Efficient and precise fabrication of Wolter type-I x-ray mirrors via nickel electroforming replication using quartz glass mandrels.

This study presents an approach for fabricating Wolter type-I mirrors for x-ray telescopes using a nickel electroforming replication process with quartz glass mandrels. The proposed method addresses the challenges encountered in conventional fabrication techniques, which involve using electroless nickel-coated aluminum mandrels that are susceptible to corrosion and thermal deformation. Quartz glass mandrels offer excellent chemical, thermal, and mechanical stability, enabling the efficient production of high-performance mirrors. Wolter type-I mirrors for telescopes possess a large aperture that collects x-ray photons from the universe. However, previous nickel electroforming replication processes using quartz glass mandrels have challenges in fabricating large mirrors, particularly due to bubble pit formation during nickel shell development. In this study, we introduced an efficient pitting inhibition technique via vacuum degassing. This technique facilitates the precise replication of pit-free Wolter type-I mirrors for telescopes using quartz glass mandrels. We demonstrated the fabrication process on a Wolter type-I mirror proposed for FOXSI-4 [(FOXSI) Focusing Optics X-ray Solar Imager], resulting in three mirrors obtained from the same mandrel without repolishing or repairing. The figure error of the mirror was within 1 µm over most areas in both longitudinal and circumferential directions. The ray-tracing simulation indicated that the performance of the mirror was ∼12 arcsec in half-power diameter, comparable to the performance achieved by previous high-resolution x-ray missions.

Fabrication of soft x-ray monolithic Wolter mirror based on surface scanning measurement using touch probe.

The monolithic Wolter mirror is an ideal optical device for focusing soft x rays to a submicron-sized spot, with the advantages of high efficiency, large acceptance, achromaticity, and robustness to alignment error. The fabrication process for this type of mirror has not been established because of the difficulty in highly accurate figure measurement of free-form surfaces with small radii of curvature and steep profiles. In this study, we employed tactile scanning measurement for surface characterization to fabricate a high-precision Wolter mirror. First, it was demonstrated that the touch probe measurement did not leave scratches on the raw surface of the mirror substrate. Next, the measurement capability of the surface profiler was assessed, and the data analysis conditions were determined. Finally, the Wolter mirror was fabricated through repeated figure correction based on the tactile measurement, and the figure error of the final surface was evaluated. Wave-optical simulations that used this error as reference suggested that the size of the beam focused by the mirror was equivalent to the theoretical value at 1000 eV. The reflected image with uniform intensity distribution obtained at SPring-8 also revealed the effectiveness of the present fabrication approach based on tactile measurement.

Apolipoprotein E binds to and reduces serum levels of DNA-mimicking, pyrrolated proteins.

Lysine N-pyrrolation, converting lysine residues to Nϵ-pyrrole-l-lysine, is a recently discovered post-translational modification. This naturally occurring reaction confers electrochemical properties onto proteins that potentially produce an electrical mimic to DNA and result in specificity toward DNA-binding molecules such as anti-DNA autoantibodies. The discovery of this unique covalent protein modification provides a rationale for establishing the molecular mechanism and broad functional significance of the formation and regulation of Nϵ-pyrrole-l-lysine-containing proteins. In this study, we used microbeads coupled to pyrrolated or nonpyrrolated protein to screen for binding activities of human serum-resident nonimmunoglobin proteins to the pyrrolated proteins. This screen identified apolipoprotein E (apoE) as a protein that innately binds the DNA-mimicking proteins in serum. Using an array of biochemical assays, we observed that the pyrrolated proteins bind to the N-terminal domain of apoE and that oligomeric apoE binds these proteins better than does monomeric apoE. Employing surface plasmon resonance and confocal microscopy, we further observed that apoE deficiency leads to significant accumulation of pyrrolated serum albumin and is associated with an enhanced immune response. These results, along with the observation that apoE facilitates the binding of pyrrolated proteins to cells, suggest that apoE may contribute to the clearance of pyrrolated serum proteins. Our findings uncover apoE as a binding target of pyrrolated proteins, providing a key link connecting covalent protein modification, lipoprotein metabolism, and innate immunity.

[A Case of Primary Testicular Mucinous Carcinoma].

A 68-year-old man presented withleft testicular painless swelling. His carbohydrate antigen 19-9 and carcinoembryonic antigen levels were elevated but his germ cell tumor markers were not high. Magnetic resonance imaging showed multiloculated cystic lesions with solid components in his left testis. Abdominal and chest computed tomography revealed multiple lung metastases, peritoneal dissemination and multiple lymph node metastases. Left high orchiectomy was performed. Histopathological examination demonstrated testicular mucinous carcinoma withsimilarity to gastric cancer. Since no tumor was found by the endoscopy of the upper gastrointestinal and the lower digestive tract, we diagnosed the patient with primary testicular mucinous carcinoma. Standard chemotherapy for gastric cancer, which consisted of tegafur, gimeracil and oteracil (TS-1) and cisplatin was administered for 16 months, and there was no progression of the disease. He died from testicular mucinous cancer 30 months after the diagnosis. In the literature, only 4 cases of testicular mucinous carcinoma have been reported. TS-1 and cisplatin are useful chemotherapeutic options for testicular mucinous carcinoma withmetastasis.

Randomized study of intravesical pirarubicin chemotherapy with low and intermediate-risk nonmuscle-invasive bladder cancer in Japan: Comparison of a single immediate postoperative intravesical instillation with short-term adjuvant intravesical instillations after transurethral resection.

PURPOSE: The objective of this study was to evaluate the efficacy, defined by the 3-year tumor recurrence-free survival rate, of intravesical chemotherapy using pirarubicin (THP) in patients with low or intermediate-risk nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Between October 2010 and January 2015, 206 patients were enrolled, and finally 113 were randomized to receive either a single immediate postoperative intravesical instillation of THP (30 mg) (Group A), or 8 additional weekly intravesical instillations of THP (30 mg) after a single postoperative instillation (Group B). The patients were examined by performing cystoscopy and urine cytology every 3 months after transurethral resection to determine bladder tumor recurrence. The primary endpoint was 3-year-recurrence-free survival rate. RESULTS: All 113 patients were bacillus Calmette-Guérin (BCG)-naïve. The 3-year recurrence free survival rate was 63.7% for Group A and 85.3% for Group B (log-rank test, P = .0070). In patients with intermediate recurrence risk, the 3-year recurrence-free survival rate was 63.4% in Group A and 86.1% in Group B (log-rank test, P = .0036). Cox regression analysis revealed that only additional instillation of THP was a significant independent factor for recurrence-free rate in patients with intermediate risk. No patient with progression was noted during this period. Frequent adverse effects (AEs) were frequent urination and micturition pain, and no severe AEs (Grade 3 or more) occurred. CONCLUSION: Additional instillation of THP (30 mg) weekly for 8 weeks reduced the risk of tumor recurrence without severe AEs in BCG-naïve NMIBC patients with intermediate risk.

Mevalonate pathway blockage enhances the efficacy of mTOR inhibitors with the activation of retinoblastoma protein in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common malignancy of kidney and remains largely intractable once it recurs after resection. mTOR inhibitors have been one of the mainstays used against recurrent RCC; however, there has been a major problem of the resistance to mTOR inhibitors, and thus new combination treatments with mTOR inhibitors are required. We here retrospectively showed that regular use of antilipidemic drug statins could provide a longer progression free survival (PFS) in RCC patients prescribed with an mTOR inhibitor everolimus than without statins (median PFS, 7.5 months vs. 3.2 months, respectively; hazard ratio, 0.52; 95% CI, 0.22-1.11). In order to give a rationale for this finding, we used RCC cell lines and showed the combinatorial effects of an mTOR inhibitor with statins induced a robust activation of retinoblastoma protein, whose mechanisms were involved in statins-mediated hindrance of KRAS or Rac1 protein prenylation. Finally, statins treatment also enhanced the efficacy of an mTOR inhibitor in RCC xenograft models. Thus, we provide molecular and (pre)clinical data showing that statins use could be a drug repositioning for RCC patients to enhance the efficacy of mTOR inhibitors.

Lysine pyrrolation is a naturally-occurring covalent modification involved in the production of DNA mimic proteins.

Covalent modification of proteins exerts significant effects on their chemical properties and has important functional and regulatory consequences. We now report the identification and verification of an electrically-active form of modified proteins recognized by a group of small molecules commonly used to interact with DNA. This previously unreported property of proteins was initially discovered when the γ-ketoaldehydes were identified as a source of the proteins stained by the DNA intercalators. Using 1,4-butanedial, the simplest γ-ketoaldehyde, we characterized the structural and chemical criteria governing the recognition of the modified proteins by the DNA intercalators and identified N(ε)-pyrrolelysine as a key adduct. Unexpectedly, the pyrrolation conferred an electronegativity and electronic properties on the proteins that potentially constitute an electrical mimic to the DNA. In addition, we found that the pyrrolated proteins indeed triggered an autoimmune response and that the production of specific antibodies against the pyrrolated proteins was accelerated in human systemic lupus erythematosus. These findings and the apparent high abundance of N(ε)-pyrrolelysine in vivo suggest that protein pyrrolation could be an endogenous source of DNA mimic proteins, providing a possible link connecting protein turnover and immune disorders.

Multispecificity of immunoglobulin M antibodies raised against advanced glycation end products: involvement of electronegative potential of antigens.

BACKGROUND: Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses. RESULTS: Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins. CONCLUSION: There is a close relationship between the formation of AGEs and innate immune responses. SIGNIFICANCE: Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies Advanced glycation end products (AGEs) are a heterogeneous and complex group of compounds that are formed when reducing sugars, such as dehydroascorbic acid, react in a nonenzymatic way with amino acids in proteins and other macromolecules. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect the extracellular and intracellular structure and function. In the present study, we studied the immune response to the dehydroascorbic acid-derived AGEs and provide multiple lines of evidence suggesting that the AGEs could be an endogenous source of innate epitopes recognized by natural IgM antibodies. Prominent IgM titers to the AGEs were detected in the sera of normal mice and were significantly accelerated by the immunization with the AGEs. Patients with systemic lupus erythematosus (SLE), a potentially fatal systemic autoimmune disease characterized by the increased production of autoantibodies, showed significantly higher serum levels of the IgM titer against the AGEs than healthy individuals. A progressive increase in the IgM response against the AGEs was also observed in the SLE-prone mice. Strikingly, a subset of monoclonal antibodies, showing a specificity toward the AGEs, prepared from normal mice immunized with the AGEs and from the SLE mice cross-reacted with the double-stranded DNA. Moreover, they also cross-reacted with several other modified proteins, including the acetylated proteins, suggesting that the multiple specificity of the antibodies might be ascribed, at least in part, to the increased electronegative potential of the proteins. These findings suggest that the protein modification by the endogenous carbonyl compounds, generating electronegative proteins, could be a source of multispecific natural antibodies.

Dacryoendoscopic observation and incidence of canalicular obstruction/stenosis associated with S-1, an oral anticancer drug.

PURPOSE: To report dacryoendoscopic observations and the incidence of lacrimal obstruction/stenosis associated with S-1, an oral anticancer drug. DESIGN: Retrospective, nonrandomized clinical trial. METHODS: A total of 52 patients (41 men, 11 women; age 42-93 years) who were prescribed the anticancer drug S-1 were studied. Patients who suffered eye complaints following S-1 treatment underwent ophthalmic examination, probing and lacrimal irrigation. Patients whose tear meniscus was high or had abnormal lacrimal irrigation were evaluated by dacryoendoscopy. RESULTS: Overall, 5 of 52 S-1-treated patients (9.6%) experienced lacrimal passage stenosis/obstruction. One patient had punctal stenosis, and four patients had canalicular obstruction/stenosis. The onset of epiphora ranged from 2 to 8 months (4.4 ± 2.2 months, mean ± SD) after the initiation of chemotherapy. CONCLUSIONS: Patients receiving S-1 treatment should be evaluated for potential lacrimal disorders, particularly canalicular obstruction/stenosis. Dacryoendoscopic observation is effective for the diagnosis of this side effect.

Comparison between stereo angiographic findings and histopathologic findings in endotoxin-induced uveitis.

PURPOSE: To carry out a three-dimensional analysis of uveitis using stereo angiography. MATERIALS AND METHODS: Endotoxin-induced uveitis was induced by injecting lipopolysaccharide into the rat footpad, and the findings of stereo angiography with a scanning laser ophthalmoscope were compared to histopathologic results. RESULTS: On day 2, multiple hyperfluorescent spots were observed by indocyanine green stereo angiography, which appeared to be in the superficial layer of the retina. Histopathologic findings showed infiltration of leukocytes into the corresponding area, which was the retinal nerve fiber layer. CONCLUSIONS: Stereo angiography was considered useful for three-dimensional analysis of uveitis lesions in the retina and choroid.

A new index of "cardiac age" derived from echocardiography: influence of hypertension and comparison with pulse wave velocity.

Although pulse wave velocity is the primary indicator of arteriosclerosis and is widely used as an index of vascular age in anti-aging medicine, no index is available to quantify cardiac age. We proposed a "cardiac age" index and sought to clarify its clinical significance. The study subjects were 234 patients with atherosclerosis-related diseases. These patients were divided into 127 normotensive (mean age: 64+/-12 years) and 107 hypertensive (mean age: 65+/-11 years) patients. Echocardiography was performed, and brachial-ankle pulse wave velocity (baPWV) was measured using an automatic waveform analyzer. The index of cardiac age was determined as 1,000xVS(ot)/BSA/(VS-AO), where VSot (mm) was the ventricular septal thickness at the left ventricular outflow tract, BSA (m2) was the body surface area, and VS-AO (degree) was the angle between the basal ventricular septum and the ascending aorta. The index of cardiac aging correlated significantly with age in both the normotensive (r=0.63, p<0.001) and hypertensive (r=0.58, p<0.001) patients, and these correlations were closer than those between transmitral E/A (early to atrial velocity) ratio and age in normotensive (r=0.54, p<0.001) and hypertensive (r=0.44, p<0.001) patients. The slope between age (x-axis) and the index of cardiac age (y-axis) was greater in hypertensive (1.50) than normotensive (1.32) patients. Stepwise regression analysis showed that age (beta coefficient=0.35, p<0.001), the presence of hypertension (beta coefficient=0.26, p<0.001), the left ventricular mass index (beta coefficient=0.34, p<0.001), the left ventricular end-diastolic dimension (beta coefficient=-0.35, p<0.001), the dimension of the left atrium (beta coefficient=0.14, p=0.014), and the ratio of E to A (E/A) (beta coefficient=-0.12, p=0.046) were independently associated with the index of cardiac age. The index was also significantly correlated with baPWV (r=0.53, p<0.001). The proposed index of cardiac age can quantitatively assess cardiac morphological changes due to aging and/or hypertension and may be a useful marker of peripheral arterial stiffening.

Preoperative administration of chlormadinone acetate reduces blood loss associated with transurethral resection of the prostate: a prospective randomized study.

OBJECTIVES: To assess the effects of giving chlormadinone acetate (CMA) before surgery on blood loss associated with transurethral resection of the prostate (TURP), in a prospective randomized controlled study. PATIENTS AND METHODS: Candidates for TURP among patients with benign prostatic hyperplasia were randomized to either treatment with CMA (CMA+) or not (CMA-). In principle, CMA was started at least 28 days before TURP and continued until just before surgery. RESULTS: In all, 33 patients in the CMA+ (median duration of treatment 34.5 days) and 38 in the CMA- group were evaluable. The mean blood loss during TURP was less in the CMA+ (237.3 mL) than in the CMA- group (263.1 mL), but the difference was not significant. There was significantly less blood loss per gram of resected prostate tissue in the CMA+ (9.6 mL/g) than in the CMA- group (13.3 mL/g) (P < 0.05). Haematuria on the day of and the day after TURP was also significantly less severe in the CMA+ than in the CMA- group (P < 0.001 and P < 0.05, respectively). The mean microvessel density of resected prostate tissue was significantly less after CMA treatment (P < 0.001). CONCLUSIONS: CMA given for 1 month before TURP could reduce blood loss to some extent during and after TURP, and this may be related to a decrease in microvessel density.

[A case of brittle diabetes in a 94-year-old man with vascular dementia, visual disturbance and hearing difficulty].

A 94-year-old man had with vascular dementia, visual disturbance, hearing difficulty and speech and motor disturbance. He had a history of diabetes mellitus over 50 years. He developed brittle type diabetes. On administration of mixed type insulin (30: 70.12-18 units in the morning and 6-8 units in the evening), his blood glucose concentrations fluctuated from almost zero to 500-600 mg/dl. After change to short acting regular insulin (4-5 units) before each meal and intermediate type insulin (2 units) before sleeping time, extreme hyperglycemia was not observed, but the brittleness with frequent hypoglycemia persisted. The hypoglycemic symptoms were absent at the time of striking hypoglycemia: it was thought that the patient was condition unaware of hypoglycemia. The cause of the brittle diabetes in the extremely elderly was thought to be depletion of endocrine insulin secretion due to marked beta-cell reduction and/or beta-cell exhaustion secondary to long term duration of diabetes. Daily detailed observation is required to care for such mentally deteriorated patient with brittle diabetes.

Ultrasonic measurement of bladder weight as a possible predictor of acute urinary retention in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

Acute urinary retention (AUR) is one of the most undesirable events for elderly men with benign prostatic hyperplasia (BPH). This study was designed to test the clinical utility of ultrasonic measurement of bladder weight as a predictor of AUR. A total number of 160 men visited our clinic with lower urinary tract symptoms (LUTS) suggestive of BPH and underwent urodynamic studies, including transrectal ultrasonography of the prostate and the measurement of ultrasound (US) estimated bladder weight (UEBW). Among them, 31 (19.4%) presented to our clinic with AUR. From the thickness of the anterior bladder wall measured by transabdominal ultrasonography and the intravesical volume, UEBW was calculated, supposing the bladder to be a sphere. Between patients with and without AUR, there were significant differences for age (75.4 vs. 71.1 years, p < 0.005), prostatic volume (45.5 vs. 35.8 g, p < 0.05), transition zone (TZ) volume (29.4 vs. 20.2 g, p < 0.05), TZ index (0.606 vs. 0.493, p < 0.005) and UEBW (50.3 vs. 34.7 g, p < 0.0001). A receiver-operating characteristic curve analysis demonstrated UEBW to be superior to the other prostatic ultrasonic measures in identifying AUR. Patients with LUTS suggestive of BPH having UEBW greater than 35.0 g were 13.4 times as likely to suffer from AUR. The significant association of UEBW with an increased risk of AUR suggests that it would be promising as a noninvasive urodynamic parameter capable of identifying patients at increased risk of AUR.

Clinical utility of ursodeoxycholic acid in preventing flutamide-induced hepatopathy in patients with prostate cancer: a preliminary study.

BACKGROUND: The present study was designed to ascertain retrospectively the validity of ursodeoxycholic acid (UDCA) in the treatment of prostate cancer in terms of prophylactic effects on the occurrence of flutamide-induced hepatopathy in a large number of patients surveyed in a multi-center cooperative study. METHODS: One hundred and eighty-one patients (74.1 +/- 4.9 years) with prostate cancer treated with flutamide with (n = 70) or without (n = 111) UDCA were retrospectively evaluated and the occurrence of hepatopathy was compared between these two patient groups. RESULTS: Between patients treated with UDCA and those without it, no significant differences were noted in age, clinical stage, grade, duration of flutamide administration and serum prostate-specific antigen (PSA) levels before treatment. However, there were significant differences in the presence or absence of previous treatments and treatments used together with flutamide. The incidence of hepatopathy was 11.4% (8/70) in patients with UDCA and 32.4% (36/111) in those without it, showing a statistically significant difference (P < 0.05). The hepatopathy-free rate obtained by the Kaplan-Meier method was also significantly higher in patients with UDCA (88.4% 1 year following flutamide administration) than that in those without it (59.6%) (P < 0.005). CONCLUSION: These results suggest that UDCA has a prophylactic effect against flutamide-induced hepatopathy in patients with prostate cancer.