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.

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.

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.

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.

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.

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.

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.

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.

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 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.

Mouse model of Bell's palsy induced by reactivation of herpes simplex virus type 1.

In order to investigate the mechanism of Bell's palsy, we developed an animal model of facial nerve paralysis induced by the reactivation of herpes simplex virus type 1 (HSV-1). Eight weeks after recovery from facial nerve paralysis caused by inoculation with HSV-1, the mice were treated with auricular skin scratch at the site of the previous inoculation, or with intraperitoneal injection of anti-CD3 monoclonal antibody (mAb), or combination of both procedures. No mice developed facial nerve paralysis when they were treated with either auricular scratch or mAb injection alone. In contrast, 20% of mice developed facial nerve paralysis with the combined treatment. With one exception, no mouse treated with either auricular scratch or mAb injection showed HSV-I DNA in their facial nerve tissue, whereas 4 out of 6 mice receiving both treatments showed HSV-1 DNA on day 10 after treatment. Histopathological findings showed neuronal degeneration in the geniculate ganglion and demyelination of the facial motor nerve in paralyzed mice. These findings suggest that a combination of stimuli, local skin irritation, and general immunosuppression is essential for successfully inducing facial nerve paralysis in mice with latent HSV-1 infection.

Characterization of insulin-like growth factor I receptor on human erythrocytes.

[125I]Insulin-like growth factor I (IGF-I) specifically bound to erythrocytes; the binding was saturable, and time and temperature dependent. Steady state binding was reached at 16 h at 4 C, and specific binding averaged 14.3 +/- 0.7% (+/- SEM) at a concentration of 3.6 X 10(9) cells/ml in seven normal subjects. [125I]IGF-I binding to the cells was displaced by unlabeled IGF-I in a dose-dependent manner. Scatchard analysis indicated a linear plot, and Ka and number of binding sites/cell were 1.43 +/- 0.07 X 10(9) M-1 and 20.7 +/- 2.2, respectively. Compared to IGF-I, the relative potencies of multiplication-stimulating activity and insulin for displacing [125I]IGF-I binding were 20% and 1%, respectively. [125I]IGF-I binding to erythrocytes from patients with acromegaly was lower than binding to cells from pituitary dwarfs. An inverse correlation between plasma IGF-I level and the number of IGF-I-binding sites per cell was found (r = -0.75; P less than 0.005). These results demonstrate that [125I]IGF-I binding to erythrocytes can be used for clinical measurement of the IGF-I receptor.

Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration.

A 52-year-old woman had a newly recognized disorder of familial hypoceruloplasminemia, blepharospasm, retinal degeneration, and high-density areas in CT of the basal ganglia and liver scan. Immunofixation electrophoresis disclosed apoceruloplasmin deficiency. Kinetic, x-ray analysis, and histochemical study showed accumulation of iron in liver and brain, but not of copper. Intestinal copper absorption was reduced, but liver uptake was increased. Ceruloplasmin is involved in iron metabolism, and the findings suggest that hypoceruloplasminemia due to lack of apoceruloplasmin was causally linked to the iron deposition in basal ganglia and other organs, leading to blepharospasm and retinal degeneration.

Rapid diagnosis of varicella zoster virus infection in acute facial palsy.

Patients with zoster sine herpete and Ramsay Hunt syndrome without pathognomonic vesicles at the initial visit are often misdiagnosed with Bell's palsy and treated without antiviral agents. With PCR, we found that varicella zoster virus genomes were frequently detectable in auricular skin exudate from patients with zoster sine herpete or Ramsay Hunt syndrome before the appearance of vesicles.

Silver nitrate cauterization: characterization of a new model of corneal inflammation and hyperalgesia in rat.

Chemical cauterization of the central cornea with silver nitrate was assessed as a superficial injury model of tissue sensitization accompanying acute inflammation. Adult male Sprague-Dawley rats were anesthetized with halothane gas, and the centers of their right corneas treated with a silver nitrate applicator stick (75% silver nitrate, 25% potassium nitrate) to produce a discrete lesion 1 mm in diameter. Edema of the corneal stroma and elevated immune cell counts became significant 4 h after cauterization, and were still evident after 48 h. Behavioral sensitization to chemical stimuli was determined by counting the number of blinks following application of 1 microM capsaicin directly to the corneal surface. A significant increase in stimulus-induced blinking was evident 2 h after cauterization. Chemical sensitization peaked at 6 h, and was no longer significant at 12 h. We conclude that silver nitrate cauterization produces acute corneal inflammation and hyperalgesia, and may prove a useful model for the study of primary afferent nociceptors.

Effect of morphine sulphate eye drops on hyperalgesia in the rat cornea.

In addition to their traditional role in centrally mediated analgesia, opiate compounds produce significant effects when administered peripherally. Using a recently characterized model of acute chemical injury to the rat cornea, we assessed the effects of morphine sulphate eye drops on corneal inflammation and hyperalgesia. Topical application of a 5 microM morphine sulphate eye drop preparation attenuated capsaicin-induced blinking in a concentration-dependent manner. However, morphine had no effect on capsaicin-induced blinking when applied to healthy, non-inflamed rat cornea. In addition, 5 microM morphine given every 2 h following cauterization retarded the development of both stromal edema and the infiltration of immune cells. Both the analgesic and anti-inflammatory effects of morphine were prevented by the opioid receptor antagonists naloxone, CTAP, and naltrindole. We conclude that morphine acts on mu and delta opioid receptors located in the rat cornea to attenuate inflammation and hyperalgesia.

Cerebral vasodilatory capacity mapping using technetium-99m-DTPA-HSA SPECT and acetazolamide in moyamoya disease.

A cerebral vasodilatory capacity map, consisting of a 99mTc-DTPA-HSA SPECT image obtained after acetazolamide injection minus the baseline image, was produced in a patient with moyamoya disease. The map demonstrated diminished capacity in the posterior region of the right cerebral hemisphere. Subsequently, cerebral infarction occurred in the corresponding area. This observation suggests that regions of low vasodilatory capacity identified by cerebral vasodilatory capacity mapping may be at high risk of ischemic stroke.

Bile duct carcinoma associated with multiple von Meyenburg complexes in the liver.

A 61-year-old white woman was found to have disseminated abdominal carcinoma at autopsy. The primary site proved to be a bile duct carcinoma arising from ductal epithelium of multiple von Meyenburg complexes of the liver. No other neoplastic lesion was found elsewhere after careful, gross, microscopic examination. This case is thought to represent malignant transformation of the hamartomatous growth, previously reported only exceptionally.