Reduction of Pneumocystis jirovecii pneumonia and bloodstream infections by trimethoprim-sulfamethoxazole prophylaxis in patients with rheumatic diseases.

Objective: Trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis against Pneumocystis jirovecii pneumonia (PJP) is routinely administered to patients with rheumatic diseases in Japan. The present study aimed to evaluate the effect of TMP/SMX prophylaxis on PJP and non-central line-associated bloodstream infections (BSIs) in patients receiving high-dose glucocorticoids for the treatment of rheumatic diseases.Method: This study enrolled patients who were admitted between 1 October 2003 and 31 March 2018 and began high-dose glucocorticoid therapy for rheumatic diseases during hospitalization. The observation period was 4 months from the commencement of high-dose glucocorticoid therapy. The effect of TMP/SMX prophylaxis on PJP and non-central line-associated BSI was analysed.Results: Of the 437 patients included in the study, 376 received TMP/SMX prophylaxis and 61 patients did not. During the observation period, TMP/SMX prophylaxis was discontinued in 76 patients (20.2%). Three PJP cases (0.7%) occurred. Among the 399 patients included in our analysis of non-central line-associated BSI, eight experienced non-central line-associated BSI (2.0%). Among the covariates, TMP/SMX prophylaxis was associated with reduced PJP and non-central line-associated BSI incidence [odds ratio (OR) 0, 95% confidence interval (CI) 0.00-0.38, and OR 0.08, 95% CI 0.01-0.42, respectively].Conclusion: Routine TMP/SMX prophylaxis reduced the incidence of both PJP and BSI in patients with rheumatic diseases undergoing high-dose glucocorticoid therapy.

Absence of microsatellite instability in extramammary Paget's disease.

Background: Deficiency of DNA mismatch repair (MMR) induces microsatellite instability (MSI). Pembrolizumab, an antibody targeting PD-1 (an immune checkpoint inhibitor), is more effective against MMR-deficient tumours than against MMR-proficient tumours. The status of MMR is a useful biomarker for predicting the effectiveness of pembrolizumab administration. Although the status of MMR has attracted attention in skin tumours, there are few reports on MSI in extramammary Paget's disease (EMPD). Objectives: To evaluate the status of MMR in patients with EMPD. Materials & Methods: One hundred one patients with EMPD were included. MMR status of the genomic DNA of each subject was analysed using Promega panel (approved as a companion diagnostic agent for the administration of pembrolizumab). Results: MSI testing showed the occurrence rates of MSI-high (more than two markers are unstable), MSI-low (one marker is unstable) and MSS (all markers are stable) tumour tissues were 0% (0/101), 1.0% (1/101) and 99.0% (100/101), respectively. Conclusion: The status of MMR may not be useful for the potential therapeutic application of pembrolizumab.

Temporal and spatial variations of 134Cs and 137Cs levels in the Sea of Japan and Pacific coastal region: Implications for dispersion of FDNPP-derived radiocesium.

To investigate the dispersion of Fukushima Dai-ichi Nuclear Power Plant (FDNPP)-derived radiocesium in the Sea of Japan and western Pacific coastal region and determine the sources of radiocesium in these areas, we examined the temporal and spatial variations of 134Cs and 137Cs concentrations (activities) during 2011-2016 in seawaters around the western Japanese Archipelago, particularly in the Sea of Japan. In May 2013, the surface concentration of 134Cs was ∼0.5 mBq/L (decay-corrected to March 11, 2011), and that of 137Cs exceeded the pre-accident level in this study area, where the effects of radiocesium depositions just after the FDNPP accident disappeared in surface waters in October 2011. Subsequently, radiocesium concentrations gradually increased during 2013-2016 (∼0.5-1 mBq/L for 134Cs), exhibiting approximately homogeneous distributions in each year. The temporal and spatial variations of 134Cs and 137Cs concentrations indicated that FDNPP-derived radiocesium around the western Japanese Archipelago, including the Sea of Japan, has been supported by the Kuroshio Current and its branch, Tsushima Warm Current, during 2013-2016. However, in the Sea of Japan, the penetration of 134Cs was limited to depths of less than ∼200 m during three years following the re-delivery of FDNPP-derived radiocesium.

The role of PSMB9 upregulated by interferon signature in the pathophysiology of cutaneous lesions of dermatomyositis and systemic lupus erythematosus.

BACKGROUND: Dermatomyositis (DM) and systemic lupus erythematosus (SLE) have common skin features, including dermal mucin deposition and interferon signature, although their roles are unknown. OBJECTIVES: To identify common or specific molecular changes in DM and SLE skin. METHODS: Proteomic analysis was performed using DM and healthy skin. Glycosaminoglycans were analysed by high-performance liquid chromatography. RESULTS: The expression of 60 proteins was upregulated or downregulated in DM skin compared with healthy skin in the proteomic analysis. Among those proteins, PSMB9, an immunoproteasome subunit, was upregulated in the epidermis of DM and SLE, but not in other skin diseases. Furthermore, versican V1, a core protein for glycosaminoglycans, was upregulated, while type I collagen was downregulated in the dermis of DM and SLE skin. Interferon stimulated PSMB9 expression in cultured keratinocytes and reduced collagen expression in dermal fibroblasts, but did not affect versican expression. The PSMB9 knock-down in keratinocytes led to significant suppression of transforming growth factor (TGF)-ß2 and TGF-ß3, inducers of versican synthesis. TGF-ß3 expression was upregulated in both DM and SLE, while TGF-ß2 expression was increased only in the DM epidermis. ΔDiHS-diS1, a component of heparan sulfate, was significantly increased only in DM. TGF-ß2 expression significantly increased the ΔDiHS-diS1 expression in dermal fibroblasts in vitro. CONCLUSIONS: The interferon signature in DM and SLE skin reduces collagen in dermal fibroblasts, whereas overexpression of PSMB9 induced by interferon stimulates versican inducers in epidermal keratinocytes. In addition, the TGF-ß2-ΔDiHS-diS1 pathway may be responsible for the specific molecular change in DM skin.

Allelopathic and bioherbicidal potential of Cladonia verticillaris on the germination and growth of Lactuca sativa.

Responses to germination and initial growth of Lactuca sativa (lettuce) submitted to organic extracts and purified compounds of Cladonia verticillaris ("salambaia") were analyzed in this work. The experiments were conducted in laboratory conditions using extracts and pure compounds at different concentrations. None of the assays showed any influence on the germination of L. sativa seeds using C. verticillaris extracts; however, modifications in leaf area and seedling hypocotyl and root development occurred. In the growth experiments, seedlings exposed to ether or acetone extract showed diminished hypocotyl growth in detriment to the root stimulus, compared to controls. Increases in extract concentrations led to the formation of abnormal seedlings. To determine the allelochemicals of C. verticillaris, its principal components, fumarprotocetraric and protocetraric acids, were isolated and then analyzed by high performance liquid chromatography (HPLC). When the seedlings were exposed to the two acids separately, presented increased leaf area at all concentrations. In contrast, hypocotyl and root stimulus was observed only in the presence of protocetraric acid at different concentrations. Fumarprotocetraric as well as protocetraric acids, isolated and purified from C. verticillaris and Parmotrema dilatatum respectively, influenced the development of L. sativa seedlings at high concentrations, indicating a possible bioherbicide potential of these acids.

Radiolabelled agents for PET imaging of tumor hypoxia.

Hypoxia has been observed in a variety of human tumor types and evaluating tumor hypoxia is important because it increases resistance to radiotherapy and chemotherapy by inducing proteomic change that allow the tumor cell to survive in their hypoxic environment. One of the major proteomic changes is HIF-1 expression, and HIF-1 has become a target for anti-cancer drugs development because of its central role in hypoxia-mediated aggressiveness of tumor cells and their resistance to therapy. Since tumor hypoxia is a key mechanism that leads to resistance of treatment, a large number of challenges for hypoxia imaging including magnetic resonance, optical, and nuclear imaging have been reported. These hypoxia imaging techniques may have potential in selecting cancer patients who would benefit from treatments that overcome the presence of hypoxia. Hypoxia imaging could also be used to document whether or not and the extent to which reoxygenation of tumors occurs during cancer treatment. One of key requirements of ideal method for imaging hypoxia is that the method should be non-invasive. From an imaging perspective, PET is also one of leading tools for imaging hypoxia because of its high spatial resolution, high sensitivity, and advantages for visualizing molecular events in living human tissue. In this review, PET-based radiopharmaceuticals including (18)F-FMISO, (18)F-FETNIM, (18)F-FAZA, and radioactive Cu-ATSM were summarized from published studies about radiosyntheses, pre-clinical data, and clinical data, which are the lead contenders for human application.

Circulating miR-142-3p levels in patients with systemic sclerosis.

BACKGROUND: Recently, increased evidence has shown that serum micro (mi)RNA levels are a useful biomarker for the diagnosis, prognosis and therapeutic value of various diseases. However, serum miRNA has not been investigated in patients with systemic sclerosis (SSc), to our knowledge. AIM: To investigate the possibility that serum levels of Homo sapiens miR-142 stem-loop (hsa-miR-142-3p), one of the miRNAs regulating the expression of integrin αV, could be a specific disease marker for SSc. METHODS: Serum samples were obtained from 61 patients with SSc and 20 healthy controls. Patients with systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma spectrum disorder (SSD), who did not fulfil American College of Rheumatology criteria for SSc but might develop SSc in the future, were included as disease controls in this study. miRNAs were purified from serum, and miR-142-3p levels were measured with a quantitative real-time PCR assay. RESULTS: Serum miR-142-3p levels in patients with SSc were significantly higher than in patients with SSD, SLE or DM, and healthy control groups. Patients with increased miR-142-3p levels tended to have a short sublingual frenulum. CONCLUSIONS: Our data indicate that serum levels of miR-142-3p may be elevated specifically in patients with SSc, correlating with the severity of this disease, and may be useful diagnostic markers for the presence of SSc and for the differentiation of SSc from SSD.

Pinguecula and contact lenses.

PURPOSE: To assess the relationship between age and the incidence and severity (determined by a grading system) of pinguecula in contact lens (CL) wearers, and to compare the grade of pinguecula between CL wearers and non-wearers. METHODS: A total of 600 CL wearers (94 wore hard CLs (HCLs) and 506 wore soft CLs (SCLs)) aged 11-60 years and 579 non-wearers aged 10-60 years were enrolled. The age, gender, medical history, ocular history, and grade of pinguecula at two locations (nasal and temporal) were determined in all subjects. RESULTS: There was an age-related increase in the grade of pinguecula among both CL wearers and non-wearers. The grade of pinguecula at the temporal conjunctiva was higher in CL wearers than in non-wearers (P=0.01907), whereas it was higher in HCL wearers than SCL wearers at both the nasal and temporal conjunctiva (P<0.00001 and P<0.00001). CONCLUSIONS: This was the first assessment of the severity of pinguecula in a large consecutive series of CL wearers. Our results suggest that the use of CLs is an important risk factor for pinguecula.

Study of change in brain activity due to blood flow while playing Shogi (Japanese chess).

BACKGROUND: The study of brain activity has been studied with the use of various techniques like electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission topography (PET) and magneto-encephalography (MEG). These techniques are unsuitable because of restriction of moving of subject's body while playing "shogi (Japanese Chess)" matching However, optical topography (OT) is possible to measure. Therefore, brain activity is here studied with use of OT. MATERIALS AND METHOD: The measurement and analyses of the activity of brain is carried out by cerebral blood flow with use of OT. The equipment of OP is 16-channel maximum OMM-2000 device (Shimadzu, Tokyo, Japan). Two subjects play the game, and the cerebral blood flow of only one subject is measured, since the capacity of the equipment is limited. RESULTS AND CONCLUSION: When the subject does decision-making for a matter of chance during the game, the right side of frontal part (Fp2) proves more activity than that of left side (Fp1), and proves that the activity of both parts of visual field (O1, O2) communicates each other. The present study with use of OT is highly useful for observing brain activity during play of shogi game.

Impaired lymphangiogenesis due to excess vascular endothelial growth factor-D/Flt-4 signalling in the skin of patients with systemic sclerosis.

BACKGROUND: Vascular abnormalities are one of the primary pathological components of systemic sclerosis (SSc). However, it has not been determined if there are also abnormalities in the formation of lymphatic vessels in SSc. OBJECTIVE: To evaluate lymphangiogenic activity in SSc skin. METHODS: The numbers of D2-40-positive lymphatic vessels in skin specimens from healthy control subjects and patients with SSc were counted and compared. Quantitative real-time polymerase chain reaction (PCR) was performed to determine mRNA levels of vascular endothelial growth factor (VEGF)-D and Flt-4 (fms-related tyrosine kinase 4, VEGFR-3, one of the receptors for VEGF-D) in the skin. Serum VEGF-D levels were measured with specific enzyme-linked immunosorbent assays. RESULTSZ: The number of lymphatic vessels in patients with SSc was significantly decreased compared with healthy control subjects. Mean relative transcript levels of FIGF (VEGF-D) and FLT4 (Flt-4) in skin tissue from patients with SSc were significantly increased compared with healthy control subjects. By the analysis of the association between serum VEGF-D levels and the clinical or laboratory features, we found that patients with SSc with higher serum VEGF-D levels more frequently have skin ulcers than those with normal VEGF-D levels. CONCLUSIONS: A systemic increase of VEGF-D, as well as local overexpression of FIGF and FLT4, may be the cause of disturbed lymphangiogenesis in SSc skin and play a role in the pathogenesis of SSc. We showed the possibility that regulation of VEGF-D/Flt-4 signalling could lead to new treatment of skin ulcers in SSc by controlling the formation of lymphatic vessels.

Serum levels of soluble vascular endothelial growth factor receptor-2 in patients with systemic sclerosis.

BACKGROUND: Although vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (KDR) signalling may play a major role in the microangiopathy of systemic sclerosis (SSc), serum levels of soluble KDR (sKDR) in this disease have not yet been determined. OBJECTIVES: To evaluate the possibility that serum sKDR levels can be a specific disease marker of SSc. METHODS: Serum sKDR levels of 42 patients with SSc, 10 patients with Raynaud's phenomenon (RP) and 22 healthy controls were measured with specific enzyme-linked immunosorbent assays. Quantitative real-time polymerase chain reaction (PCR) was performed to determine KDR mRNA levels. RESULTS: In females, the serum sKDR levels were significantly higher in patients with SSc, especially limited cutaneous SSc, than in patients with RP or healthy controls. Quantitative real-time PCR with RNA from skin sections revealed that KDR mRNA levels were also increased in the skin of patients with SSc with elevated serum sKDR levels. A significantly lower prevalence of pulmonary fibrosis, higher percentage vital capacity, and a higher incidence of telangiectasia were seen in female patients with SSc with elevated serum sKDR levels than those with normal levels. CONCLUSIONS: These results suggest that the skin can be one of the sources of elevated serum sKDR levels, and that serum sKDR levels are useful for diagnosis and may be a marker of microangiopathy in patients with SSc, especially females. The VEGF-A/KDR signalling system may be involved in the pathogenesis of the disease.

Antimycobacterial activity of lichen substances.

We describe here the extraction and identification of several classes of phenolic compounds from the lichens Parmotrema dilatatum (Vain.) Hale, Parmotrema tinctorum (Nyl.) Hale, Pseudoparmelia sphaerospora (Nyl.) Hale and Usnea subcavata (Motyka) and determined their anti-tubercular activity. The depsides (atranorin, diffractaic and lecanoric acids), depsidones (protocetraric, salazinic, hypostictic and norstictic acids), xanthones (lichexanthone and secalonic acid), and usnic acid, as well seven orsellinic acid esters, five salazinic acid 8',9'-O-alkyl derivatives and four lichexanthone derivatives, were evaluated for their activity against Mycobacterium tuberculosis. Diffractaic acid was the most active compound (MIC value 15.6mug/ml, 41.6 microM), followed by norstictic acid (MIC value 62.5 microg/ml, 168 microM) and usnic acid (MIC value 62.5 microg/ml, 182 microM). Hypostictic acid (MIC value 94.0 microg/ml, 251 microM) and protocetraric acid (MIC value 125 microg/ml, 334 microM) showed moderate inhibitory activity. The other compounds showed lower inhibitory activity on the growth of M. tuberculosis, varying from MIC values of 250 to 1370 microM.

Relationship between refraction and allergic conjunctivitis.

PURPOSE: External allergens are the main causative factor in the pathogenesis of allergic diseases; however, little is known about internal factors such as the biometrical structure of the eye. We investigated the relationship between refractive error and allergic conjunctivitis in order to reveal possible insights into the pathogenesis in 1015 subjects. METHODS: The patients were divided into four groups: contact lens wearers with allergic conjunctivitis (n=73), contact lens wearers without allergic conjunctivitis (n=59), non-contact lens wearers with allergic conjunctivitis (n=224), and non-contact lens wearers without allergic conjunctivitis (n=659). The spherical power, cylindrical power, corneal radius, and minimum and maximum corneal refractive powers were measured in all subjects. RESULTS: In the non-contact lens wearers, the spherical equivalent and spherical power were significantly lower in patients with allergic conjunctivitis than in patients without allergic conjunctivitis (-3.01+/-3.83 D vs-1.36+/-3.08 D, P<0.0001, and -2.64+/-3.63 D vs-1.05+/-2.88 D, P<0.0001, respectively), while there was no significant difference in any of the parameters between the contact lens wearers with and without allergic conjunctivitis. CONCLUSION: Refractive error may be a risk factor for allergic conjunctivitis.

Longitudinal analysis of corneal topography in suspected keratoconus.

AIMS: To examine the incidence of progression of suspected keratoconus to true keratoconus and compare quantitative descriptors of corneal topography between eyes with and without progression. METHODS: 34 eyes with suspected keratoconus were retrospectively reviewed in 34 patients. Their age at the initial examination was 13 to 40 years (24.1 (7.5), mean (SD)), and the follow-up periods ranged from 3 to 10 years (6.0 (2.2) years). Suspected keratoconus was defined as the fellow eye of a clinically apparent keratoconus but that had no slit-lamp signs of keratoconus (Fleischer ring, Vogt striae and Munson sign) with a best spectacle-corrected visual acuity of 20/20 or better. Eyes were monitored for the progression of apparent slit-lamp findings of keratoconus during the follow-up period. Using a Fourier analysis of the corneal topography data, regular astigmatism, asymmetry component and higher-order irregularity component were calculated in the central 3 mm zone. Quantitative descriptors of corneal topography were compared between eyes which progressed to true keratoconus and those which did not. RESULTS: Five eyes (14.7%) progressed to apparent keratoconus from suspected keratoconus (progression group), and 29 eyes did not (non-progression group). On average, it took 5.2 years for the eyes to develop apparent slit-lamp findings of keratoconus. The cumulative incidence of progression by Kaplan-Meier analysis was 21.5% in 6 years. The asymmetry component and regular astigmatism by Fourier analysis at the initial examination were significantly larger in the progression group than in the non-progression group. CONCLUSION: In our retrospective study, approximately 20% of eyes with suspected keratoconus progressed to true keratoconus in 6 years, and these eyes had presented greater asymmetry and regular astigmatism at the initial examination.

Penetrating keratoplasty for bullous keratopathy after trabeculectomy.

PURPOSE: To evaluate the results of penetrating keratoplasty (PK) in eyes with bullous keratopathy having previously undergone trabeculectomy. METHODS: We reviewed medical records of patients that had undergone PK for bullous keratopathy having previously undergone trabeculectomy. A total of 34 eyes in 34 patients were included in the study. As a control group, we reviewed the medical records of 26 eyes in 26 patients that had no history of glaucoma and who had undergone PK for bullous keratopathy in the same period at the same institutes. Kaplan-Meier survival analysis was performed to estimate the cumulative probability of successful intraocular pressure (IOP) control, immune reaction-free graft, and graft survival. RESULTS: Visual acuity improved by more than two lines in 30-34 eyes (88%). Log-rank tests showed a statistically significant difference in the cumulative probability of successful IOP control between eyes with functioning blebs and eyes with non-functioning blebs (P=0.0005), but not between the experimental subjects of 34 eyes and the control group (P=0.198). The log-rank test did not show statistically significant differences in the cumulative probability of immune reaction-free grafts and graft failure between the subjects and the control group and between eyes with functioning blebs and eyes with non-functioning blebs. CONCLUSION: The outcomes for PK in bullous keratopathy are good for patients having previously undergone trabeculectomy. Surgical procedures should be performed before PK in eyes with non-functioning blebs even when IOP is controllable with medication.

Testicular sperm extraction and ICSI in patients with post-chemotherapy non-obstructive azoospermia.

146 MD-TESE procedures were performed in 74 patients presenting with non-obstructive azoospermia (NOA). Five of the 74 patients displayed a history of chemotherapy. Etiology of chemotherapies included testicular cancer, osteosarcoma, Ewing sarcoma, and malignant lymphoma of the stomach. Post-chemotherapy duration was 2.5-18 years. All patients underwent MD-TESE using local anesthesia with spermatic block and sedation. Extracted sperm was cryopreserved for ICSI. Histopathologic examination revealed Sertoli cell-only syndrome in all five patients; however, sperm were retrieved in 3 subjects. Post-chemotherapy MD-TESE and ICSI can be applied successfully in some patients with NOA. However, freezing semen prior to chemotherapy is recommended.

The co-existence of an aberrant origin of the right subclavian artery and a coronary myocardial bridge.

We encountered the co-existence of an aberrant origin of the right subclavian artery and a myocardial bridge on the left anterior descending coronary artery in the cadaver of an 80-year-old Japanese woman during the course of educational dissection at Nagoya City University Medical School. We document the precise gross anatomical findings with some morphometric measurements. Neither an aberrant origin of the right subclavian artery nor the cardial myocardial bridge is a very rare anomaly, but a case of both anomalies being found in the same body is very rare. We believe this is the first report of the simultaneous occurrence of these two anomalies.