Sézary syndrome managed with histone deacetylase inhibitor followed by anti-CCR4 monoclonal antibody.

A 70-year-old man presented to our clinic with a 10-year history of recurrent pruritic erythema and plaques on his trunk and limbs. Based on the pathological findings and monoclonal rearrangement of the T-cell receptor (TCR)-Cß1 gene, mycosis fungoides (T2N0M0B0 stage IB) was diagnosed. Despite combination therapy including histone deacetylase inhibitor (vorinostat), the symptoms slowly evolved into Sézary syndrome (SS; T4N1M0B2) over 4 years, with dense infiltrates due to atypical lymphocytes expressing CCR4 developing in the entire dermis. Anti-CCR4 monoclonal antibody (mogamulizumab) treatment was started. After seven courses, the CCR4-positive atypical lymphocytes decreased in the dermis to levels below those seen at the outset of treatment. To our knowledge, there is no previous report of a case of SS managed with vorinostat followed by mogamulizumab demonstrating such a remarkable change in the pathological state following treatment.

Clinical and immunological profiles in 17 Japanese patients with drug-induced pemphigus studied at Kurume University.

BACKGROUND: Drug-induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP. OBJECTIVES: To characterize clinical and immunological profiles in patients with DIP. METHODS: We studied 17 Japanese patients with DIP who were treated at Kurume University Hospital or who consulted from other hospitals between 1997 and 2012. Complicated diseases, clinical and histopathological manifestations, responsible drugs and findings in immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), immunoblotting (IB) and prognosis were analysed. RESULTS: Eight of the 17 patients with DIP showed pemphigus foliaceus-like appearance, three showed pemphigus herpetiformis-like appearance, and six showed atypical bullous lesions. Responsible drugs were thiol-containing drugs in 16 patients (bucillamine in nine cases, d-penicillamine in four cases, and cetapril, thiopronine and captopril in one patient each), and a nonthiol drug, sulfasalazine, in one patient. By ELISAs and/or IB analyses, nine patients reacted only with desmoglein 1 (Dsg1), four reacted with Dsg1 and Dsg3, and four showed no specific reactivity. By IB of normal human epidermal extracts, in addition to positive reactivity with Dsg1, four patients with no detectable malignancy showed paraneoplastic pemphigus-like reactivity with the 210-kDa envoplakin and the 190-kDa periplakin. Four cases showed anti-Dsg3 antibodies without mucosal lesions. While 11 cases recovered after discontinuation of the causative drugs, six patients had a very protracted or intractable disease course, and might develop true pemphigus. CONCLUSIONS: The present study indicated that the majority of the patients with DIP studied showed a pemphigus foliaceus-type phenotype with anti-Dsg1 autoantibodies, caused by thiol-containing drugs.

Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis.

BACKGROUND: Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. PATIENTS AND METHODS: This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. RESULTS: Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1-2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. CONCLUSION: In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

Potent anticonflict activity and lessening of memory impairment with a series of novel [1]benzothieno[2,3-c]pyridines and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines.

[1]Benzothieno[2,3-c]pyridines (10a-c, 11, 12a-t, and 13a,b) and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines (3a-c, 7, 8a-c, and 9) were synthesized. The compounds are bioisosteres of beta-carbolines and 1,2,3,4-tetrahydro-beta-carbolines where the indole nitrogen is replaced by sulfur. Their pharmacological activity was evaluated in a water lick conflict test in rats and a passive avoidance test in mice. In the 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine series, the presence of ethyl ester (3b) or cyclohexyl carboxamide (7) groups at C-3 conferred good anticonflict activity and lessening of memory impairment, while N-acylation of 3b abolished activity. In the [1]benzothieno(2,3-c]pyridine series, the aminoethyl carboxamide (12a) group at C-3 also conferred activity, but other amides studied were not active. The most potent compounds (3b, 7, and 12a) were also administered orally and had potent anticonflict and antiscopolamine amnesia-reversal activity. These compounds did not bind to the BZP receptor in spite of having structures similar to those of beta-carbolines. Compound 7 bound strongly to 5-HT1A receptors and would be expected to be a novel anxiolytic.

(R)-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines: novel optically active compounds with strong 5-HT1A receptor binding ability exhibiting anticonflict activity and lessening of memory impairment.

(R)-1,2,3,4-Tetrahydro[1]benzothieno[2,3-c]pyridine derivatives (60-114) were synthesized. The (R)-isomers have affinity for the 5-HT1A receptor while the (S)-isomers have no such ability. The affinity of the (R)-isomers was discussed on the basis of structure-activity relationships between the affinity and hydrophobicity of the (R)-isomers. Compounds 71 and 107, which are representative derivative compounds, have anticonflict activity and lessening of memory impairment. In particular, compound 107 cannot bind to receptors other than the 5-HT1A receptor, demonstrating that it is a unique compound with a different mechanism of action from that of conventional anxiolytics.

T cells expressing killer cell inhibitory receptors do not carry TCR for alloantigens.

The role of T cells carrying the killer cell inhibitory receptor (KIR) is unknown. Here we investigate the allo-response of KIR+ CD3+ cells (KIR+ T cells). KIR+ T cells was found in 4.6-14.7% of the T cells from the PBMC of healthy individuals. Flow cytometry analysis showed that the percentage of KIR+ T cells in T cells from three individuals was decreased after stimulation with allogeneic PBMC. These findings suggest that KIR+ T cells do not respond to alloantigens. Furthermore, the analyses using purified KIR+ T cells also confirmed that KIR+ T cells do not respond to alloantigens.

Interleukin-6 (IL-6) in patients with Behçet's disease.

We have examined the levels of interleukin-6 (IL-6) in plasma and supernatants of peripheral blood mononuclear cells (PBMC) from patients with Behçet's disease and healthy controls using a sensitive enzyme-linked immunosorbent assay (ELISA). Plasma IL-6 level was not detected in any subjects. The IL-6 concentrations in culture supernatants of patients with active Behçet's disease were significantly high compared with patients with inactive disease and healthy controls. Moreover, we investigated IL-6 gene expression in cultured PBMC from patients with Behçet's disease. IL-6 gene expression was enhanced in active patients compared with inactive patients. These results show that IL-6 may play a role in the pathogenesis of Behçet's disease.

Pharmacological profile of a potential anxiolytic: AP159, a new benzothieno-pyridine derivative.

AP159 [N-cyclohexyl-1,2,3,4-tetrahydrobenzo(b)thieno(2,3c)pyridine]-3- carboamide,hydrochloride) showed clear anti-conflict activity in rats in the absence of effects on muscle relaxation, potentiation of anesthesia (in mice) or anticonvulsant activity (in mice). This anti-conflict effect was antagonized by treatment with Ro15-1788. By contrast with the deficits produced by diazepam, AP159 did not impair passive avoidance. The latter drug also improved scopolamine-induced amnesia in the same task. AP159 did not inhibit 3H-flunitrazepam binding, but potently inhibited 3H-8OH-DPAT binding. This compound increased serotonin and 5HIAA content of the midbrain raphe nuclei and of the amygdala centralis. AP159 has been shown to be a novel non-BZP anxiolytic agent with no side effects in laboratory animals; it could be a clinically effective anxiolytic agent.

A polymerase chain reaction system for rapid diagnosis of scrub typhus within six hours.

A rapid diagnostic system for scrub typhus (tsutsugamushi disease) was established using the polymerase chain reaction (PCR) combined with microplate hybridization. With this system, diagnosis can be made within six hours without the need for radioisotopes, electrophoresis, or membrane hybridization. The use of a PCR processor and DNA-precoated enzyme-linked immunosorbent assay plates allows a rapid and precise diagnosis to be easily made even in primary medical care clinics.

Diagnosis of typhus infection with Rickettsia tsutsugamushi by polymerase chain reaction.

Two sets of oligonucleotide primers were used to amplify the genomic DNA of Rickettsia tsutsugamushi, the causative agent of scrub typhus (tsutsugamushi disease), by the polymerase chain reaction. Each set of primers amplified 538-bp and 109-bp products, representing part of a gene encoding a possible major 58-kDa immunogenic protein, from whole genomic DNA extracted from R. tsutsugamushi strains Karp, Kato, Gilliam, Kuroki and Kawasaki. No amplification was observed from R. sibirica, R. rickettsii, mouse and human genomic DNA. DNA amplification was observed from crude lysates of peripheral whole blood, tissue homogenates and paraffin-embedded skin biopsy sections obtained from patients with scrub typhus disease. Southern blot analysis demonstrated the specificity of the amplified DNA fragments following hybridisation with a DNA probe generated from R. tsutsugamushi strain Karp. By means of this procedure, a rapid and sensitive diagnosis of scrub typhus disease can be made during the acute stage of this infection.

Expression of three cell proliferation-associated antigens, DNA polymerase alpha, Ki-67 antigen and transferrin receptor in nodal and cutaneous T-cell lymphomas.

We studied the expression of three cell proliferation-associated antigens: DNA polymerase alpha, Ki-67 antigen, and transferrin receptor, in 35 T-cell lymphomas of nodal origin (T-NL) and 40 cutaneous T-cell lymphomas (CTCL). Immunohistochemical staining was carried out on frozen tissue sections of these specimens using three monoclonal antibodies, DAKO-PC, CL22-2-42B (DNA polymerase alpha), and OKT9. The proportion of cells positive for CL22-2-42B, DAKO-PC, or OKT9 among all tumor cells was correlated with four histologic subtypes: malignant lymphoma (ML), diffuse, small; mixed; large; and large cell immunoblastic in both T-NL and CTCL. A strong correlation was noted between positivity for CL22-2-42B and that for DAKO-PC or OKT9. On the other hand, no difference in the expression of these three antigens was noted between T-NL and CTCL in the high, intermediate or low grade-malignancy group. In CTCL as well as in T-NL, cells positive for CL22-2-42B, DAKO-PC or OKT9 were significantly more numerous in the high-grade group than the intermediate-grade group, and in the intermediate-grade group than the low-grade group. Furthermore, a significant correlation between survival period and the number of CL22-2-42B-positive cells was noted when the T cell malignancies, CTCL and T-NL were considered (t value = 2.015, p less than 0.05). Thus, the expression of DNA-polymerase alpha, Ki-67 antigen or OKT9 seems to well reflect the biological behavior and/or clinical prognosis of T-cell lymphoma.

Antagonism by propyl-beta-carboline-3-carboxylate of passive avoidance impairment induced by diazepam.

We investigated the effects of propyl-beta-carboline-3-carboxylate (beta-CCP) on learning and memory tasks in a passive avoidance test in mice to clarify whether beta-CCP is an agonist or antagonist at benzodiazepine (BZP) receptors. At doses up to 10 mg/kg i.v., beta-CCP had no effect on mice in the passive avoidance test. Diazepam impaired passive avoidance behavior and methyl-beta-carboline-3-carboxylate(beta-CCM) enhanced it. beta-CCP blocked these effects of diazepam and beta-CCM in a dose-dependent manner similar to the effect of Ro15-1788. These effects of beta-CCP, which are thought to be mediated by BZP receptors, indicate that beta-CCP is an antagonist in the passive avoidance test.

The effect of diazepam and of agents which change GABAergic functions in immobility in mice.

When mice are forced to swim a restricted space, they will cease attempts to escape and adopt a characteristic immobile posture. In this study, this immobility was reduced by antidepressants and monoamineoxidase inhibitors. We found that diazepam had the ability to enhance this immobility. It is well known that diazepam exerts its pharmacological effect at least in part through GABAergic functions. Muscimol and aminooxyacetic acid enhanced the immobility. In addition, semicarbazide, bicuculline, picrotoxin and pentylenetetrazol reduced the immobility and pretreatment with bicuculline decreased this enhancement with muscimol, aminooxyacetic acid and diazepam. It seems that GABAergic functions play some role in the mechanism of this immobility.

Buspirone enhances head twitch behavior in mice.

We studied the effects of buspirone, a 5-HT1A receptor agonist, on head twitch behavior induced by 5-hydroxy-L-tryptophan (5-HTP) administered together with pargyline in mice. Buspirone dose dependently (0.1-10 mg/kg i.p.) enhanced head twitch behavior. This effect was blocked by (-)-propranolol and NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide). The enhancing effect of buspirone was also observed when mice were pretreated with p-chlorophenylalanine. These findings suggest that the enhancing effect of buspirone on head twitch behavior may be exerted through the activation of post-synaptic 5-HT1A receptors.

The effect of agonists at the GABA-benzodiazepine receptor complex on the duration of immobility of mice in the forced swimming test.

In the present study, we examined the effect of various agents which affect in a different manner the GABA-benzodiazepine receptor-chloride ionophore complex system in relation to the immobile behavior of mice in the forced swimming test. The benzodiazepines diazepam and flurazepam, the barbiturates pentobarbital and phenobarbital, zopiclone and beta-CCP (propyl-beta-carboline-3-carboxylate) enhanced the immobile behavior in a dose-dependent manner. In the doses used here, these agents produced almost no muscle relaxant action. Ro15-1788 and beta-CCM (methyl-beta-carboline-3-carboxylate) themselves had no effect on the duration of immobility. However, Ro15-1788 and beta-CCM reversed the enhancing effect produced by all 6 drugs. These results indicate that the enhancement of the duration of immobility of mice may be somehow correlated to the anxiolytic action but not to the muscle relaxant action. The effect may be mainly mediated by the benzodiazepine receptor, which forms a part of the GABA-benzodiazepine receptor-chloride ionophore complex. Furthermore it is suggested that there were behavioral similarities in the effects of beta-CCP and benzodiazepines.

Effects of corticosterone on 5-HT1A and 5-HT2 receptor binding and on the receptor-mediated behavioral responses of rats.

The effects of corticosterone after binding to 5-HT1A and 5-HT2 receptors were studied in rats. Binding of [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) to 5-HT1A receptors in the hippocampus decreased 24 h after both acute and chronic (14 day) administration of CORT (50 mg/kg, s.c.). Chronic, but not acute, CORT treatment increased [3H]ketanserin binding to 5-HT2 receptors in the frontal cortex. Receptor-mediated behavioral responses were also examined following acute and chronic CORT treatment. Flat body posture and hypothermia induced by 8-OH-DPAT, a 5-HT1A receptor agonist, were attenuated following chronic, but not acute, CORT administration. (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, induced wet-dog shakes, but not hyperthermia and this response was increased 24 h after the chronic administration of CORT. These findings indicate that both 5-HT1A and 5-HT2 receptor functions were changed following chronic exposure to high levels of CORT. Such changes in these receptor systems may play an important role in the etiology of affective disorders.

Chronic forced swim stress of rats increases frontal cortical 5-HT2 receptors and the wet-dog shakes they mediate, but not frontal cortical beta-adrenoceptors.

We studied the effects of chronic forced swim stress on 5-HT2 receptors and beta-adrenoceptors in the rat frontal cortex. The number of 5-HT2 receptors was increased immediately after the last chronic stress, but not after an acute stress. In vivo, the number of wet-dog shakes induced by a 5-HT2 receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), was increased 24 h after the last chronic stress. However, the concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA), measured by high pressure liquid chromatography (HPLC), were not altered by this stress. Binding sites for [3H]CGP-12177, i.e., beta-adrenoceptor sites, were unchanged after both the acute and the chronic stress. These results suggest that, in the rat, the chronic forced swim stress increases the number of frontal cortical 5-HT2 receptors and the number of wet-dog shakes mediated by these receptors, while the number of frontal cortical beta-adrenoceptors is not increased by this treatment.

Idiopathic hypertrophic cranial pachymeningitis: clinicoradiological spectrum and therapeutic options.

OBJECTIVE: Idiopathic hypertrophic cranial pachymeningitis is a rare disease, of undetermined pathogenesis, that is characterized by inflammation and fibrosis of the dura mater. METHODS: We encountered six patients with idiopathic hypertrophic cranial pachymeningitis and analyzed their clinical presentations, radiological findings, and treatment. RESULTS: In the six patients, the main manifestations were cranial nerve palsies and headache. Three associations were present, namely optic neuropathy, Tolosa-Hunt syndrome, and diabetes insipidus. Gadolinium-enhanced magnetic resonance imaging was diagnostic, showing intense dural enhancement in a linear or nodular pattern. The responses to corticosteroid therapy were better for patients who exhibited linear, rather than nodular, dural enhancement. For one patient, surgical decompression of the superior orbital fissure provided lasting relief. The course of the disease followed one of three patterns, i.e., sustained remission, relapse with corticosteroid independence, or relapse with corticosteroid dependence. Pulse corticosteroid therapy provided significant relief, while reducing the daily corticosteroid requirement and avoiding side effects, for a corticosteroid-dependent relapsing patient. CONCLUSION: Idiopathic hypertrophic cranial pachymeningitis exhibits varied clinical courses. It is important to prevent irreversible cranial neuropathy during the active phase of the disease, using daily administration of corticosteroids, pulse corticosteroid therapy, or surgical decompression.

Effect of natural interferon-beta on the growth of melanoma cell lines.

Malignant melanoma is one of the fulminant skin cancers. The 5-year survival of patients with stage III (N0, N1) malignant melanoma treated with multi-agent chemoimmunotherapy, including natural interferon-beta (nIFNbeta), was found in our department to be better than that of patients treated with other forms of therapy. In order to study the effects of nIFNbeta on melanoma, the growth inhibition effect of nIFNbeta was assessed in vitro using the melanoma cell lines, MM8.1, MM28, MM33.1, Bowes and A375-2. The growth of these cell lines was inhibited by nIFNbeta. Incorporation of [3H]thymidine and [3H]uridine was also inhibited by nIFNbeta in a dose-dependent manner. Apoptosis was demonstrated using the TUNEL method in melanoma cell lines cocultured with nIFNbeta. Results showed that nIFNbeta had direct killer activity on melanoma cell lines.

Role of 5-HT1A receptors in the forced swimming wheel test in reserpine-treated mice.

The antidepressant-like effect of 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT), a selective 5-HT1A receptor agonist, was studied in the forced swimming wheel test in reserpine-treated mice. 8-OH-DPAT and the antidepressant imipramine, dose-dependently increased the number of turns of a water wheel made by mice. This effect of imipramine (30 mg/kg, i.p.) was enhanced by reserpine treatment 24 hr before the test. The effect of 8-OH-DPAT (0.3 mg/kg, i.p.) was also enhanced in reserpine-treated mice. This enhanced effect of 8-OH-DPAT was blocked by pretreatment with the 5-HT1A receptor antagonists, (-)-propranolol (3 mg/kg, i.p.) and NAN-190 (1 mg/kg, i.p.), but was not blocked by a beta-blocker, (-)-atenolol (3 mg/kg, i.p.). 8-OH-DPAT did not affect locomotor activity in the reserpinized mice and did not affect the reduction of monoamine content induced by reserpine. These results suggest that the effect of 8-OH-DPAT in increasing the number of turns of the wheel made by mice was exerted through a 5-HT1A receptor and that this effect did not reflect only changes in the locomotor activity of the mice.