Axonal TDP-43 aggregates in sporadic amyotrophic lateral sclerosis.

AIMS: Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system. METHODS: Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course. RESULTS: (i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features - dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident. CONCLUSIONS: There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones.

Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma.

BACKGROUND: Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. OBJECTIVE: We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. METHODS: In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. RESULTS: High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. CONCLUSION AND CLINICAL RELEVANCE: IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

Increased Facet Fluid Predicts Dynamic Changes in the Dural Sac Size on Axial-Loaded MRI in Patients with Lumbar Spinal Canal Stenosis.

BACKGROUND AND PURPOSE: Axial-loaded MR imaging, which simulates the spinal canal in a standing position, demonstrates reductions of the dural sac cross-sectional area in patients with lumbar spinal canal stenosis. However, there has been no useful conventional MR imaging finding for predicting a reduction in the dural sac cross-sectional area on axial-loaded MR imaging. Previous studies have shown that increased facet fluid is associated with the spinal instability detected during positional changes. The purpose of this study was to analyze the correlations between facet fluid and dynamic changes in the dural sac cross-sectional area on axial-loaded MR imaging. MATERIALS AND METHODS: In 93 patients with lumbar spinal canal stenosis, the dural sac cross-sectional area was measured by using axial images of conventional and axial-loaded MR imaging. Changes in the dural sac cross-sectional area induced by axial loading were calculated. The correlation between the facet fluid width measured on conventional MR imaging and the change in dural sac cross-sectional area was analyzed. The change in the dural sac cross-sectional area was compared between the intervertebral levels with and without the facet fluid width that was over the cutoff value determined in this study. RESULTS: The dural sac cross-sectional area was significantly smaller on axial-loaded MR imaging than on conventional MR imaging. The facet fluid width significantly correlated with the change in the dural sac cross-sectional area (r = 0.73, P < .001). The change in the dural sac cross-sectional area at the intervertebral level with the facet fluid width over the cutoff value was significantly greater than that at the other level. CONCLUSIONS: The increased facet fluid on conventional MR imaging is highly predictive of the dynamic reduction of dural sac cross-sectional area detected on axial-loaded MR imaging in the clinical assessment of lumbar spinal canal stenosis.

Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET.

Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX) is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative (KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3'-UTR of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore, co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX will increase PTX efficacy.

Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1α expression in patients with glioma.

BACKGROUND AND PURPOSE: Hypoxic tissue evaluation in glioma is important for predicting treatment response and establishing antihypoxia therapy. In this preliminary study, (62)Cu-ATSM PET was used to determine its validity as a biomarker for distinguishing tumor grade and tissue hypoxia. MATERIALS AND METHODS: (62)Cu-ATSM PET was performed in 22 patients with glioma, and the (62)Cu-ATSM SUV(max) and T/B ratio were semiquantitatively evaluated. (62)Cu-ATSM uptake distribution was qualitatively evaluated and compared with MR imaging findings. HIF-1α expression, a hypoxia marker, was compared with (62)Cu-ATSM uptake values. RESULTS: The (62)Cu-ATSM SUV(max) and T/B ratio were significantly higher in grade IV than in grade III gliomas (P = .014 and .018, respectively), whereas no significant differences were found between grade III and grade II gliomas. At a T/B ratio cutoff threshold of 1.8, (62)Cu-ATSM uptake was predictive of HIF-1α expression, with 92.3% sensitivity and 88.9% specificity. The mean T/B ratio was also significantly higher in HIF-1α-positive glioma tissue than in HIF-1α-negative tissue (P = .001). Using this optimal threshold of T/B ratio, (62)Cu-ATSM PET showed regional uptake in 61.9% (13/21) of tumors within the contrast-enhanced region on MR imaging, which was significantly correlated with presence of a necrotic component (P = .002). CONCLUSIONS: Our results demonstrated that (62)Cu-ATSM uptake is relatively high in grade IV gliomas and correlates with the MR imaging findings of necrosis. Moreover, the (62)Cu-ATSM T/B ratio showed significant correlation with HIF-1α expression. Thus, (62)Cu-ATSM appears to be a suitable biomarker for predicting highly malignant grades and tissue hypoxia in patients with glioma.

Supercooling and vitrification of aqueous glycerol solutions at normal and high pressures.

The supercooling and vitrification of aqueous glycerol solutions was studied at high pressures. Homogeneous ice nucleation temperatures (T(H)) were obtained for aqueous glycerol solutions of R=50, 30, 20, 12, and 10 (R: moles of water/moles of glycerol) up to 300MPa. The R=20 glycerol solution formed a glass above 200MPa at a cooling rate of 200°C/min, indicating that pressure enhances glass-formation of aqueous glycerol solutions. The (dT(g)/dP) values were obtained for vitrified aqueous glycerol solutions of R=3, 5, 10, and 20. These data can be used for the development of cryo-preservation liquids for living cells at high pressures.

Dynamic changes in the dural sac cross-sectional area on axial loaded MR imaging: is there a difference between degenerative spondylolisthesis and spinal stenosis?

BACKGROUND AND PURPOSE: Axial loaded MR imaging, which can simulate the spinal canal of patients in a standing position, demonstrates a significant reduction of the DCSA compared with conventional MR imaging and provides valuable imaging findings in the assessment of the lumbar spinal canal. The purpose of this study was to compare the DCSA on axial loaded MR imaging between patients with DS and SpS. MATERIALS AND METHODS: Eighty-eight consecutive patients were divided into DS and SpS groups. DCSA on conventional MR imaging and axial loaded MR imaging and changes in the DCSA induced by axial loading were compared between DS and SpS groups. The prevalence of a significant change (>15 mm(2)) in the DCSA was compared between the 2 groups. RESULTS: Axial loaded MR imaging demonstrated significantly smaller DCSA in the DS group (35 ± 22 mm(2)) than in the SpS group (50 ± 31 mm(2)), though conventional MR imaging did not show any differences between the 2 groups. The change in the DCSA induced by axial loading was significantly larger in the DS group (17 ± 12 mm(2)) compared with the SpS group (8 ± 8 mm(2)). The prevalence of a >15-mm(2) change in the DCSA was significantly higher in the DS group (62.5%) than in the SpS group (16.7%) (odds ratio, 8.33; 95% confidence interval, 3.09-22.50). CONCLUSIONS: Axial loaded MR imaging demonstrated significantly larger changes in the DCSA in patients with DS compared those with SpS. A significant change in the DCSA was more frequently observed in patients with DS. Axial loaded MR imaging may therefore be a more useful tool to decrease the risk of underestimating the spinal canal narrowing in patients with DS than in those with SpS.

Geissoschizine methyl ether, an alkaloid in Uncaria hook, is a potent serotonin 1A receptor agonist and candidate for amelioration of aggressiveness and sociality by yokukansan.

Yokukansan (YKS), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situation for treating psychiatric disorders such as aggressiveness in patients with dementia. We previously demonstrated that YKS and Uncaria hook (UH), which is a constituent herb of YKS, had a partial agonistic effect to 5-HT(1A) receptors in vitro. However, it has still been unclear whether this in vitro effect is reflected in in vivo, and what the active ingredients are. The purpose of the present study is to find the active ingredient in YKS and to demonstrate the effect in in vivo. In the present study, we first studied the effect of YKS and UH on aggressiveness and sociality in socially isolated mice. YKS and UH ameliorated the isolation-induced increased aggressiveness and decreased sociality, and these ameliorative effects were counteracted by coadministration of 5-HT(1A) receptor antagonist WAY-100635, or disappeared by eliminating UH from YKS. These results suggest that the effect of YKS is mainly attributed to UH, and the active ingredient is contained in UH. To find the candidate ingredients, we examined competitive binding assay and [(35)S] guanosine 5'-O-(3-thiotriphosphate) (GTPγS) binding assay of seven major alkaloids in UH using Chinese hamster ovary cells expressing 5-HT(1A) receptors artificially. Only geissoschizine methyl ether (GM) among seven alkaloids potently bound to 5-HT(1A) receptors and acted as a partial agonist. This in vitro result on GM was further demonstrated in the socially isolated mice. As did YKS and UH, GM ameliorated the isolation-induced increased aggressiveness and decreased sociality, and the effect was counteracted by coadministration of WAY-100635. These lines of results suggest that GM in UH is potent 5-HT(1A) receptor agonist and a candidate for pharmacological effect of YKS on aggressiveness and sociality in socially isolated mice.

Supercooling of aqueous dimethylsulfoxide solution at normal and high pressures: Evidence for the coexistence of phase-separated aqueous dimethylsulfoxide solutions of different water structures.

Supercooling behavior of aqueous dimethylsulfoxide (DMSO) solution was investigated as a function of DMSO concentration and at high pressures. A linear relationship was observed for T(H) (homogeneous ice nucleation temperature) and T(m) (melting temperature) for the supercooling of aqueous DMSO solution at normal pressure. Analysis of the DTA (differential thermal analysis) traces for homogeneous ice crystallization in the bottom region of the T(H) curve for a DMSO solution of R=20 (R: moles of water/moles of DMSO) at high pressures supported the contention that the second critical point (SCP) of liquid water should exist at P(c2)= approximately 200 MPa and at T(c2)<-100 degrees C (P(c2): pressure of SCP, T(c2): temperature of SCP). The presence of two T(H) peaks for DMSO solutions (R=15, 12, and 10) suggests that phase separation occurs in aqueous DMSO solution (R

Efficient growth inhibition of human osteosarcoma cells using a peptide derived from the MDM-2-binding site of p53.

Protein transduction therapy is a promising alternative to gene therapy, but has not previously been investigated for osteosarcoma. We here demonstrate efficient growth inhibition of human osteosarcoma cells using a p53 peptide. Our result suggests that protein transduction therapy has significant potential as a novel therapeutic approach for osteosarcoma.

Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells.

To clarify the mechanism of yokukansan (TJ-54), a traditional Japanese medicine, against glutamate-mediated excitotoxicity, the effects of TJ-54 on glutamate uptake function were first examined using cultured rat cortical astrocytes. Under thiamine-deficient conditions, the uptake of glutamate into astrocytes, and the levels of proteins and mRNA expressions of glutamate aspartate transporter of astrocytes significantly decreased. These decreases were ameliorated in a dose-dependent manner by treatment with TJ-54 (100-700 microg/ml). The improvement of glutamate uptake with TJ-54 was completely blocked by the glutamate transporter inhibitor DL-threo-beta-hydroxyaspartic acid. Effects of TJ-54 on glutamate-induced neuronal death were next examined by using cultured PC12 cells as a model for neurons. Addition of 17.5 mM glutamate to the culture medium induced an approximately 50% cell death, as evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TJ-54 (1-1000 microg/ml) inhibited the cell death in a dose-dependent manner. Furthermore, competitive binding assays to glutamate receptors showed that TJ-54 bound potently to N-methyl-D-aspartate receptors, in particular, to its glutamate and glycine recognition sites. These results suggest that TJ-54 may exert a neuroprotective effect against glutamate-induced excitotoxicity not only by amelioration of dysfunction of astrocytes but also by direct protection of neuronal cells.

Spinal cord hemangioblastomas in von Hippel-Lindau disease.

STUDY DESIGN: Retrospective data analysis. OBJECTIVE: To clarify the clinical features and surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease (VHL). SETTING: Clinical VHL Research Group in Japan, Japan. METHODS: Forty-eight out of 66 patients with associated spinal cord hemangioblastoma among 142 VHL patients were retrospectively examined with respect to clinical features, accompanying lesions and outcome of surgical treatment. RESULTS: Among these 48 patients, 46 of them (95.8%) also had a central nervous system (CNS) hemangioblastoma at another site: 42 (87.5%) with cerebellar hemangioblastoma and 11 (22.9%) with brain stem hemangioblastoma. Twenty-three patients (47.9%) had more than one spinal cord hemangioblastoma. The 48 patients with spinal cord hemangioblastomas collectively had a total of 74 tumors. The tumor was accompanied with a syrinx in 64 and without it in 10 patients. Forty of the 48 patients underwent surgical treatment for their spinal cord hemangioblastomas, and 7 of these 40 underwent surgical treatment twice. When functional changes in the patients after these 47 operations were examined by postoperative evaluation by McCormick's classification, 39 of these operations (83.0%) resulted in improvement/no change and 8 (17.0%) in aggravation of symptoms. CONCLUSION: Von Hippel-Lindau disease patients bearing spinal cord hemangioblastomas mostly had a CNS hemangioblastoma at another site. These tumors can be removed in the majority of VHL patients without aggravation. In these patients, when the timing of treatment for spinal cord hemangioblastoma is determined, the probability of occurrence and treatment of other lesions should be considered.

Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes.

Eighteen unrelated pyruvate kinase (PK)-deficient Indian patients were identified in the past 4 years with varied clinical phenotypes ranging from a mild chronic haemolytic anaemia to a severe transfusion-dependent disorder. We identified 17 different mutations in the PKLR gene among the 36 mutated alleles. Ten novel mutations were identified: 427G>A, 499C>A, 1072G>A, 1180G>T, 1216G>A, 1220A>G, 644delG, IVS5 (+20) C>A, IVS9 (+44) C>T, and IVS9 (+93) A>C. A severe syndrome was commonly associated with some mutations, 992A>G, 1436G>A, 1220A>G, 644delG and IVS9 (+93) A>C, in the PKLR gene. Molecular graphics analysis of human red blood cell PK (RPK), based on the crystal structure of human PK, shows that mutations located near the substrate or fructose 1,6-diphosphate binding site may change the conformation of the active site, resulting in very low PK activity and severe clinical symptoms. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. In particular, the 1216G>A and 1219G>A mutations significantly affect the interdomain interaction because they are located near the catalytic site in the A/B interface domains. The most frequent mutations in the Indian population appear to be 1436G>A (19.44%), followed by 1456C>T (16.66%) and 992A>G (16.66%). This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non-spherocytic haemolytic anaemia were identified.

Adhesion of Epstein-Barr virus-positive natural killer cell lines to cultured endothelial cells stimulated with inflammatory cytokines.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized by chronic recurrent infectious mononucleosis-like symptoms. Approximately one-fourth of CAEBV patients develop vascular lesions with infiltration of EBV-positive lymphoid cells. Furthermore, EBV-positive natural killer (NK)/T cell lymphomas often exhibit angiocentric or angiodestructive lesions. These suggest an affinity of EBV-positive NK/T cells to vascular components. In this study, we evaluated the expression of adhesion molecules and cytokines in EBV-positive NK lymphoma cell lines, SNK1 and SNK6, and examined the role of cytokines in the interaction between NK cell lines and endothelial cells. SNKs expressed intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) at much higher levels than those in EBV-negative T cell lines. SNKs produced the larger amount of tumour necrosis factor (TNF)-alpha, which caused increased expression of ICAM-1 and VCAM-1 in cultured human endothelial cells, than that from EBV-negative T cell lines. Furthermore, SNKs exhibited increased adhesion to cultured endothelial cells stimulated with TNF-alpha or interleukin (IL)-1beta, and the pretreatment of cytokine-stimulated endothelial cells with anti-VCAM-1-antibodies reduced cell adhesion. These indicate that the up-regulated expression of VCAM-1 on cytokine-stimulated endothelial cells would be important for the adhesion of EBV-positive NK cells and might initiate the vascular lesions.

Surgical method for catheter placement via the occipital artery by an approach from the posterior of the mastoid process.

Catheter placement for continuous intra-arterial chemotherapy in head and neck cancer is generally performed via the superficial temporal artery. If placement via this artery is impossible, other arteries, such as the occipital artery, are chosen. A surgical method has been developed for catheter placement in the occipital artery by approaching from the posterior of the mastoid process. Catheter placement was performed by this method in 15 patients with oral squamous cell carcinoma. Target arteries were the lingual artery in seven cases, facial artery in three cases, maxillary artery in three cases, superior thyroid artery in one case, and the occipital artery itself in one case. The occipital artery was exposed without fail and catheter placement was completed in all patients. The wound healed without complication after treatment. This approach via the occipital artery is a useful technique to achieve continuous intra-arterial chemotherapy in head and neck cancer, especially for cases in which catheter placement is impossible via the superficial temporal artery.

First-trimester prenatal diagnosis of pyruvate kinase deficiency in an Indian family with the pyruvate kinase-Amish mutation.

Pyruvate kinase (PK) deficiency is a rare red cell glycolytic enzymopathy. The purpose of the present investigation was to offer prenatal diagnosis for PK deficiency to a couple who had a previous child with severe enzyme deficiency and congenital non-spherocytic hemolytic anemia. PK deficiency was identified in the family by assaying the enzyme activity in red cells. Chorionic villus sampling was performed in an 11-week gestation and the mutation was located in exon 10 of the PKLR gene characterized by polymerase chain reaction and using restriction endonuclease digestion with the MspI enzyme, which was confirmed by DNA sequencing on the ABI 310 DNA sequencer. Both the parents were heterozygous for the 1436G-->A [479 Arg-->His] mutation in exon 10 and the proband was homozygous for this mutation. The fetus was also heterozygous for this mutation and the pregnancy was continued. Prenatal diagnosis allowed the parents with a severely affected child with PK deficiency to have the reproductive choice of having the fetus tested in a subsequent pregnancy.

Adhesion of peripheral blood mononuclear cells and CD4+ T cells from patients with psoriasis to cultured endothelial cells via the interaction between lymphocyte function-associated antigen type 1 and intercellular adhesion molecule 1.

BACKGROUND: The adhesion of CD4+ T cells to endothelial cells and their subsequent migration to skin tissue are essential to develop the psoriatic skin lesion. However, few studies have examined the role of adhesion molecules in the binding of T cells from patients with chronic plaque psoriasis to endothelial cells in vitro; thus, the adhesion molecules responsible for the development of skin lesions are still unclear. OBJECTIVES: To identify the responsible adhesion molecules in the interaction between CD4+ T cells in patients with chronic plaque psoriasis and cytokine-stimulated endothelial cells. METHODS: An in vitro adhesion assay between Calcein-labelled peripheral blood mononuclear cells (PBMC) and cytokine-stimulated human endothelial cultures, which exhibit a higher adhesion capacity to PBMC, was established, and the adhesion-inhibitory effects of a panel of antiadhesion molecule antibodies on the adhesion of PBMC from patients with psoriasis to endothelial cells were examined. Then, the inhibitory effects of selected antibodies acting on the interaction between CD4+ T cells from patients with psoriasis (purified by negative magnetic cell sorting) and cultured endothelial cells were examined. RESULTS: A significant increase (P < 0.01) in the adhesion of psoriatic PBMC to both endothelial cultures, human skin microvascular endothelial cells from adults (HMVEC-Ad) and human coronary arterial endothelial cells (HCAEC), compared with healthy PBMC, was demonstrated in our in vitro cell adhesion assay. Pretreatment of both endothelial cultures with tumour necrosis factor (TNF)-alpha (1000 U mL(-1)) induced the most frequent adhesion of PBMC from patients with psoriasis among the three inflammatory cytokines examined, i.e. TNF-alpha, interleukin-1beta and interferon-gamma [TNF-alpha-treated vs. nontreated: P < 0.001 (in both HMVEC-Ad and HCAEC)]. In both endothelial cultures treated with TNF-alpha, PBMC from patients with psoriasis exhibited significantly more frequent adhesion compared with those from healthy individuals (P < 0.001). The TNF-alpha-stimulated HMVEC-Ad, which exhibited the most frequent adhesion of PBMC, were selected for adhesion-inhibition experiments using monoclonal antibodies (mAbs) to adhesion molecules that are upregulated in psoriatic lesions, and the combination of antilymphocyte function-associated antigen type 1 (LFA-1) and anti-intercellular adhesion molecule 1 (ICAM-1) mAbs gave the greatest reduction of adhesion of PBMC from patients with psoriasis (approximately 69% reduction; P < 0.01). This combination of mAbs significantly reduced also the adhesion of CD4+ T cells from patients with psoriasis to TNF-alpha-stimulated HMVEC-Ad (approximately 62% reduction), compared with pretreatment with isotype control mAbs (P < 0.01). CONCLUSIONS: These findings indicate that the LFA-1/ICAM-1 interaction plays a major role in the adhesion of CD4+ T cells to endothelial cells and that TNF-alpha might play an important role for the induction of adhesion molecules on endothelial cells at psoriatic skin lesions.

Progressive wild-type transthyretin deposition after liver transplantation preferentially occurs onto myocardium in FAP patients.

To elucidate whether progressive wild-type transthyretin (TTR) deposition can actually occur after liver transplantation (LT), amyloid fibrils were investigated in two familial amyloid polyneuropathy patients with TTR Val30Leu variant, who died 1 year after LT. Amyloid fibrils were extracted from cardiac muscles, sciatic nerves and kidney, which were investigated by the immunoprecipitation-mass spectrometry method and liquid chromatography-ion trap mass spectrometry analysis. The ratio of wild-type to variant TTR in cardiac muscle was approximately 5:5 before LT, but greatly increased to about 9:1 after transplantation. The ratios in sciatic nerves and kidney obtained at autopsy were approximately 5:5. Wild-type TTR was undetectable in kidney amyloid obtained before LT. Our results indicate that paradoxical wild-type TTR deposition after LT can preferentially occur in myocardium, leading to fatal cardiac dysfunction, but it is quite likely that this phenomenon can also occur in other visceral organs.