Regional alterations of myocardial norepinephrine transporter density in streptozotocin-induced diabetic rats: implications for heterogeneous cardiac accumulation of MIBG in diabetes

Cardiac scintigraphic studies using iodine-123 labeled metaiodobenzylguanidine ([¹²³I]MIBG) have previously demonstrated the heterogeneous myocardial accumulation of radioactivity in diabetes. In this study, we investigated the myocardial regional distribution of [¹²⁵I]MIBG and the effects of regional myocardial blood flow, myocardial norepinephrine (NE) content, and norepinephrine transporter (NET) function on regional [¹²⁵I]MIBG accumulation in streptozotocin-induced diabetic (STZ-D) rats. Dual-isotope autoradiographic studies using [¹²⁵I]MIBG and technetium-99m labeled hexakis (2-methoxy-2-isobutylisonitrile) (^99mTc-MIBI), a tracer for the measurement of myocardial blood flow, were carried out to investigate the changes in regional myocardial blood flow in STZ-D rats. Uptake of [¹²⁵I]MIBG was similar between the anterior wall and the inferior wall in control rats. On the other hand, in STZ-D rats, uptake of [¹²⁵I]MIBG in the inferior wall was significantly less than that in the anterior wall. Uptake of ^99mTc-MIBI was not significantly different between the anterior and inferior walls in control or STZ-D rats, indicating that myocardial blood flow did not change regionally in either control or STZ-D rats, and that the blood flow was not responsible for the heterogeneity of the distribution of [¹²⁵I]MIBG in STZ-D rats. In STZ-D rats, cardiac NE concentrations determined using an HPLC-electrochemical detection (ECD) system were significantly increased in both the anterior and the inferior wall, although there was no significant difference in NE concentration between the anterior and inferior walls in control or STZ-D rats. Furthermore, the density and affinity of NET were investigated by studying the binding of [³H]desipramine to cardiac membranes. The B_max values of the NET in the anterior wall were not significantly different between control and STZ-D rats, but the B_max value of the NET in the inferior wall was significantly lower in STZ-D rats than in controls. In conclusion, myocardial MIBG uptake was reduced in the inferior wall of STZ-D rats compared with control rats; this decrease was correlated with the decrease in NET density, but was not dependent on the regional myocardial blood flow and NE concentration. These results suggest that regional fluctuations in NET levels in the inferior wall contribute to heterogeneous MIBG accumulation in diabetes.     

Two cases of reactive hemophagocytic syndrome: a patient with adult-onset Still's disease and a patient with herpes zoster and autoimmune abnormalities

We report two cases of bone marrow hemophagocytosis. One patient had adult-onset Still's disease, and the other had herpes zoster associated with potential autoimmune abnormalities. Our findings suggested a pos-sible role of cytokines and/or antibodies in the induction of hemophagocytosis in patients with connective tissue diseases and/or immune abnormalities. Received: November 28, 2000 / Accepted: March 12, 2001     

Function of oleic acid on epidermal barrier and calcium influx into keratinocytes is associated with N-methyl D-aspartate-type glutamate receptors

Background  Unsaturated fatty acids from sebum affect calcium dynamics in epidermal keratinocytes, disrupt the barrier function and induce abnormal keratinization. However, the mechanisms of these effects have not been clarified.
Objectives  To investigate the function of unsaturated fatty acids in epidermis.
Methods  Antagonists of calcium channel receptors were applied to mouse skin together with oleic acid. Measurements were made of transepidermal water loss (TEWL), and hyperproliferation was assessed. The effects of the antagonists on calcium influx into cultured normal human keratinocytes and on cytokine production were also evaluated.
Results  N -methyl- d -aspartate (NMDA) receptor antagonists such as MK801 and D-AP5 specifically inhibited the increase in TEWL caused by oleic acid, and suppressed keratinocyte hyperproliferation. These compounds also inhibited the increase in the intracellular concentration of calcium ions induced by oleic acid. MK801 suppressed the production of interleukin-1α by keratinocytes induced by oleic acid.
Conclusions  Unsaturated fatty acids such as oleic acid might function via NMDA receptors.     

Adjuvant effect of lipopolysaccharide on the induction of contact hypersensitivity to haptens in mice

BACKGROUND: Toll-like receptor (TLR) 4 is a critical receptor and signal transducer for lipopolysaccharide (LPS), a major component of Gram-negative bacteria. The MyD88-independent pathway downstream of TLR4 leads to functional dendritic cell (DC) maturation, although LPS-induced cytokine production from DCs is MyD88-dependent. OBJECTIVES: We investigated whether intracutaneously injected LPS alters the functions of cutaneous DCs, leading to enhanced contact hypersensitivity (CH). METHODS: The ear swelling response was measured to evaluate the magnitude of CH. Cell proliferation of allogeneic splenocytes stimulated by DC-enriched draining lymph node (LN) cells was measured by performing a [(3)H]-thymidine incorporation assay. Epidermal I-A+ cells were evaluated under an epifluorescent microscope. I-A+ FITC-bearing cells from the draining LNs 24h after FITC application were analyzed on FACScan. RESULTS: LPS augmented CH induction in C3H/HeN (HeN) and MyD88-knockout (KO) mice but not in C3H/HeJ (HeJ) and H-2S(d)-bearing strains such as BALB/c mice. LPS failed to augment the allo-stimulatory ability of DCs in the draining LNs after hapten applications. LPS altered the density and morphology of epidermal I-A+ cell in HeN and BALB/c mice but not in TLR4-deficient HeJ mice. LPS increased the proportion of I-A+ FITC-bearing cells in the LNs 24h after FITC application in HeN, but not in BALB/c and HeJ. CONCLUSIONS: LPS augments the ability of DCs to migrate to the draining LNs, leading to enhanced CH via a TLR4-dependent, MyD88-independent pathway. The different effects of LPS on CH in some strains of mice may explain individual differences in the susceptibility to establish CH to daily antigen exposures in clinical settings.     

Two mechanisms of the enhanced antibody-dependent cellular cytotoxicity (ADCC) efficacy of non-fucosylated therapeutic antibodies in human blood

Background  

Antibody-dependent cellular cytotoxicity (ADCC) has recently been identified as one of the critical mechanisms underlying the clinical efficacy of therapeutic antibodies, especially anticancer antibodies. Therapeutic antibodies fully lacking the core fucose of the Fc oligosaccharides have been found to exhibit much higher ADCC in humans than their fucosylated counterparts. However, data which show how fully non-fucosylated antibodies achieve such a high ADCC in human whole blood have not yet been disclosed. The precise mechanisms responsible for the high ADCC mediated by fully non-fucosylated therapeutic antibodies, even in the presence of human plasma, should be explained based on direct evidence of non-fucosylated antibody action in human blood.     

Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity

Objective  Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 (⁹⁰Y)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of ⁹⁰Y-MAb 92-13. Methods  FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with ⁹⁰Y-MAb 92-13 in vitro. Biodistribution study of indium-111 (¹¹¹In)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with ⁹⁰Y-MAb 92-13 (100, 150, and 200 μCi), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor. Results  Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of ¹¹¹In-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0 ± 4.2 and 22.0 ± 4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with ⁹⁰Y-MAb 92-13 (tumor volume decreased to less than 0.1 cm³ at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with ⁹⁰Y-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor. Conclusions  The therapeutic efficacy of RIT seems to largely depend on the tumor radiosensitivity.     

Facial dismasking flap for removal of tumors in the craniofacial region

OBJECTIVE: This study was aimed at estimating the usefulness of the facial dismasking flap for craniofacial surgery. STUDY DESIGN: Anatomical study and retrospective case study. MATERIALS AND METHODS: The facial dismasking flap is a combination of a coronal skin incision and a circumpalpebral incision. By adding a circumpalpebral incision, the skin can be detached from the orbital structures and the coronal skin flap can be elevated more inferiorly together with the facial nerves and muscles. We retrospectively reviewed patients who underwent the facial dismasking flap with regard to the extent of the surgical field and resectability under this flap. Postoperative facial scarring and movements were also evaluated. Facial palsy was estimated according to the House-Brackmann grading system. RESULT: Twenty-three patients with tumors in various locations, such as, the nasal cavity, paranasal sinus, zygoma, and infratemporal fossa, who had undergone a facial dismasking flap, were studied. Sufficient surgical fields were obtained for removal of the tumor in all patients. Tumors were totally resected in 21 patients and were subtotally resected in two patients to avoid optic nerve damage. Facial nerves were anatomically preserved and facial scarring was minimal in all patients. No facial palsy remained in any patients except one who showed a deterioration of the facial palsy (House-Brackmann grade V-VI). CONCLUSION: This flap allows the surgeon to obtain wide exposure of the upper two-thirds of the facial skull. Moreover, damage to the facial skin is minimal and facial movements are well preserved. This technique is not well known to head and neck surgeons, and this is the first comprehensive report of this technique applied to removal of craniofacial lesions.