

AIMS/HYPOTHESIS: T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice. METHODS: We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis. RESULTS: IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4(+) T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4(+)CD25(-) T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice. CONCLUSIONS/INTERPRETATION: These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.

Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice.

Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of ß cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that ß cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non-obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB(-/-) mice developed diabetes spontaneously with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with regulatory T cell (Treg )-depleted splenocytes (SPCs) into NOD-SCID mice or in-vivo Treg depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB(-/-) mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB(-/-) mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4(+) , CD8(+) and CD4(+) CD25(+) T cells in SPCs from NOD.GzmB(-/-) mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for ß cell destruction in NOD mice.

Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues.

Over the past decade a number of murine models of Graves' disease (GD) have been described. The full symptom complex, including typical orbital changes, however, could not yet be induced. In this report, we examined the influence of modified immunization protocols on orbital pathology. C57BL/6 and BALB/c mice were immunized against the human TSH receptor (TSHR), using either a TSHR encoding plasmid or a TSHR A-subunit adenovirus. Prior to immunization with the TSHR plasmid, regulatory T cells were depleted in one group of each strain. TSHR-stimulating antibodies (TSAbs) were evaluated and orbits were stained immunohistochemically for F4/80, uncoupling protein-1 (UCP-1) and the TSHR. We found that after depletion of regulatory T cells, incidence of TSAb was increased in TSHR plasmid immunized C57BL/6 mice. Examination of early immunized mice showed no antibody production. However, a TSHR epitope-specific cellular immune response could be detected by tetramer-analyses. Adenoviral immunization lead to TSAb production in all but one animal. Analysis of F4/80 positive cells in retrobulbar fat revealed no significant macrophage infiltration in the orbits of immunized mice. Immunohistochemical staining shows co-localization of F4/80 positive cells, UCP-1 and the TSHR in retrobulbar fat. Though targets for TSHR autoimmunity could clearly be shown, immunization methods were not efficient enough to cause clear signs of orbital inflammation.

Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice.

Major histocompatibility complex (MHC) class I-restricted T cell epitopes are generated mainly by the immunoproteasome in antigen-presenting cells. Therefore, inhibition of activity of this proteolytic complex molecule is thought to be a potential treatment for cell-mediated autoimmune diseases. We therefore studied the efficacy of an immunoproteasome inhibitor, ONX 0914 (formerly PR-957), for the treatment of autoimmune thyroid diseases, including cell-mediated Hashimoto's thyroiditis and autoantibody-mediated Graves' hyperthyroidism using mouse models. Our data show that ONX 0914 was effective prophylactically and therapeutically at suppressing the degree of intrathyroidal lymphocyte infiltration and, to a lesser degree, the titres of anti-thyroglobulin autoantibodies in non-obese diabetic (NOD)-H2(h4) mice, an iodine-induced autoimmune thyroiditis model. It also inhibited differentiation of T cells to T helper type 1 (Th1) and Th17 cells, effector T cell subsets critical for development of thyroiditis in this mouse strain. In contrast, its effect on the Graves' model was negligible. Although ONX 0914 exerts its immune-suppressive effect through not only suppression of immune proteasome but also other mechanism(s), such as inhibition of T cell differentiation, the present results suggest that the immunoproteasome is a novel drug target in treatment of Hashimoto's thyroiditis in particular and cell-mediated autoimmune diseases in general.

Virtual magnetic resonance lumbar spine images generated from computed tomography images using conditional generative adversarial networks.

INTRODUCTION: The aim of this study was to generate virtual Magnetic resonance (MR) from computed tomography (CT) using conditional generative adversarial networks (cGAN). METHODS: We selected examinations from 22 adults who obtained their CT and MR lumbar spine examinations. Overall, 4 examinations were used as test data, and 18 examinations were used as training data. A cGAN was trained to generate virtual MR images from the CT images using the corresponding MR images as targets. After training, the generated virtual MR images from test data in epochs 1, 10, 50, 100, 500, and 1000 were compared with the original ones using the mean square error (MSE) and structural similarity index (SSIM). Additionally, two radiologists also performed qualitative assessments. RESULTS: The MSE of the virtual MR images decreased as the epoch of the cGANs increased from the original CT images: 8876.7 ± 1192.9 (original CT), 1567.5 ± 433.9 (Epoch 1), 1242.4 ± 442.0 (Epoch 10), 1065.8 ± 478.1 (Epoch 50), 1276.1 ± 718.9 (Epoch 100), 1046.7 ± 488.2 (Epoch 500), and 1031.7 ± 400.0 (Epoch 1000). No considerable differences were observed in the qualitative evaluation between the virtual MR images and the original ones, except in the structure of the spinal canal. CONCLUSION: Virtual MR lumbar spine images using cGANs could be a feasible technique to generate near-MR images from CT without MR examinations for evaluation of the vertebral body and intervertebral disc. IMPLICATIONS FOR PRACTICE: Virtual MR lumbar spine images using cGANs can offer virtual CT images with sufficient quality for attenuation correction for PET or dose planning in radiotherapy.

CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse.

C/EBP homologous protein (CHOP) has been proposed as a key transcription factor for endoplasmic reticulum (ER) stress-mediated ß-cell death induced by inflammatory cytokines in vitro. However, the contribution of CHOP induction to the pathogenesis of type 1 diabetes is not yet clear. To evaluate the relevance of CHOP in the pathogenesis of type 1 diabetes in vivo, we generated CHOP-deficient non-obese diabetic (NOD.Chop (-/-)) mice. CHOP deficiency did not affect the development of insulitis and diabetes and apoptosis in ß-cells. Interestingly, NOD.Chop (-/-) mice exhibited a delayed appearance of insulin autoantibodies compared to wild-type (wt) mice. Adoptive transfer with the diabetogenic, whole or CD8(+)-depleted splenocytes induced ß-cell apoptosis and the rapid onset of diabetes in the irradiated NOD.Chop (-/-) recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets from NOD.Chop (-/-) compared to those from wt mice or NOD-scid mice. These findings suggest that CHOP expression is independent of the development of insulitis and diabetes but might affect the early production of insulin autoantibodies in the NOD mouse.

B cell-targeted therapy with anti-CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism.

Graves' disease is a B cell-mediated and T cell-dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen-presenting/immune-modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti-mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A-subunit (Ad-TSHR289). We observe that a single injection of 250 µg/mouse anti-mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR-specific splenocyte secretion of interferon (IFN)-γ, anti-TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time-point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN-γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody-producing cells but also as antigen-presenting/immune-modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.

Observation of long-distance radial correlation in toroidal plasma turbulence.

This Letter presents the discovery of macroscale electron temperature fluctuations with a long radial correlation length comparable to the plasma minor radius in a toroidal plasma. Their spatiotemporal structure is characterized by a low frequency of ∼1-3 kHz, ballistic radial propagation, a poloidal or toroidal mode number of m/n=1/1 (or 2/1), and an amplitude of ∼2% at maximum. Nonlinear coupling between the long-range fluctuations and the microscopic fluctuations is identified. A change of the amplitude of the long-range fluctuation is transmitted across the plasma radius at the velocity which is of the order of the drift velocity.

Observation of reversed-shear Alfvén eigenmodes excited by energetic ions in a helical plasma.

Reversed-shear Alfvén eigenmodes were observed for the first time in a helical plasma having negative q0'' (the curvature of the safety factor q at the zero shear layer). The frequency is swept downward and upward sequentially via the time variation in the maximum of q. The eigenmodes calculated by ideal MHD theory are consistent with the experimental data. The frequency sweeping is mainly determined by the effects of energetic ions and the bulk pressure gradient. Coupling of reversed-shear Alfvén eigenmodes with energetic ion driven geodesic acoustic modes generates a multitude of frequency-sweeping modes.

Metal Artifact Reduction in Head CT Performed for Patients with Deep Brain Stimulation Devices: Effectiveness of a Single-Energy Metal Artifact Reduction Algorithm.

BACKGROUND AND PURPOSE: Deep brain stimulation electrodes induce massive artifacts on CT images, deteriorating the diagnostic value of examinations. We aimed to investigate the usefulness and potential limitations of a single-energy metal artifact reduction algorithm in head CT performed in patients with implanted deep brain stimulation devices. MATERIALS AND METHODS: Thirty-four patients with deep brain stimulation (bilateral, n = 28) who underwent head CT on a 320-detector row scanner and whose images were reconstructed with and without single-energy metal artifact reduction at the examinations were retrospectively included. The severity of artifacts around electrodes was assessed objectively using SDs and an artifact index. Two radiologists subjectively evaluated the severity of artifacts from electrodes, the visibility of electrode localization and surrounding structures, and overall diagnostic confidence on 4-point scales. Background image quality (GM-WM contrast and image noise) was subjectively and objectively assessed. The presence and location of artifacts newly produced by single-energy metal artifact reduction were analyzed. RESULTS: Single-energy metal artifact reduction provided lower objective and subjective metal artifacts and improved visualization of electrode localization and surrounding structures and diagnostic confidence compared with non-single-energy metal artifact reduction images, with statistical significance (all, P < .01). No significant differences were observed in GM-WM contrast and image noise (all, P ≥ .11). The new artifacts from single-energy metal artifact reduction were prominently observed in patients with bilateral deep brain stimulation at high convexity, possibly induced by deep brain stimulation leads placed under the parietal scalp. CONCLUSIONS: Single-energy metal artifact reduction substantially reduces the metal artifacts from deep brain stimulation electrodes and improves the visibility of intracranial structures without affecting background image quality. However, non-single-energy metal artifact reduction images should be simultaneously reviewed to accurately assess the entire intracranial area, particularly in patients with bilateral deep brain stimulation.

An insertion in the human thyrotropin receptor critical for high affinity hormone binding.

Thyrotropin (TSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are structurally related glycoprotein hormones, which bind to receptors that share a high degree of sequence similarity. However, comparison of the primary amino acid sequences of the TSH and LH-CG receptors reveals two unique insertions of 8 and 50 amino acids in the extracellular domain of the TSH receptor. The functional significance of these insertions were determined by site-directed mutagenesis. Deletion of the 50-amino acid tract (residues 317 to 366) had no effect on TSH binding or on TSH and thyroid-stimulating immunoglobulin (TSI) biological activities. In contrast, either deletion or substitution of the eight-amino acid region (residues 38 to 45) abolished these activities. This eight-amino acid tract near the amino terminus of the TSH receptor appears to be an important site of interaction for both TSH and TSI.

Role of the transgenic human thyrotropin receptor A-subunit in thyroiditis induced by A-subunit immunization and regulatory T cell depletion.

Transgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (T(reg)) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A-Z). In transgenic and WT mice, regardless of T(reg) depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After T(reg) depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4(+) T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA-d). High affinity subsequences (inhibitory concentration of 50% < 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.

Type B insulin resistance syndrome induced by increased activity of systemic lupus erythematosus in a hemodialysis patient.

A-23-year-old woman with systemic lupus erythematosus (SLE) and on hemodialysis for 5 years was admitted to the hospital because of severe general fatigue. On admission, laboratory findings showed that fasting plasma glucose levels ranged from 25 â 45 mg/dl, a test for antinuclear antibody (ANA) was positive (1 : 320, with a discrete-speckled pattern), serum C3 and C4 complement and CH50 level were remarkably depressed (22.5 mg/dl, < 5.1 mg/dl, < 13 U/ml, respectively), and insulin receptor antibodies were present (89.3% inhibition of 125I-insulin binding to cultured human lymphocytes by a binding inhibition assay). She also showed acanthosis nigricans. The patient was diagnosed to suffer from a Type B insulin resistance syndrome. The patient's serum insulin and C-peptide levels were markedly elevated during hypoglycemia without insulinoma (2,313.8 microU/ml, 55 ng/ml, respectively). Interestingly, not only postprandial hyperglycemia but also fasting hypoglycemia was observed. Treatment with steroid pulse and subsequent high dose of prednisolone resulted in restoration of euglycemia associated with disappearance of insulin receptor antibodies and improvement of both serum hypocomplementemia and the high titer of ANA. Later, the patient's course was complicated by hemorrhagic shock due to duodenal ulcer and she died of subsequent pneumocystis carinii pneumonia. The presented patient developed a Type B insulin resistance syndrome induced by increased activity of SLE after she had been treated with hemodialysis for 5 years. This is the first reported case with such a history and constellation. It is recommended that SLE patients on dialysis are carefully followed-up by clinical and serological monitoring. Type B insulin resistance syndrome must be considered in the differential diagnosis of hypoglycemia in SLE patients on dialysis.

Binding domains of stimulatory and inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-lutropin/chorionic gonadotropin receptors.

We examined the relative effects of thyrotropin (TSH) and TSH receptor autoantibodies in the sera of patients with autoimmune thyroid disease on three TSH-lutropin/chorionic gonadotropin (LH/CG) receptor extracellular domain chimeras. Each chimera binds TSH with high affinity. Only the chimera with TSH receptor extracellular domains ABC (amino acids 1-260) had a functional (cAMP) response to thyroid stimulatory IgG. The chimeras with TSH receptor domains CD (amino acids 171-360) and DE (amino acids 261-418) were unresponsive. The lack of response of the chimera with TSH receptor domains DE was anticipated because it fails to transduce a signal with TSH stimulation, unlike the other two chimeras. A different spectrum of responses occurred when the TSH-LH/CG chimeras were examined in terms of autoantibody competition for TSH binding. IgG with TSH binding-inhibitory activity when tested with the wild-type TSH receptor also inhibited TSH binding to the chimera with TSH receptor domains DE. Dramatically, however, these IgG did not inhibit TSH binding to the chimera with TSH receptor domains CD, and had weak or absent activity with the chimera with TSH receptor domains ABC. Chimeras with TSH receptor domains ABC and DE were equally effective in affinity-purifying IgG with thyroid-stimulatory and TSH binding-inhibitory activities. Nonstimulatory IgG with TSH binding-inhibitory activity inhibited the action of stimulatory IgG on the wild-type TSH receptor, but not with the chimera containing TSH receptor domains ABC. In summary, TSH receptor autoantibodies and TSH bind to regions in both domains ABC and DE of the TSH receptor extracellular region. Stimulatory and inhibitory TSH receptor autoantibodies, as well as TSH, appear to bind to different sites in domains ABC, but similar sites in domains DE, of the receptor. Alternatively, TSH and the different TSH receptor antibodies bind with differing affinities to the same site in the ABC region.

Development of 2-D horn-antenna millimeter-wave imaging device (HMID) for the plasma diagnostics.

The two-dimensional (2-D) Horn-antenna Millimeter-wave Imaging Device (HMID) has been developed for the O-mode Microwave Imaging Reflectometry (O-MIR) in the Large Helical Device (LHD). The detectable frequency range of the HMID is 23-33 GHz, which corresponds to the cutoff electron density of 0.8-1.5 × 1019 m-3 in the O-MIR. The HMID is a 2-D imaging device that improves on the horn-antenna mixer array, which had been developed for the X-mode MIR in the LHD. In the HMID, the signal (RF) wave from the horn antenna is transmitted to the microstrip line by the finline transmitter, and this is mixed by the double-balanced-mixer with the local oscillation wave that is fed by a coaxial cable. By using the HMID, the MIR optical system can be significantly simplified.