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Human T-cell leukemia virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare inflammatory disease causing unremitting and progressive neurological disorders, such as spastic paraparesis, neurogenic bladder, and sensory disturbance of the lower extremities. Although there is no cure, immune-modulating agents such as corticosteroids are most widely used to slow disease progression. Biomarkers for the clinical assessment of HAM/TSP should be identified because the prediction of functional prognosis and the assessment of treatment efficacy are challenging due to the slowly progressive nature of the disease. The lack of surrogate biomarkers also hampers clinical trials of new drugs. This review summarizes biomarker candidates for the clinical assessment of patients with HAM/TSP. Most of the reported biomarker candidates are associated with viral components or inflammatory mediators because immune dysregulation provoked by HTLV-1 infection is thought to cause chronic inflammation and damage the spinal cord of patients with HAM/TSP. Although information on the diagnostic accuracy of most of the reported biomarkers is insufficient, several molecules, including inflammatory mediators such as CXCL10 and neopterin in the cerebrospinal fluid, have been suggested as potential biomarkers of functional prognosis and treatment response. Several clinical trials for HAM/TSP are currently underway, and we expect that these studies will provide not only evidence pertaining to treatment, but also novel findings regarding the utility of biomarkers in this disease. The establishment of clinical biomarkers will improve patient care and promote the development of therapies for HAM/TSP.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease without effective treatment; therefore, development of disease modifying therapy that improves long-term functional outcomes is an unmet need for patients. However, it is virtually impossible to consider this as a primary endpoint in clinical trials owing to the prolonged disease course. Therefore, development of surrogate markers that help predict the effectiveness of new interventions is essential. Currently, several candidate surrogate markers have been identified for HAM/TSP. Cerebrospinal fluid (CSF) C-X-C motif chemokine 10 (CXCL10) is involved in the pathogenesis of HAM/TSP and was shown to correlate with disease progression. However, it remains unclear whether changes in CSF CXCL10 levels are observed in response to treatment and whether these correlate with prognosis. Here we investigated several markers, including CSF CXCL10, in this respect. Data pertaining to patient characteristics and results of motor function evaluation and CSF examination of 13 HAM/TSP patients who received steroid treatment were retrospectively analyzed. Osame motor disability scores (OMDS), 10 m walking time, and CSF levels of CXCL10, neopterin, total protein, cell counts, and anti-HTLV-1 antibody titer were compared before and after steroid therapy. Levels of all CSF markers, with the exception of cell count, were significantly decreased after treatment. Nine of the 13 patients (69.2%) showed improvement in OMDS and were considered responders. Pre-treatment CSF levels of CXCL10 and anti-HTLV-1 antibody titer in responders were higher than those in non-responders (p = 0.020 and p = 0.045, respectively). Patients who continued low-dose oral prednisolone maintenance therapy after methylprednisolone pulse therapy showed sustained improvement in OMDS and CSF CXCL10 and neopterin levels lasting for 2 years. In contrast, OMDS and the CSF marker levels in patients who discontinued treatment returned to pre-treatment levels. This rebound phenomenon was also observed in patients who discontinued oral prednisolone therapy independently of pulse therapy. Our findings suggest that CSF CXCL10 may serve as a therapy-response and therapy-predictive marker for HAM/TSP. In addition, since decrease in CSF CXCL10 level was associated with good functional prognosis, CSF CXCL10 is a potential surrogate marker for treatment of HAM/TSP.

Human T-cell leukaemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) damages the spinal cord by chronic inflammation and causes progressive lower limb motor disability.1 Because the associated symptoms gradually progress over the years, it is challenging for clinicians to predict long-term functional prognosis and evaluate the treatment response. Recently, we proposed criteria for classifying disease activity in untreated patients.2 As per this classification, disease activity is classified as low, moderate or high based on the clinical course and concentrations of inflammatory cytokines C-X-C motif chemokine 10 (CXCL10) and neopterin in the cerebrospinal fluid (CSF). Although corticosteroids are widely used to slow disease progression,3 biomarkers for steroid-treated patients have not yet been validated. In the present study, we investigated whether these markers are associated with the progression of motor dysfunction in this population. This was a single-centre, retrospective cohort study of patients diagnosed with HAM/TSP based on the WHO criteria.4 Patients who were continuously treated with oral prednisolone (PSL) therapy and had the following data were enrolled: CXCL10 and neopterin concentrations in the CSF measured before and after the initiation of PSL therapy and serial data of the Osame motor disability score (OMDS) (online supplementary figure S1).5 ### Supplementary data [jnnp-2019-321955supp001.pdf] Patients visited St. Marianna University hospital every 1 to 3 months for treatment for HAM/TSP; motor disability was assessed using the OMDS at each visit. The PSL dose and the interval between the initiation of PSL therapy and CSF testing were not standardised. Oral PSL therapy was initiated at a median dose of 5.0 mg/day (IQR 3.0–5.0), and the dose was adjusted thereafter according to the symptoms (dose range 1.5–8.0 mg/day). The median time from …

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. While the disease usually progresses slowly without remission, there is a subgroup of patients with rapid progression and another subgroup with very slow progression. However, there have been no reports to date that have successfully determined the criteria to differentiate these subgroups. Therefore, we initially conducted a statistical modeling analysis to explore representative patterns of disease progression using data from our nationwide HAM/TSP patient registration system (“HAM-net”). The latent class mixed model analysis on the retrospective data (n = 205) of disease progression measured by the change in Osame Motor Disability Score from the onset of the disease to diagnosis demonstrated three representative progression patterns of HAM/TSP. Next, to test the effect of the progression rate at the initial phase of the disease on long-term prognosis, we divided 312 “HAM-net” registered patients into three groups (rapid, slow, and very slow progressors) based on the progression rate, then analyzed long-term functional prognosis of each group using the Kaplan–Meier method. Our data clearly demonstrated that the rapid progression at the early phase of the disease is an important poor prognostic factor. Moreover, to determine the biomarkers capable of discriminating the difference in disease activity, we compared the value of potential biomarkers of HAM/TSP among rapid (n = 15), slow (n = 74), very slow (n = 7), and controls (non-HAM/TSP patients, n = 18). The cerebrospinal fluid (CSF) levels of neopterin and C-X-C motif chemokine 10 (CXCL10) were the most valuable markers to discriminate among rapid, slow, and very slow progressors. To differentiate between rapid and slow progressors, the cut-off values of neopterin and CXCL10 were determined to be 44 pmol/mL and 4400 pg/mL, respectively. Furthermore, to differentiate between slow and very slow progressors, these values were determined to be 5.5 pmol/mL and 320 pg/mL, respectively. Notably, we found that CSF levels of these markers in very slow progressors were within the reference range. Thus, we propose a new classification criteria for disease activity of HAM/TSP that may contribute to improving the treatment algorithm for HAM/TSP.

We aimed to identify a serum biomarker for evaluating the disease activity of relapsing polychondritis (RP). We measured and compared serum levels of 28 biomarkers potentially associated with this disease, including soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), high-sensitivity C-reactive protein (hs-CRP), and cartilage oligomeric matrix protein (COMP), in 15 RP patients and 16 healthy donors (HDs). We divided the 15 RP patients into active RP (n = 8) and inactive RP (n = 7) groups, depending on the extent of the disease, and compared candidate markers between groups. The localization of membrane-bound TREM-1 in the affected tissue was examined by immunohistochemistry. Serum levels of sTREM-1, interferon-γ, chemokine (C–C motif) ligand 4, vascular endothelial growth factor, and matrix metalloproteinases-3 were significantly higher in RP patients than HDs. Among these markers, sTREM-1 had the highest sensitivity and specificity (86.7 and 86.7 %, respectively). Furthermore, the serum level of sTREM-1 was significantly higher in active RP patients than inactive RP patients (p = 0.0403), but this was not true for hs-CRP or COMP. TREM-1 was expressed on endothelial cells in RP lesions. The serum level of sTREM-1 may be a useful marker of disease activity in RP.

We prepared water-soluble anthracene-cored poly(aryl ether) dendrimers wG1 and wG2 , together with lipophilic dendrimers G1 and G2 , and examined their photochemical properties. Water-soluble dendrimers wG1 and wG2 produced excimer emissions peaking at 463 nm and 447 nm, respectively, in water at a concentration of 10 −5 M, indicating that these dendrimers could form aggregates under highly diluted conditions. The results presented here are the first clear report of the observations of the excimer emission of anthracene in very low fluid solutions in which appropriate substituents were introduced.

Intramolecularly hydrogen-bonded organic compounds often exhibit fluorescence emission at considerably longer wavelengths than typical fluorescence as a result of excited-state intramolecular proton transfer (ESIPT). The structure-property relationship of such ESIPT molecules, however, remains obscure. The present article reports the excited-state dynamics of a new family of ESIPT molecules, 2-(2'-hydroxynaphthyl)benzazoles 1-3, based on steady-state and time-resolved spectroscopy measurements. In comparison with the parent compound HBO, all three compounds 1-3 exhibited absorption bands at longer wavelengths and emitted fluorescence from the excited keto-tautomer K* at shorter wavelengths, indicating that the introduction of a naphthalene ring increases the energy gap between the ground and excited states for the keto-tautomer despite the expansion of the aromatic ring. Time-resolved fluorescence spectra revealed dual emission for compounds 1 and 3, consisting of two distinct fluorescence bands originating from K* and the excited rotamer E'*, whereas 2 exhibited fluorescence only from the K* state. In the transient absorption spectra, both the T-T absorption band and the ground state absorption band of the Z-keto tautomer were observed for 1, whereas only the T-T absorption band was observed for 2 and only the Z-keto tautomer band was observed for 3.

Water-soluble naphthalene dendrimers WN1, WN2, and WN3, together with the lipophilic compounds N1, N2, and N3 were prepared and their photochemical properties were examined. Whereas lipophilic dend...

HTLV-1 associated myelopathy/tropic spastic paraparesis (HAM/TSP) is induced by chronic inflammation in spinal cord due to HTLV-1 infection. Cerebrospinal fluid (CSF) neopterin or proviral load are clinically measured as disease grading biomarkers, however, they are not exactly specific to HAM/TSP. Therefore, we aimed to identify HAM/TSP-specific biomarker molecules and establish a novel less-invasive plasma diagnostic model for HAM/TSP. Proteome-wide quantitative profiling of CSFs from 6 asymptomatic HTLV-1 carriers (AC) and 51 HAM/TSP patients was performed. Quantitative analysis for 1,871 nonredundant CSF proteins identified from 57 individuals defined 14 CSF proteins showing significant correlation with Osame’s motor disability score (OMDS). The 14 severity grade biomarker proteins were further examined plasma ELISA assays (n = 71). This results confirmed secreted protein acidic and rich in cysteine (SPARC) and vascular cell adhesion molecule-1 (VCAM-1) demonstrated the same correlations in plasma (R = −0.373 and R = 0.431, respectively). Finally, we constructed three-factor logistic regression model and evaluated the diagnostic power using 105 plasma samples. In this training set, we constructed a HAM/TSP diagnostic model using SPARC, VCAM1, and viral load. Sensitivity and specificity to diagnose HAM/TSP patients from AC (AC vs. OMDS 1–11) were 85.3% and 81.1%, respectively. Importantly, this model could be also useful for determination of therapeutic intervention point (OMDS 1–3 + AC vs. OMDS 4–11), exhibiting 80.0% sensitivity and 82.9% specificity. We propose a novel less-invasive diagnostic model for early detection and clinical stratification of HAM/TSP. Authors’ details Division of Biosciences, Functional Proteomics Center, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan.

We report herein the selective preparation of normal, tautomeric, and dual-fluorescent molecules with a common ESIPT core. 2′-Hydroxyacetophenone (OHAP) is known as a typical molecule that undergoes excited-state intramolecular hydrogen transfer (ESIPT) to display fluorescence emission from the excited state of the tautomer. In this study, a series of ten OHAP-cored fluorescent molecules were prepared and their excited state properties have been explored. The bathochromic shift of the π–π* absorption band with π-extensions of substituents of these molecules indicates that the excitation energy of the normal form of the OHAP unit was reduced due to the substituents, while the energy of the excited tautomer appeared to be independent of the π-extension of the substituents. When pyrene or anthracene was connected at the end (molecules 4 and 5), only normal fluorescence appeared, and the tautomer fluorescence disappeared. An anthracene derivative (molecule 10) displayed dual fluorescence, indicating that the normal and the tautomer excited states were energetically “balanced”. A fluorescence lifetime analysis revealed the ESIPT reaction rate of 10 to be much slower than those of other derivatives and that the normal and tautomer forms were in equilibrium in the excited state.

Systematic series of indium tin oxide (ITO) electrodes modified co- valently with self-assembled monolay- ers (SAMs) of ferrocene-porphyrin- fullerene triads and porphyrin-fuller- ene dyads were designed to gain valu- able insight into the development of molecular photovoltaic devices. The structures of SAMs on ITO have been investigated by UV/Vis absorption spectroscopy, atomic force microscopy, and cyclic voltammetry. The photoelec- trochemical and photophysical (fluores- cence lifetime and time-resolved tran- sient absorption) properties were also determined. The highest quantum yield of photocurrent generation (11 %) amongdonor-acceptor linked systems which are covalently attached to the surface of ITO electrodes was achieved with SAMs of ferrocene-zinc porphy- rin-fullerene linked triad on ITO elec- trodes. The quantum yields of photo- current generation correlate well with the charge-separation efficiency and the lifetime of the charge-separated state of the porphyrin-fullerene linked systems in solution. These results pro- vide valuable information for the con- struction of photonic molecular devices and artificial photosynthetic systems on ITO electrodes.

Self-assembled monolayers (SAMs) of porphyrins have been prepared to examine the substituent effects of porphyrin monolayers on the structure and photoelectrochemical properties of the SAMs on an ITO electrode. The ultraviolet (UV)−visible absorption, steady-state fluorescence, and cyclic voltammetry measurements for the porphyrin SAMs revealed that the interaction between the porphyrins without bulky tert-butyl groups is much larger than that of the porphyrins with bulky tert-butyl groups. Photoelectrochemical measurements were performed in nitrogen-saturated Na2SO4 aqueous solution containing triethanolamine as an electron sacrificer using the modified ITO working electrode, a platinum wire counter electrode, and an Ag/AgCl reference electrode. The internal quantum yields of photocurrent generation together with the porphyrin fluorescence lifetimes remain virtually the same irrespective of the steric hindrance, which is in sharp contrast with severe self-quenching of the porphyrin excited singlet state ...

The ultrafast photodynamics of porphyrin−fullerene dyads in which the distance between the porphyrin and C60 moieties is varied systematically at close proximity has been examined using fluorescence up-conversion and pump−probe transient absorption techniques with time resolutions of ca. 100 fs. The porphyrin−fullerene dyads examined are MP-D-C60 (M = Zn and 2H) in which the C60 moiety is directly connected with the porphyrin ring at the meso position and MP-O-C60, MP-M-C60, and MP-P-C60 in which the C60 moiety is linked with porphyrin moieties through the benzene ring at the ortho, meta, and para positions, respectively. The charge transfer (CT) bands are observed for MP-D-C60 and MP-O-C60, whereas no CT band is seen for MP-M-C60 and MP-P-C60. Time-resolved absorption spectral measurements indicate that the photoexcitation of ZnP-D-C60 in benzonitrile (PhCN) results in formation of the exciplex, which decays to the ground state without forming the charge-separated state. The strong interaction between th...

ITO electrodes modified with a meso,meso-linked porphyrin oligomer have been prepared for the first time to achieve improved light-harvesting efficiency and a larger quantum yield for photocurrent generation as compared to the corresponding porphyrin monomer system. An increase in the number of the porphyrins in meso,meso-linked porphyrins results in an improvement of the photoenergy conversion efficiency per mol cm-2 in the visible light region as well as a larger quantum yield of photocurrent generation. The relative integrated values of the photocurrents for all of the frequencies in the action spectrum per mol cm-2 in the porphyrin dimer and tetramer systems are determined to be 2.5 and 6.5, respectively, as compared with the values of the porphyrin monomer system.

Stilbene-cored dendrimers having benzophenone peripheries with alkyl chains formed 1 µm and 4 nm aggregates in methylcyclohexane (MCH) for trans-1 and trans-2, respectively. Even in the aggregates,...

We found a unique spectroscopic property of silver nanodisks covered with J-aggregate. The spectral hole around the position of the J-band was remarkably observed in the surface plasmon band. The o...

Background Human T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP. Methodology/Principal Findings Peripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined “deteriorating HAM/TSP” as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and “stable HAM/TSP” as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set. Conclusions/Significance As the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials., Author Summary HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease caused by infection with human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 infects 10–20 million people worldwide, and, depending on the region, 0.25–3.8% of infected individuals develop HAM/TSP. As the disease progresses, chronic inflammation damages the spinal cord and lower limb and bladder function gradually decline. In the worst cases, even middle-aged patients can become perpetually bedridden. Today, there are treatments that may alleviate the symptoms to a certain degree, but there is no cure that can halt disease progression, and there are no known biomarkers to indicate the level and speed of disease progression. In this study, we successfully identified three promising candidate biomarkers. We believe that the use of these biomarkers could lead to more accurate prognoses and more prudent, patient-specific treatment plans. We not only hope that these biomarkers are sensitive enough to use as selection criteria for clinical trials, but also that measurements of these biomarkers can be used to accurately evaluate drug effectiveness. In short, the biomarkers we identified have the potential to help more effectively treat current HAM/TSP patients and to pave the way for new drugs to potentially cure future HAM/TSP patients.

The redox properties of two-dimensional (2D) J-aggregates of a typical thiacarbocyanine dye have been studied directly by the standard electrochemical method in conjunction with the recently developed technique for controlled layering of 2D J-aggregates on a self-assembled cysteamine monolayer on an atomically flat Au(111). The cyclic voltammograms measured at widely ranging scan rates from 10 mV/s to 100 V/s illuminated unique mechanistic features of the J-aggregate oxidation, which proved to be a convolution of reversible and irreversible oxidations involving the charge transfer of up to 4 electrons/molecule. The oxidation-induced irreversible bleaching of the J-band was accompanied by negligibly small changes in its peak position and sharpness, suggesting that the irreversible reaction occurs preferentially along the domain edges or boundaries. The two different phases of oxidation could be more or less clearly separated under the fast scan mode (scan rate larger than ∼10 V/s), giving us the unpreceden...

An anionic cyanine dye with disulfopropyl substituents allowed its two-dimensional (2D) J-aggregate of highest-ever quality to be successfully layered on top of the self-assembled monolayer (SAM) of cysteamine (CA) on atomically flat Au(111). The chemisorption of CA from millimolar ethanolic solutions was rapid, producing an estimated density of surface amino groups of ∼4 × 1014 cm-2 well within a minute. However, sufficient ordering of the CA SAM, which we found by scanning tunneling microscopy imaging to yield a characteristic 7 × √3 superlattice structure, took a considerably long extra immersion time of a few hours at room temperature. The highest-quality 2D J-aggregate with an extraordinary sharp J-band formed preferentially on densest but still not fully ordered CA SAMs, from typically 0.1 mM dye solutions in 1:1 mixed water and ethanol solvent at considerably high adsorption temperatures of 50−65 °C. A detailed analysis of the 2D J-aggregate and its molecular linkage with the CA SAM indicated that ...

2-(2′-Hydroxynaphthalenyl)benzoxazole (1) emits fluorescence with small Stokes shift from its excited tautomer (K*), produced by excited-state intramolecular proton transfer. Intramolecular hydroge...

Chitosan (CTO) films containing ammonium 1,1′-disulfopropyl-9-aminothiacarbocyanine (KP2) were fabricated by dropping an aqueous solution of CTO and KP2 on the quartz plate. Although KP2 molecules take a monomeric form in aqueous solutions, most dye molecules form the H-aggregate in the presence of CTO, as evidenced by an exceptionally sharp H-band. The formation of the H-aggregate was further promoted in the CTO films. In contrast, the formation of the H-aggregate reported thus far has been accompanied with the coexistence of large amounts of dye monomers and oligomers. We could devise, for the first time, a reproducible method for preferred formation of the H-aggregate in polymer films.

The J-aggregates of quinocyanine dyes (5,6,5'6'-dibenzo-1,1'-diethyl-2,2'-cyanine chloride (Sh) and 1-methyl-1'-octadecyl-2,2'-cyanine perchlorate (S120)) have been fabricated in a Langmuir trough and transferred onto quartz substrate. The formation of the J-aggregates has been studied by methods of conventional absorption and fluorescence time resolved spectroscopy. The mixed J-aggregate of S120 and Sh shows two distinct absorption bands and one fluorescence band intermediate between those of the J-aggregates of the individual component dyes. These results have some anomaly compared with the mixed J-aggregates of quinocyanine dyes and its benzothiazole or benzoselenazole derivative formed in solutions (Scheibe et al., Naturwissenschaften 29 474 (1937)) and in Langmuir-Blodgett films (Penner and Mobius, Thin Solid Films 132 185 (1985)).

We prepared dispersions of composite particles of thiacarbocyanine dye and colloidal silver or gold and examined an effect of the composite on the third-order nonlinear susceptibility (χ(3)) measured by using degenerate four-wave mixing method. The χ(3) of the dispersion was enhanced about 3.5 times the sum of those of dye solution and colloidal metal dispersion. A new absorption band (Δ=600 nm) which was bathochromically shifted from monomer band (Δ=551 nm) was formed and this band was related to the enhancement of χ(3).

Polymer films containing cationic cyanine dye, 1,1′-diethyl-2,2′-cyanine chloride (PIC), were fabricated by dropping aqueous solutions of the dye and the water-soluble polymer on the quartz plate and drying. The aggregation state of PIC in thin polymer films was dependent on the kind of polymers. The aggregation state could be controlled by varying the amount of anionic sites on the polymer chain or by mixing two kinds of polymers.

We incorporated an amphiphilic azobenzene derivative, 4-octyl-4′-(5-carboxypentamethyleneoxy) azobenzene (8A5), into the liposome membrane of L-α-dimyristoylphosphatidylcholine (DMPC). Photoisomerization of 8A5 and changes in K + ion permeability, P cm s −1 , of the membrane under irradiation with ultraviolet light were examined. The temperature of the liposome dispersion was controlled in the range T = 283–303 K . Trans -to- cis isomerization of 8A5 induces the increase of ion permeability in the whole temperature range. A specific permeability enhancement is observed around T = 290–293 K, where the ratio P (cis)/ P (trans) amounts to 200–300. It is suggested that the permeability enhancement around the phase transition temperature is caused by the increase of the phase separation boundaries as well as by the expansion of pores due to trans -to- cis isomerization.

Molecular J-aggregate formation in Langmuir-Blodgett (LB) films and polymer films has been investigated. Mixed monolayers 5,6,5′,6′-dibenzo-1,1′-diethyl-2,2′-cyanine chloride (Sh), 1-methyl-1′-octadecyl-2,2′-cyanine perchlorate (S120) with arachidic acid (AA) (Y-type) and 1,1′-diethyl-2,2′-cyanine iodide (PIC) and Sh in sodium alginate (SA) films were deposited onto quartz substrates. The LB films and the polymer films were built-up with different dye concentrations. By means of the time-correlated single-photon counting technique, the fluorescence lifetime of the J-aggregates of cyanine dyes has been measured. The evidence of the excitation energy transfer from the donor J-aggregate (S120 or PIC) to the acceptor J-aggregate (Sh) have been obtained from the fluorescence spectroscopy and the fluorescence lifetime measurements. The difference of energy transfer in the LB films and the polymer films would reflect different distributions of dyes in the each films.

The thin film of silver salt of alginic acid is available for synthesis of small silver particles and aggregates embedded in the polymer matrix. Variations in the Raman spectrum of the silver alginate film with UV irradiation have been examined. A Raman signal at 1398–1405 cm−1 corresponding to symmetric COO− stretching vibration of silver alginate has been increased, manifesting the contribution of surface-enhanced Raman scattering (SERS).

Thin films of chloroauric acid salt of chitosan (CTOAu films) were photolyzed with 253.7 nm light. On irradiating with UV light in air at room temperature, the CTOAu film first became yellow-blue colored due to the formation of colloidal gold. When irradiation was continued, the irradiated surface of the film finally changed into clear gold mirror. Primary photochemical products are assumed to be gold atom, quaternary ammonium chloride of chitosan and chlorine. With aids of UV-visible absorption spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscopy, aggregation of small gold particles to form colloidal gold and gold metal film has been investigated. It has been found that the aggregation state of small gold particles is controlled by reaction conditions; temperature, evacuation, the amount of chloroauric acid. When the CTOAu film was photolyzed in vacuum at room temperature, the gold particulate film was formed. Irradiation at liquid nitrogen temperature resulted in absorption spectrum characterized by the structureless absorption extending from λ = 400 nm to shorter wavelength. However, an introduction of air after photolysis brought about the development of the broad colloidal absorption band.

The third-order nonlinear susceptibility ( χ (3) of silver sol prepared by a photochemical method was measured by the degenerate four-wave mixing method. The χ (3) of the silver sol of brown-green color was larger than that of yellow-brown color. The photo-induced aggregation of silver particles affects the χ (3) of the sol. It has been found that the χ (3) of the silver sol is proportional to the intensity of surface-enhanced raman scattering from carboxylate ions adsorbed on the silver particle. The increase of χ (3) by the enhanced local electric field due to surface plasmon resonance is proposed.

An aqueous silver perchlorate–sodium dodecylsulfate (SDS)–benzophenone (BP) solution was photolyzed with either UV or near-UV light. Irradiation with 253.7 nm light, which was absorbed by both BP and silver ions, brought about the formation of collidal silver and the photobleach of BP. Peptization of colloidal silver agglomerates after prolonged irradiation was ascribed to electron injection from the benzophenone ketyl radical (BPK). The formation of colloidal silver and the photobleach of BP were also caused by irradiation with 365 nm light, which was absorbed solely by BP (sensitized reaction). A simple reaction scheme was introduced and the initial rates for the sensitized photoreduction of silver ions and the photobleach of BP were expressed in closed forms. Suitable combinations of the kinetics parameters and the extinction coefficient of colloidal silver were proposed in order to interpret the dependences of the initial rates on the reactant concentrations.

An application of chitosan for the polymer support to fabricate thin gold films was examined. When a thin film of chloroauric acid salt of chitosan was irradiated with UV-light in air, a clear gold mirror was formed. It is suggested that the gold mirror is made of aggregated colloidal gold particles stabilized by chitosan.

The clinical course and disease activity of patients with HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP) are different among patients. Therefore, the treatment plan should be designed based on these backgrounds of patients. However, there is little information about the natural history of HAM/TSP and biomarkers of disease activity that is associated with prognosis. As the candidate for biomarkers to evaluate the disease activity in HAM/TSP, HTLV-1 proviral load in PBMC, several cytokines and chemokines in serum or cerebrospinal fluid (CSF) are known to be increased in HAM/TSP patients. However, little is known which parameter of these candidates is most associated with disease severity. Therefore, we investigated the clinical course of 30 HAM/TSP patients without any history of treatment. Furthermore, we measured quantitatively the concentration of a series of cytokines and chemokines in serum and CSF, and HTLV-1 proviral DNA load in PBMC. Then, the level of these markers was evaluated for the correlation with disease severity. In HAM/TSP patients, the level of CXCL10/IP-10 and neopterin in CSF was strongly correlated with disease severity. Interestingly, the level of soluble IL-2 receptor and CXCL10/IP-10 in serum was also correlated with disease severity with statistical significance. Furthermore, based on the clinical course and laboratory findings, HAM/TSP was classified into 4 different clinical subtypes as follows; (1) Rapidly progressive (active), (2-A) Chronic progressive (active), (2-B) Chronic progressive (inactive), (3) Chronic mild (inactive). This classification might be useful to determine the therapeutic strategy for patients with HAM/TSP.

Background Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus that causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia (ATL). A higher viral load in individuals with HTLV-1 infection increases their risk of developing HAM/TSP and ATL. Moreover, the high proviral load is associated with the clinical progression of HAM/TSP. Reduction of the number of HTLV-1-infected cells is therefore crucial for preventing and treating HTLV-1-associated diseases. Recently, fucoidan, a complex sulphated polysaccharide derived from marine seaweed, has been demonstrated to exert inhibitory effects on HTLV-1 infection in vitro. In this study, we examined the in vivo effects of fucoidan on HTLV-1 infection. Methods In this single-centre open-label trial, 13 patients with HAM/TSP were treated with 6 g fucoidan daily for 6–13 months. The HTLV-1 proviral DNA load and frequencies of HTLV-1-specific CD8+ T-cells, natural killer cells, invariant natural killer T-cells and dendritic cells in the peripheral blood were analysed. Furthermore, the in vitro inhibitory effect of fucoidan on cell-to-cell HTLV-1 infection was examined by using luciferase reporter cell assays. Results Fucoidan inhibited the cell-to-cell transmission of HTLV-1 in vitro. Furthermore, fucoidan therapy resulted in a 42.4% decrease in the HTLV-1 proviral load without affecting the host immune cells. During the treatment, no exacerbation was observed. Four patients with HAM/TSP developed diarrhoea, which improved immediately after stopping fucoidan administration. Conclusions Fucoidan is a new potential therapeutic agent for the prevention and treatment of HTLV-1-associated diseases.

A Raman signal arising from carboxylate ions in thin films of silver salt of carboxymethylcellulose (CMCAg film) was fairly increased, when the CMCAg film was photolyzed with UV-light. The maximum enhancement was achieved in the CMCAg film irradiated for 180 min. It is likely that the intensity enhancement of the carboxylate ions reflects the contribution of surface-enhanced Raman scattering (SERS).

Luminescence and excitation energy transfer of the J-aggregate of cyanine dyes: 5,6,5',6'-dibenzo-1,1'-diethyl-2,2'-cyanine chloride (dye I), 5,5'-dichloro-3,3'-diethyl-9-phenyl-thiacarbocyanine chloride (dye II), 3,3'-dimethyl-9-phenyl-4,5,4',5'-naphthothiacarbocyanine chloride (dye III), 1,1'-diethyl-2,2'-cyanine iodide (dye IV), in the monolayer assemblies have been studied. Sensitization of resonance fluorescence of the acceptor aggregate (dyes II and III) by the donor aggregate (dyes I and IV) is evident in the mixed assemblies, donor: acceptor, which contain two kinds of the J-aggregates in the same layer plane. The dependence of sensitization efficiency on the composition of the dye I: dye II assembly has been interpreted in terms of an empirical Perrin relation. The slope of the Perrin type plot of sensitized fluorescence is consistent with the model that the dye I aggregate and the dye II aggregate are distributed at random in the layer plane as if each of them were a large supermolecule.

Objectives Matrix metalloproteinase (MMP) 13 is a pathogenic collagenase that causes cartilage destruction and plays a leading role in causing osteoarthritis. This study focused on 114 genes that are differentially expressed between intact and damaged osteoarthritis cartilage, in order to determine which molecules are involved in suppressing MMP-13 expression. Methods MMP-13 concentrations were measured in the supernatant of human osteoarthritis chondrocyte cultures transfected with small interfering RNA (siRNA) against the 114 genes. MMP-13 levels changed most dramatically in response to siRNA against prostaglandin EP2 receptor. The authors performed further measurements of MMP-13 production in osteoarthritis chondrocytes stimulated by the EP2 agonist butaprost in the presence or absence of interleukin-1β (IL-1β) and/or cyclooxygenase-2 (COX-2) inhibitor. They also assessed the effect of butaprost on chondrocyte viability, and investigated the involvement of the cAMP–protein kinase A (PKA) pathway on EP2 signalling using inhibitors. Cartilage-related gene expression was examined in chondrocytes treated with butaprost. The authors also investigated which E series of prostaglandin (EP) receptors are expressed in osteoarthritis cartilage. Results MMP-13 messenger RNA expression was significantly affected by two molecules, EP2 receptor and SLC14A1, a urea transporter. In IL-1β-treated osteoarthritis chondrocytes, butaprost suppressed MMP-13 production, which was further decreased by COX-2 inhibitor. EP2 signalling downregulated MMP-13 mRNA expression via the cAMP–PKA pathway without affecting cell viability. Although EP2 signalling enhanced IL-6 expression, the expressions of several catabolic factors (MMP-1, MMP-3, MMP-13, ADAMTS5, IL-1β and tumour necrosis factor alpha) were inhibited. EP2 receptor was the major EP receptor in osteoarthritis cartilage. Conclusion The results suggest that EP2 signalling has ‘anti-catabolic’ effects in osteoarthritis chondrocytes.

A bright silver mirror was formed by photolysis of silver salt of carboxymethylcellulose with 253.7 nm light. The silver metal film was proved to be useful for the substrate to deposit dye monolayers. Fluorescence quenching of rhodamine B on the silver metal film was interpreted in terms of excitation energy transfer.

The photoelectric properties of the planar bilayer lipid membrane (BLM) of soybean lecithin doped with an amphiphilic azobenzene derivative, 4-octyl-4′-(5-carboxypentamethyleneoxy) azobenzene (8A5), were examined. When a DC voltage is applied across the BLM, the trans-membrane current changes under alternate irradiation with ultraviolet and visible light. A comparative study on the photoresponse of soybean lecithin liposomes doped with 8A5 revealed that the photoelectric properties of the BLM result from the change in the membrane conductivity due to photoisomerization of 8A5.

Carboxypeptidase R (CPR) is a heat-labile enzyme found in serum in addition to stable carboxypeptidase N. CPR cleaves the C-terminal basic amino acids, arginine and lysine, from inflammatory peptides such as complement C3a and C5a, bradykinin, and enkephalin. This enzyme is generated from procarboxypeptidase R (proCPR), also known as thrombin-activatable fibrinolysis inhibitor, following cleavage by proteolytic enzymes such as thrombin, plasmin, and trypsin. We generated proCPR-deficient mice by knocking out exons 4 and 5 of the proCPR gene, which are regarded as essential for CPR function. At LPS challenge, there was virtually no difference in lethality among proCPR+/+, proCPR+/−, and proCPR−/− mice. However, challenge with cobra venom factor, which can activate and deplete almost all complement in vivo, induced a lethal effect on proCPR−/− mice following LPS sensitization which up-regulates C5a receptor expression. In contrast, proCPR+/+ and proCPR+/− mice were able to tolerate the cobra venom factor challenge with the limited dose (30 U). Although carboxypeptidase N plays a role in inactivation of inflammatory peptides in vivo, CPR may also be important in the regulation of hyperinflammation.

A hydrogen bonding effect on photocurrent generation has been evaluated successfully in a mixed film of porphyrin and fullerene with hydrogen bonding on an ITO electrode, which exhibits efficient cathodic photocurrent generation as compared to the reference system without hydrogen bonding.

The planar bilayer lipid membrane (BLM) of egg lecithin containing amphiphilic azobenzene 8A5 (approx. 10 mol%) was fabricated. Electrical properties of the BLM were examined to clarify the mechanism of the recently observed novel photoelectric response; transient photocurrent and the change of AC impedance by alternate irradiation with UV and visible light. It has been concluded that the photoelectric response is caused by the change of membrane capacitance due to cis-trans isomerization of 8A5.

LB films and liposomes incorporating J-aggregates of two kinds of cyanine dyes at the same membrane surface have been prepared. Four cyanine dyes, 1,1′-diethyl-2,2′-cyanine chloride or iodide (dye-I), 5,6,5′,6′-dibenzo-1,1′-diethyl-2,2′-cyanine chloride (dye-II), 5,5′-dichloro-3,3′-diethyl-9-phenylthiacarbocyanine chloride (dye-III), 3,3′-dimethyl-9-phenyl-4,5,4′,5′-naphthothiacarbocyanine chloride (dye-IV) were employed. In the case of a couple of dye-II:dye-III aggregates, quenching of resonance fluorescence of dye-II aggregate and sensitization of resonance fluorescence of dye-III aggregate, due to excitation energy transfer, were observed. The energy transfer also occurs in the dye-I:dye-III, dye-I:dye-IV, dye-II:dye-IV aggregates. In these cases, quinocyanine dye (dye-I, dye-II) aggregates and thiacarbocyanine dye (dye-III, dye-IV) aggregates act as the energy donor and acceptor, respectively.

We have found, for the first time, a unique spectroscopic property of noble metal nano-particles (colloidal silver in solution or noble metal island film) covered with a J-aggregate monolayer. The spectral dip or hole at the position of the J-band was observed in the surface plasmon band. The appearance of the hole was related to the interaction between the surface plasmon of the noble metal nano-particles and the Frenkel exciton of the J-aggregate.

A simple and useful new method to fabricate high-quality 2D J-aggregates of anionic cyanine dyes on a solid surface has been established by using an Au(111) covered with cysteamine self-assembled monolayer. It was also found that this method allows easy control of dye aggregation ranging from a 2D crystalline J-aggregate to a high density of dye monomers without aggregation.

When an aqueous AgClO4–sodium dodecylsulphate (SDS)–isopropyl alcohol (Pri OH) solution was photolysed with 253.7 nm light, a sharp and intense absorption band of colloidal silver (λ= 390–400 nm) appeared after a relatively long induction period. In contrast, the sharp colloidal absorption rapidly developed when an AgClO4–SDS–acetone [(CH3)2CO] solution was irradiated under the same conditions. It has been shown by chemical analysis and TEM characterization of the reduced silver that some of the colloidal silver agglomerates formed as a result of photolysis were peptized to fine silver particles during irradiation. Acetone ketyl radical formed by excitation of (CH3)2CO with 253.7 nm light seems to have an ability to peptize colloidal agglomerate in the solution phase (peptizing action). A novel ‘photo-acetone method’ available for preparation of fine metal particles has been proposed and applied to obtain colloidal gold, copper and platinum.

The J aggregate of two cyanine dyes—dye I (5,6,5′,6′-dibenzo-1,1′-diethyl-2,2′- cyanine chloride) and dye II (5,5′-dichloro-3,3′-diethyl-9-phenyl-thiacarbocyanine chloride)—can be incorporated into acidic-phospholipid-containing Langmuir- Blodgett (LB) films. Dipalmitoyl-phosphatidylcholine (DPPC) and dipalmitoyl- phosphatidic acid (DPPA) were used for preparation of the LB films. An observation that J aggregation was difficult in the absence of negatively charged lipid species (DPPA) in the membrane reconfirms the importance of electrostatic interaction between negative charge at the matrix molecules and positive charge at the chromophore. The luminescence properties of the J aggregate in the more elaborate LB films with dye I and dye II aggregates at the same lipid surface were examined and interpreted in terms of excitation energy transfer from dye I to dye II aggregates.

Etude de l'adsorption de deux colorants cyaniniques sur des vesicules de dimyristoylphosphatidylcholine et de phosphate de dicetyl