Quantitative assessment of outer retinal folds on enface optical coherence tomography after vitrectomy for rhegmatogenous retinal detachment.

We aimed to investigate the possible causes of metamorphopsia for rhegmatogenous retinal detachment (RRD) based on findings of enface optical coherence tomography (OCT). The study was a retrospective, consecutive case series of 33 eyes with macula-off RRD. Metamorphopsia was measured by M-CHARTS and enface OCT images covering a macular area of 6 × 6 mm square obtained at 1, 3, and 6 months postoperatively. Within the outer retinal slabs of enface OCT, multiple lines that looked like folds were delineated in all eyes at month 1, and we succeeded in extracting images of folds by subtracting retinal vessels. We calculated their density by an image-processing technique. The mean M-CHARTS scores were 0.62 ± 0.47 at month 1 and 0.30 ± 0.29 at month 6 (P < 0.001). The fold density was 8.3 ± 4.2 at month 1 and 6.1 ± 3.1 at month 6 (P = 0.0044). The M-CHARTS scores at 6 months were significantly associated with the fold density at 1 month (r = 0.515, P = 0.002). In conclusion, enface OCT visualized the outer retinal folds in eyes that had undergone successful RRD surgery, and a larger number of folds was related to the remaining metamorphopsia.

Generation of articulatory movements by using a kinematic triphone model.

The method described here predicts the trajectories of articulatory movements for continuous speech by using a kinematic triphone model and the minimum-acceleration model. The kinematic triphone model, which is constructed from articulatory data obtained from experiments using an electro-magnetic articulographic system, is characterized by three kinematic features of a triphone and by the intervals between two successive phonemes in the triphone. After a kinematic feature of a phoneme in a given sentence is extracted, the minimum-acceleration trajectory that coincides with the extremum of the time integral of the squared magnitude of the articulator acceleration is formulated. The calculation of the minimum acceleration requires only linear computation. The method predicts both the qualitative features and the quantitative details of experimentally observed articulation.

Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily. Specialized binding regions for transforming growth factor-beta and inhibin A.

Betaglycan, also known as the transforming growth factor-beta (TGF-beta) type III receptor, is a membrane-anchored proteoglycan that binds TGF-beta via its core protein. Deletion mutagenesis analysis has revealed two regions of betaglycan ectodomain capable of binding TGF-beta: one at the amino-terminal half, the endoglin-related region (López-Casillas, F., Payne, H., Andres, J. L., and Massagué, J. (1994) J. Cell Biol. 124, 557-568), and the other at the carboxyl-terminal half, the uromodulin-related region (Pepin, M.-C., Beauchemin, M., Plamondon, J., and O'Connor-McCourt, M. D. (1994) Proc. Natl. Acad. Sci. U. S. A 91, 6997-7001). In the present work we have functionally characterized these ligand binding regions. Similar to the wild type receptor, both regions bind TGF-beta2 with higher affinity than TGF-beta1. However, only the endoglin-related region increases the TGF-beta2 labeling of the TGF-beta type II receptor, the so-called "TGF-beta -presentation" function of the wild type receptor. Despite this preference, both regions as well as the wild type receptor mediate the TGF-beta2-dependent Smad2 phosphorylation, indicating that they can function indistinguishably as TGF-beta-enhancing co-receptors. On the other hand, we found that the recently described ability of the wild type betaglycan to bind inhibin A is a property of the core protein that resides in the uromodulin-related region. Binding competition experiments indicate that this region binds inhibin and TGF-beta with the following relative affinities: TGF-beta2 > inhibin A > TGF-beta1. All together, the present results suggest that betaglycan ectodomain is endowed with two bona fide independent ligand binding domains that can perform specialized functions as co-receptors of distinct members of the TGF-beta superfamily.

Kinematic construction of the trajectory of sequential arm movements.

A kinematic construction rule determining the trajectory of human sequential movements is formulated using minimum-jerk and minimum-angular-jerk trajectories. The kinematic construction rule states that the observed trajectory of sequential movements coincides with a weighted average of the minimum-jerk trajectory and the segmented minimum-angular-jerk trajectory. This rule covers not only point-to-point movements but also simple sequential movements. Five kinds of experiments that measure the trajectories in planar, multijoint sequential arm movements were conducted. The measured trajectories coincide with the predictions made on the basis of the kinematic construction rule presented here. Moreover, predictions of previous models such as the minimum-jerk, the equilibrium-trajectory, and the minimum-torque-change models are shown to be incompatible with our observations of sequential movements.

A novel type I receptor serine-threonine kinase predominantly expressed in the adult central nervous system.

Receptor serine-threonine kinases (RSTK) mediate inhibitory as well as stimulatory signals for growth and differentiation by binding to members of the transforming growth factor-beta (TGF-beta) superfamily. Over 12 different RSTKs have been isolated so far, displaying wide expression in peripheral tissues and in the nervous system. Here we report the isolation and characterization of a novel type I RSTK termed activin receptor-like kinase-7 (ALK-7) that, unlike other members of this receptor family, is predominantly expressed in the adult central nervous system. The ALK-7 gene encodes a 55-kDa cell-surface protein that exhibits up to 78% amino acid sequence identity in the kinase domain to previously isolated type I receptors for TGF-beta and activin. In the extracellular domain, however, ALK-7 is more divergent, displaying comparable similarities with all members of the ALK subfamily. RNase protection and in situ hybridization studies demonstrated a highly specific mRNA distribution restricted to neurons in several regions of the adult rat central nervous system, including cerebellum, hippocampus, and nuclei of the brainstem. Receptor reconstitution and cross-linking experiments indicated that ALK-7 can form complexes with type II RSTKs for TGF-beta and activin in a ligand-dependent manner, although direct binding of ALK-7 to ligand in these complexes could not be demonstrated. The specific expression pattern of ALK-7, restricted to the postnatal central nervous system, indicates that this receptor may play an important role in the maturation and maintenance of several neuronal subpopulations.

Characterization of the interaction of FKBP12 with the transforming growth factor-beta type I receptor in vivo.

The type I transforming growth factor-beta receptor (TbetaR-I) is the efferent component of the receptor complex, which presumably phosphorylates intracellular targets. FKBP12, a binding protein for FK506 and rapamycin, is shown to associate with the cytoplasmic region of TbetaR-I in vitro. In this report, we investigated the interaction of FKBP12 with TbetaR-I in vivo. FKBP12 interacts with TbetaR-I in mammalian cells as well as in yeast. Ligand addition does not affect the interaction, and both constitutively active and kinase-negative mutants of TbetaR-I bind FKBP12. FKBP12 dissociates from TbetaR-I in the presence of a high concentration of FK506. The juxtamembrane region of TbetaR-I, containing the major phosphorylation sites by the type II receptor, is required for the interaction. One of the deletion mutants in this region, which was shown to mediate transcriptional response, does not bind FKBP12, suggesting that FKBP12 is not directly involved in TGF-beta signaling. Furthermore TbetaR-I does not phosphorylate FKBP12 in vitro. FKBP12 may not be a direct substrate of TbetaR-I but possibly modulates the TbetaR-I function through its interaction with the regulatory domain of the kinase.

Human T-cell lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis with acute type of adult T-cell leukemia.

We report a 47-year-old Japanese woman with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) combined with acute type adult T-cell leukemia (ATL). The susceptibility for HAM/TSP and acute type of ATL is hitherto explained by human leukocyte antigen (HLA) haplotype-linked immune responsiveness to HTLV-I. This patient's HLA (A24Cw1B54DR4DQ4/A24Cw3B51DR8DQ1) included a HAM-associated HLA haplotype. This suggests that HAM patients with HAM-associated HLA haplotype can also develop the acute type of ATL.

Cloning and characterization of a human type II receptor for bone morphogenetic proteins.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta superfamily. Several members of this family have been shown to transduce their signals through binding to type I and type II serine-(threonine) kinase receptors. Here we report the cDNA cloning and characterization of a human type II receptor for BMPs (BMPR-II), which is distantly related to DAF-4, a BMP type II receptor from Caenorhabditis elegans. In transfected COS-1 cells, osteogenic protein (OP)-1/BMP-7, and less efficiently BMP-4, bound to BMPR-II. BMPR-II bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type I receptors for BMPs. Binding of OP-1/BMP-7 to BMPR-II was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by BMPR-II in the presence of type I receptors after stimulation by OP-1/BMP-7.

A rat pituitary tumor cell line (GH3) expresses type I and type II receptors and other cell surface binding protein(s) for transforming growth factor-beta.

A rat pituitary tumor cell line (GH3) has been reported to express transforming growth factor-beta (TGF-beta) binding components of 70-74 kDa (ligand included), denoted TGF-beta type IV receptor. We investigated whether the type IV receptor corresponds to any of the recently cloned type I receptors for proteins in the TGF-beta super-family. TGF-beta type I receptor (T beta R-I) complexes of 69-72 kDa formed a heteromeric complex with T beta R-II in GH3 cells, as detected by immunoprecipitation. In addition, TGF-beta formed complexes of 72-74 kDa, which were different from T beta R-I and the other known type I receptors, and were not dependent on T beta R-II for binding. The GH3 cells were resistant to the growth inhibitory activity of TGF-beta, but a transcriptional response was activated by TGF-beta in this cell line, presumably through the T beta R-II and T beta R-I complex. These results indicate that GH3 cells have T beta R-I and T beta R-II and, in addition, other binding protein(s) which form 72-74-kDa complexes with TGF-beta; the function of the latter component(s) remains to be elucidated.

Distinct roles of the intracellular domains of transforming growth factor-beta type I and type II receptors in signal transduction.

Transforming growth factor-beta (TGF-beta) transduces signals through binding to type I (T beta R-I) and type II (T beta R-II) serine/threonine kinase receptors. T beta R-I requires T beta R-II for ligand binding, whereas T beta R-II requires T beta R-I for signaling. We generated two different chimeric TGF-beta receptors, i.e. T beta R-1.2 containing the extracellular domain of T beta R-I and the intracellular domain of T beta R-II, and T beta R-2.1 containing the extracellular domain of T beta R-II and the intracellular domain of T beta R-I. T beta R-2.1 bound 125I-TGF-beta 1 alone, whereas T beta R-1.2 bound the ligand only in the presence of T beta R-II or T beta R-2.1. When transfected into a mutant mink lung epithelial cell line that lacks functional T beta R-II, T beta R-II cDNA, but not T beta R-2.1 cDNA, restored the responsiveness to TGF-beta 1 with regard to transcriptional activation of plasminogen activator inhibitor-1 gene promoter and 12-O-tetradecanoylphorbol-13-acetate-responsive elements. In a mutant mink lung epithelial cell line lacking T beta R-I, T beta R-I cDNA stimulated promoter activity, but the T beta R-1.2 cDNA did not. T beta R-2.1 formed an oligomer with T beta R-II when transfected into COS cells, but the complex did not transduce the signal after ligand stimulation. On the other hand, co-transfection of T beta R-1.2 and T beta R-2.1 cDNAs restored the responsiveness to TGF-beta 1. These results indicate that an interaction between the intracellular regions of T beta R-I and T beta R-II, triggered by ligand binding to the extracellular domains of these receptors, leads to efficient signal transduction by TGF-beta.

Urinary excretion of parathyroid hormone-related protein as a predictor of hypercalcemia in patients with adult T-cell leukemia.

Hypercalcemia with adult T-cell leukemia (ATL) is chiefly caused by an excessive production by tumor cells of parathyroid hormone-related protein (PTHrP). We have previously reported hypercalcemic patients with solid tumors to excrete a large amount of the C-terminal fragments of PTHrP (C-PTHrP) into their urine. To elucidate whether PTHrP production correlates with or predicts the development of hypercalcemia, we studied the urinary excretion of C-PTHrP in 36 ATL patients. The urinary excretion of C-PTHrP was in the normal range (< 0.40 nmol equivalent to PTHrP (109-141)/g creatinine) in HTLV-1-positive carriers (n 3), ATL patients in complete remission (n 2) and chronic type ATL patients (n 2). It was marginally increased in seven patients in partial remission, and gradually increased as the disease progressed. In 20 patients who died without or with hypercalcemia, it was increased to 1.98 +/- 0.69 (n 9) and 7.6 +/- 2.1 nmol/g creatinine (mean +/- SD, n 11, P < 0.01), respectively. Urinary C-PTHrP excretion was significantly correlated with serum calcium and LDH levels as well as with CD25-positive cells in the peripheral blood. In four patients whose urinary excretion had been serially determined, it increased prior to the development of hypercalcemia. The findings suggest the urinary excretion of C-PTHrP to be of use as a predictor of the development of hypercalcemia in ATL patients. In ATL patients whose urinary excretion of C-PTHrP is progressively increasing, the serum calcium concentration should be carefully monitored to prevent hypercalcemic crisis.

Immunocytochemical study on endothelial markers with the cerebral vessel from a patient with familial moyamoya disease.

The immunocytochemical study of thrombomodulin (TM), a newly recognized anticoagulant endothelial surface protein, was performed with a surgical specimen of a superficial temporal artery (STA) obtained from a 29-year-old woman with familial moyamoya disease. The staining of TM showed positive immunoreactivity in smaller vessels in the surrounding connective tissue of the specimen, whereas negative in STA. Immunoelectronmicroscopically the luminal plasma membrane of endothelial cells was positive for TM. These staining pattern was the same as that in controls. She concurrently suffered from von Willebrand disease type I, and she had two cerebral hemorrhagic attacks. A quantitative defect of the von Willebrand factor in the endothelium was demonstrated immunocytochemically.

[A case of scapuloperoneal atrophy with rigid spine having lobulated fibers in muscle biopsy].

The patient, a 52-year-old male, noticed abnormalities on walking at about 20 years of age, followed by slowly progressive muscle weakness of arms and neck. The family history was negative. He showed muscular atrophy and weakness with a preferential involvement of the scapular, arms and peroneal muscles. Deep tendon reflexes were absent. He had a limited range of motion in the spine, but the onset was unclear. Creatine kinase (CK) was elevated (324 IU/L) and the EMG study showed myogenic pattern. Muscle biopsy was obtained from the biceps brachii muscle; on NADH dehydrogenase stain, there was subsarcolemmal increase in the oxidative enzyme activity showing "lobulated fiber" mostly seen in type 1 fibers. On electron-microscopy, the sub-sarcoplasmic areas which had high NADH activity, contained many mitochondria and glycogen particles. However, iodine-glycogen complex spectrum analysis pattern and debranching enzyme activity were normal. CT scan revealed low density in the paravertebral muscles, suggesting degeneration. This is a rare type of scapuloperoneal atrophy different from Emery-Dreifuss syndrome, rigid spine syndrome and FSH type muscular dystrophy.

[A study on the frequency of von Willebrand factor deficiency state].

In order to elucidate the prevalence of von Willebrand factor (vWF) deficiency state, we investigated plasma vWF levels among 343 patients with bleeding tendency, 465 patients without bleeding tendency and 704 random unrelated normals living in Kagoshima prefecture. The prevalence of symptomatic vWF deficiency state was at least 2.3 per 100,000 of the population, and that of asymptomatic one in healthy individuals was 1.3%. These results indicate that the overall incidence of vWF deficient state in general population would be considerably higher than that previously reported.

[T-cell malignant lymphoma with hemophagocytic histiocytosis, hyperferritinemia and disseminated intravascular coagulation syndrome].

A 57-year-old man was admitted to our hospital with high fever and nasal obstruction. The diagnosis of T cell type malignant lymphoma (T-ML) was made by the biopsy of left nasal cavity tumor. After admission, his general condition was improved by chemotherapy and radiotherapy, but relapsed a month later. He was then treated with chemotherapy, and the partial remission was obtained. During the clinical course, he had a high fever again without any significant infections or exacerbation of T-ML. The data of coagulation system showed DIC. The levels of serum ferritin and LDH were extremely elevated. Bone marrow aspiration showed markedly increased hemophagocytic histiocytes. These data suggested that he was complicated by DIC and hyperferritinemia closely associated with hemophagocytic histiocytosis a part from the underlying T-ML. Causes of DIC and hyperferritinemia associated with hemophagocytic histiocytosis in the present case were discussed.

[Pure red cell aplasia with monoclonal gammopathy and von Willebrand disease].

We report a case of pure red cell aplasia (PRCA) with benign monoclonal gammopathy (BMG) of IgA.lambda type and type I von Willebrand disease (vWD). A 61-year-old female patient was treated initially with prednisolone, azathioprine and cyclophosphamide with transient and unsatisfactory reticulocyte response. Oral administration of 200 mg of cyclosporine A (CyA)/day was started from July, 1987. A rapid and marked reticulocytosis was seen from a week later and there was a rapid increase in hemoglobin levels, and remission has been maintained for over 22 months. Patient's serum and IgA taken on admission did not show inhibitory activity to both CFU-E growth from her own bone marrow cells obtained in remission and von Willebrand factor. T cell-mediated suppression to CFU-E growth was detected. On family study, the patient's second son was found to be a type I vWD. These results indicate that there is no direct causal relationships between BMG and PRCA or vWD, and that CyA may have a place in the management of PRCA.

[A family with von Willebrand disease and hypofibrinogenemia].

A family with two complex disorders of hemostasis, von Willebrand disease (vWD) and hypofibrinogenemia was reported. The probands were 21- and 16-year-old full brothers suffering from serious bleeding tendencies from childhood. The elder brother had a subarachnoid hemorrhage at the age of 15. The younger brother had repeated episodes of gastrointestinal bleedings since he was 10 years of age. Coagulation studies revealed that both of them had almost the same hemostatic abnormalities, i.e. severe vWD, 9 to 12% of plasma vWF levels, and mild hypofibrinogenemia, 125 to 130 mg/dl of plasma fibrinogen levels. Multimeric compositions of their vWF were normal, and functional assay for fibrinogen concentration yielded essentially the same values as did immunologic assay. These results indicated that they had two complex disorders, extreme type I vWD and heterozygous state of afibrinogenemia resulting in serious bleeding tendency. Family study showed that these two hemostatic disorders were paternal inheritance, and it was strongly postulated that vWD and hypofibrinogenemia might be highly-combined hemostatic disorders.

[Fetal survival after the corticosteroid and low-dose aspirin regimen in a case of anti-phospholipid antibody syndrome].

A 27-year-old woman with anti-phospholipid antibody syndrome, whose first pregnancy had ended in intrauterine fetal death, was treated with prednisolone 0.6 mg/kg/day before second pregnancy. Suppression of anti-cardiolipin antibody activity was rapidly achieved and maintained during the pregnancy. After conception, low-dose aspirin 81 mg/day was started and continued until delivery. She gave birth to a normal live infant with natural full-term delivery. It is strongly suggested that the corticosteroid and low-dose aspirin regimen can lead to successful pregnancy in cases with anti-phospholipid antibody syndrome like the present case.

[Clinical characteristics of anti-phospholipid antibodies].

Twenty-one patients with anti-phospholipid antibodies (APLA), who were selected from 104 patients with antinuclear antibody or anti-DNA antibody, were studied to define clinical characteristics of APLA. Of the 21 patients, the incidences of IgG anti-cardiolipin antibody (ACA), IgM ACA, lupus anticoagulant (LAC) and BFP-STS were 20, 7, 11 and 12, respectively, and they were highly related with each other. The number of items of the 1982 ARA revised criteria for the classification of SLE was significantly low (mean value = 3.3), and also the level of serum C 4 was significantly high (mean value = 88% of normal) compared with those in patients without APLA. The incidence of thrombocytopenia and hemolysis was significantly high when compared with those in patients without APLA, and they were closely related to the presence of LAC. The incidence of thrombosis was markedly high (48%), 10 of 21 patients, especially those of cerebral infarction and deep vein thrombosis. Cerebral infarction was significantly associated with LAC. The obstetric complication was 4 of 13 patients (31%) in the incidence, which was significantly high compared with that in patients without APLA. Of them, natural abortion was closely associated with LAC. Based on these observations, it seems that autoimmunological disease activity in patients with APLA may be slight to mild, and strongly suggested that APLA may play an important role particularly in the pathogenesis of acquired thrombotic tendency.