Autoimmune abnormality affects ovulation and oocyte-pick-up in MRL/MpJ-Fas lpr/lpr mice.

Ovulation and oocyte-pick-up are essential processes in fertilization. Herein, we found associations between autoimmune disease and the aforementioned processes in mice. At three and six months, along with the evaluation of autoimmune disease indices, the ovary, mesosalpinx, and oviducts were histologically examined in C57BL/6, MRL/MpJ, and MRL/MpJ-Fas lpr/lpr mice as healthy control, mild and severe models of autoimmune disease, respectively. In superovulated mice, the number of "oocyte cumulus complexes" found in the ampulla was macroscopically counted, and that of "ovulated oocytes" was histologically evaluated, as indicated by ruptured follicles or corpora hemorrhagica in ovaries. Finally, the oocyte-pick-up rate was calculated. In MRL/MpJ-Fas lpr/lpr mice, the oocyte-pick-up rate decreased with disease-related deterioration, unlike in other mouse strains. Further, more ovulated oocytes were found in MRL/MpJ mice than in C57BL/6 mice, and this number significantly decreased with aging in MRL/MpJ-Fas lpr/lpr mice. Numerous T-cells infiltrated into the infundibulum or a part of the mesosalpinx in aged MRL/MpJ-Fas lpr/lpr mice, and their infundibulum showed swelling and fewer ciliated epithelial cells compared to that of C57BL/6 mice. In conclusion, the progression of severe autoimmune disease affected the oocyte-pick-up process through histopathological changes in the infundibulum. These results provide important insights into female infertility associated with autoimmune disease.

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway.

BACKGROUND: Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies. OBJECTIVES: To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity. METHODS: The expression of HSP90 protein in angiosarcoma was examined using immunohistochemistry and immunoblotting. The effects of HSP90 inhibition were proven using proliferation, migration and invasion assay in angiosarcoma cells. The mechanism of antitumour effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA). RESULTS: The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared with those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose-dependent manner. HSP90 siRNA suppressed the proliferation, migration and invasion of angiosarcoma cells. Knock-down of HSP90 did not suppress vascular endothelial growth factor receptor 2 directly, but selectively suppressed several downstream targets of vascular endothelial growth factor signalling in angiosarcoma cells. CONCLUSIONS: HSP90 could be a novel therapeutic target for angiosarcoma.

Age-dependent decrease in desflurane concentration for maintaining bispectral index below 50.

BACKGROUND: We examined the hypothesis that the minimum alveolar concentration of desflurane for maintaining bispectral index (BIS) below 50 (MACBIS 50 ) decreases with advance of age. METHODS: Sixty young (20-30 year), middle-aged (31-65 year) and elderly (66-80 year) patients were included (n = 20, each group). Five minutes following the start of continuous intravenous administration of remifentanil at 0.25 µg/kg/min, general anaesthesia was induced with propofol 2 mg/kg and rocuronium 0.8 mg/kg to facilitate tracheal intubation. Infusion of remifentanil was stopped immediately after tracheal intubation. When BIS began to increase > 60, maintenance of anaesthesia was started with an end-tidal desflurane concentration of 4.0% and maintained for 10 min followed by 1-min assessment of BIS taken at 10-s intervals. MACBIS 50 of each age group was estimated by up-down methodology. RESULTS: MACBIS 50 of desflurane in young, middle-aged and elderly patients was 4.25% end-tidal (95% confidence intervals 4.04-4.46), 3.58% (3.38-3.79) and 2.75% (2.50-3.00) respectively. MACBIS 50 was higher (P = 0.011) in young patients and lower (P = 0.012) in elderly patients than those in middle-aged patients. CONCLUSIONS: Advance in age significantly decreased the concentrations of desflurane required to maintain BIS below 50. BIS reflected age-associated decrease in end-tidal concentrations of desflurane required for maintaining adequate depth of anaesthesia during resting state.

Very-low-voltage operation of Mach-Zehnder interferometer-type electroabsorption modulator using asymmetric couplers.

We have proposed and developed a new type of electroabsorption modulator (EAM) that employs both optical absorption and interferometric extinction. The EAM operates at a record low voltage of 0.2 V at 25.8-Gbit/s modulation, which can reduce optical transmitter power consumption and allows the adoption of cost-effective CMOS drivers.

Load distribution and forearm muscle activity during cylinder grip at various grip strength values.

This study aimed to investigate load distribution and forearm muscle activity from strong to weak grip strength, using a cylindrical device (Grip Sensor). We invited 15 students and measured the pressure distribution and forearm muscle activity during grip tasks at 25%, 50%, 75%, and 100% maximum voluntary force (MVF). Pressure data from the Grip Sensor were assigned to seven anatomical regions; the sum of the data from the seven regions (Total force) and proportionate load distribution for each grip task were calculated. Electromyography recorded activity in the extensor carpi radialis longus (ECRL), flexor carpi radialis (FCR), extensor carpi ulnaris (ECU) and flexor carpi ulnaris (FCU) muscles. Forearm muscle activity increased significantly with grip strength (p < 0.05). The load proportion corresponding to the thumb did not significantly change with increasing strength. On the other hand, the fingertip ratio significantly decreased, and the palm ratio significantly increased with increasing strength (p < 0.05). The Grip Sensor showed a shift in the load distribution in the hand from fingertips to palm as grip strength increased. This result indicates that more detailed evaluations of hand function may be possible.

Efficient multi-keV x-ray generation from a high-Z target irradiated with a clean ultra-short laser pulse.

Kα line emissions from Mo and Ag plates were experimentally studied using clean, ultrahigh-intensity femtosecond laser pulses. The absolute yields of Kα x-rays at 17 keV from Mo and 22 keV from Ag were measured as a function of the laser pulse contrast ratio and irradiation intensity. Significantly enhanced Kα yields were obtained for both Mo and Ag by employing high contrast ratios and irradiances. Conversion efficiencies of 4.28×10⁻5/sr for Mo and 4.84×10⁻5/sr for Ag, the highest values obtained to date, were demonstrated with contrast ratios in the range 10⁻¹° to 10⁻¹¹.

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.

High temporal and spatial quality petawatt-class Ti:sapphire chirped-pulse amplification laser system.

Optical parametric chirped-pulse amplification (OPCPA) operation with low gain by seeding with high-energy, clean pulses is shown to significantly improve the contrast to better than 10(-10) to 10(-11) in a high-intensity Ti:sapphire laser system that is based on chirped-pulse amplification. In addition to the high-contrast broadband, high-energy output from the final amplifier is achieved with a flat-topped spatial profile of filling factor near 77%. This is the result of pump beam spatial profile homogenization with diffractive optical elements. Final pulse energies exceed 30 J, indicating capability for reaching peak powers in excess of 500 TW.

Molecular mechanism of kallikrein-related peptidase 8/neuropsin-induced hyperkeratosis in inflamed skin.

BACKGROUND: Hyperkeratosis and acanthosis occur in inflamed skin. Proliferation and differentiation of keratinocytes are important processes during epidermal repair after inflammation. Neuropsin and its human homologue kallikrein-related peptidase 8 (KLK8) have been reported to be involved in epidermal proliferation and differentiation, but the involved molecular mechanisms are obscure. OBJECTIVES: To explore the molecular mechanism of KLK8/neuropsin-induced hyperkeratosis and acanthosis in inflamed skin. METHODS: The molecular mechanism involved in KLK8/neuropsin-induced hyperkeratosis and acanthosis in inflamed skin was investigated both in vivo and in vitro using neuropsin knockout mice and KLK8 knockdown human keratinocytes. Neuropsin-related genes were identified by differential gene display. The localization and functional relationship of the molecules affected downstream of KLK8/neuropsin in normal and inflamed skin were analysed by in situ hybridization and immunohistochemistry. RESULTS: Hyperkeratosis and acanthosis in sodium lauryl sulphate-stimulated skin were markedly inhibited in neuropsin knockout mice. Knockdown of KLK8/neuropsin increased transcription factor activator protein-2α (AP-2α) expression and decreased keratin 10 expression in human keratinocytes and mouse skin, respectively. AP-2α has been reported to inhibit epidermal proliferation and keratin 10 expression. Distributional analysis showed that KLK8/neuropsin was expressed in the stratum spinosum, AP-2α was expressed in the stratum basale and the lower part of the stratum spinosum, and keratin 10 was expressed throughout the stratum spinosum. CONCLUSIONS: The above findings suggest the following mechanism of events underlying KLK8/neuropsin-induced hyperkeratosis: (i) skin inflammation increases KLK8/neuropsin expression in the stratum spinosum; (ii) the released KLK8/neuropsin inhibits AP-2α expression in the cells of the stratum basale and stratum spinosum; (iii) the decrease in AP-2α results in cell proliferation in the stratum basale and cell differentiation in the stratum spinosum, with an increase in keratin 10 expression.

Image-guided core biopsy of 2-cm or smaller renal tumors.

PURPOSE: The purpose of this study was to retrospectively evaluate diagnostic yield, risk factors for diagnostic failure, and safety of image-guided core biopsy of renal tumors≤2cm. MATERIALS AND METHODS: Eighty-four biopsies of 84 renal tumors (mean size, 1.5±0.4[SD] cm; range, 0.6-2.0cm) from 84 patients (53 men, 31 women; mean age, 61.7±12.7 [SD] years; age range, 34-87 years) were included. All adverse events (AEs) were evaluated based on the CIRSE classification. The 84 procedures were classified as diagnostic or nondiagnostic. Multiple variables related to the patients, tumors, and procedures were assessed to identify variables associated with diagnostic failure. RESULTS: All 84 biopsies (100%) were technically successful, defined as penetration of the target and acquisition of some specimens. Eighty (80/84; 95.2%) biopsy procedures were diagnostic and four (4/84; 4.8%) procedures were nondiagnostic. Among 80 diagnosed renal tumors, 71/80 (88.8%) tumors were malignant (49 clear cell renal cell carcinomas [RCCs], 14 papillary RCCs, 3 chromophobe RCCs, 3 metastatic renal cancers, 1 lymphoma, and 1 unclassified RCC) and 9/80 (11.2%) lesions were benign (5 angiomyolipomas, 3 oncocytomas, and 1 inflammatory lesion). No significant differences existed in any variables between the two groups. A total of 57 (57/84; 67.9%) procedures resulted in 56 Grade 1, 2 Grade 2, and 1 Grade 3 AEs. CONCLUSION: Image-guided biopsy of renal tumors≤2cm is safe and has a high diagnostic yield.

Embolization using hydrogel-coated coils for pulmonary arteriovenous malformations.

PURPOSE: To prospectively evaluate the efficacy and safety of embolization using hydrogel-coated coils for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: The outcomes of 21 PAVMs in 19 patients (3 men and 16 women; mean age, 58.8±15.2 [SD] years; age range 14-78 years) treated by venous sac embolization (VSE) with additional feeding artery embolization were prospectively evaluated. For VSE, using one or more 0.018-inch hydrogel-coated coils was mandatory. Recanalization and/or reperfusion were evaluated by pulmonary arteriography 1 year after embolization. RESULTS: The mean feeding artery and venous sac sizes were 4.0mm and 8.5mm, respectively. Embolization was successfully completed in 20/21 PAVMs, yielding a technical success rate of 95%. The feeding artery was also embolized in 17/20 successful PAVMs (85%). A technical failure occurred in one PAVM, where embolization was abandoned because of migration of one bare coil to the left ventricle. The mean numbers of hydrogel-coated coils and bare platinum detachable coils used for VSE were 3.3±2.1 (SD) (range, 1-8) and 4.4±3.9 (SD) (range, 1-17), respectively. The mean percentages of hydrogel-coated coils in number, length, and estimated volume were 42.9%, 33.3%, and 72.7% respectively. One patient with one PAVM was lost to follow-up after 3 months. Neither recanalization nor reperfusion was noted in the remaining 19 PAVMs (success rate, 19/19 [100%]). One grade 4 (coil migration) adverse event occurred, and it was treated without any sequelae. CONCLUSION: VSE using hydrogel-coated coils with additional feeding artery embolization is a safe and effective treatment for PAVM.

Electron optical injection with head-on and countercrossing colliding laser pulses.

A high stability electron bunch is generated by laser wakefield acceleration with the help of a colliding laser pulse. The wakefield is generated by a laser pulse; the second laser pulse collides with the first pulse at 180 degrees and at 135 degrees realizing optical injection of an electron bunch. The electron bunch has high stability and high reproducibility compared with single pulse electron generation. In the case of 180 degrees collision, special measures have been taken to prevent damage. In the case of 135 degrees collision, since the second pulse is countercrossing, it cannot damage the laser system.

Percutaneous thermal ablation for renal cell carcinoma in patients with Birt-Hogg-Dubé syndrome.

PURPOSE: The purpose of this study was to analyze the outcome of patients with Birt-Hogg-Dubé (BHD) syndrome who underwent percutaneous thermal ablation of renal cell carcinoma (RCC). MATERIALS AND METHODS: Six patients with genetically proven BHD syndrome who underwent one or more sessions of percutaneous thermal ablation for the treatment of RCC were included. There were 4 men and 2 women, with a mean age of 57.3±7.5 [SD] years (range: 44-67years). A total of 29 RCCs (1-16 tumors per patient) were treated during 20 thermal ablation sessions (7 with radiofrequency ablation and 13 with cryoablation). Outcomes of thermal ablation therapy were assessed, including technical success, adverse events, local tumor progression, development of metastases, survival after thermal ablation, and changes in renal function. RESULTS: Technical success was achieved in all ablation sessions (success rate, 100%). No grade 4 or 5 adverse events were observed. All patients were alive with no distant metastasis during a median follow-up period of 54months (range: 6-173months). No local tumor progression was found. The mean decrease in estimated glomerular filtration rate during follow-up was 10.7mL/min/1.73m2. No patients required dialysis or renal transplantation. CONCLUSION: Radiofrequency ablation and cryoablation show promising results for the treatment of RCCs associated with BHD syndrome. Percutaneous thermal ablation may be a useful treatment option for this rare hereditary condition.

Phase I study of chemoradiation with nedaplatin and ifosfamide in patients with advanced squamous cell carcinoma of the uterine cervix.

Cisplatin and ifosfamide are considered among the most active drugs in both neoadjuvant and salvage treatments for patients with cervical cancer. Nedaplatin is an analog of cisplatin and it exhibits lesser nephrotoxicity, neurotoxicity, and gastrointestinal toxicity than cisplatin. This study aimed to determine the recommended dosage of nedaplatin plus ifosfamide chemoradiotherapy for advanced squamous cell carcinoma (SCC) of the uterine cervix. Beginning with a dose of 65 mg/m(2), nedaplatin (day 1) combined with ifosfamide 1 g/m(2) (days 1-5) was designed to be administered for three cycles (minimum: two cycles); its dose was gradually escalated up to 80 mg/m(2). Dose-limiting toxicity (DLT) was defined as a more than 7-day delay in the planned radiation therapy and/or planned chemotherapy (prior to the completion of two cycles) due to toxicity. Chemotherapy was not interrupted prior to the completion of two cycles in any patients. Of the 12 patients, 11 received three cycles of chemotherapy. DLT did not occur in any patient. We confirmed a clinical complete response (CR) in ten and partial response (PR) in two patients. The median follow-up period was 39 months (range: 18-57 months). Ten patients (83%) were alive and disease free, one patient was alive with disease, and only one patient died due to the disease. Nedaplatin and ifosfamide combination chemotherapy is a feasible and active chemoradiation strategy for patients with advanced SCC of the uterine cervix. With the ifosfamide dose fixed to 1 g/m(2), the recommended nedaplatin dosage was determined to be 80 mg/m(2) to be administered for three cycles.

Phase I study of weekly nedaplatin and concurrent pelvic radiotherapy as adjuvant therapy after radical surgery for cervical cancer.

Nedaplatin is an analog of cisplatin that was developed in Japan, and it exhibits less nephrotoxicity, neurotoxicity, and gastrointestinal toxicity than cisplatin. This study aimed to determine the recommended dose of weekly nedaplatin chemoradiotherapy in high-risk patients following radical surgery. Fifteen patients who required postoperative pelvic radiotherapy after radical surgery for cervical cancer were enrolled in the present study. Nedaplatin was designed to be administered for eight cycles (minimum five cycles) beginning at a weekly dose of 22.5 mg/m(2) and then escalating to 25, 27.5, and then to 30 mg/m(2). Dose-limiting toxicity was defined as a more than 7-day delay in the planned radiation therapy and/or planned chemotherapy (prior to the completion of five cycles) due to toxicity. Nedaplatin administration was interrupted prior to the completion of five cycles in one of six patients at a dose of 27.5 mg/m(2). A more than 7-day delay in the planned radiation therapy did not occur in any patient. Nedaplatin at a dose of 30 mg/m(2) was safely administered, and two of three patients could receive the planned chemotherapy consisting of eight cycles of weekly nedaplatin. Our recommended weekly nedaplatin dose was determined to be 30 mg/m(2) administered for more than five cycles and up to eight cycles if possible. Weekly administration of nedaplatin may be more tolerable and less toxic than weekly administration of cisplatin.

Short hookwire placement under imaging guidance before thoracic surgery: A review.

During video-assisted thoracic surgery (VATS), localization is sometimes needed to detect a target lesion that is too small and/or too far from the pleura. In 1995, Kanazawa et al. developed short hookwire and suture system. Since then, this system has been placed often for selected targets before VATS in Japan. This short hookwire and suture system is a representative preoperative localization method and the placement procedure is well-established. Its placement success rates are very high (range: 97.6%-99.6%), and dislodgement of this short hookwire rarely occurs with an incidence of 0.4%-2.5%. The most common complication of short hookwire placement is pneumothorax (incidence: 32.1%-68.1%), followed by pulmonary hemorrhage (incidence: 8.9%-41.6%). Complications are frequent; however, most complications are minor and asymptomatic.

CT fluoroscopy-guided core needle biopsy of anterior mediastinal masses.

OBJECTIVE: To retrospectively evaluate the safety, diagnostic yield, and risk factors of diagnostic failure of computed tomography (CT) fluoroscopy-guided biopsies of anterior mediastinal masses. MATERIALS AND METHODS: Biopsy procedures and results of anterior mediastinal masses in 71 patients (32 women/39 men; mean [±standard deviation] age, 53.8±20.0years; range, 14-88years) were analyzed. Final diagnoses were based on surgical outcomes, imaging findings, or clinical follow-up findings. The biopsy results were compared with the final diagnosis, and the biopsy procedures grouped by pathologic findings into diagnostic success and failure groups. Multiple putative risk factors for diagnostic failure were then assessed. RESULTS: Seventy-one biopsies (71 masses; mean size, 67.5±27.3mm; range 8.6-128.2mm) were analyzed. We identified 17 grade 1 and one grade 2 adverse events (25.4% overall) according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Sixty-nine biopsies (97.2%) provided samples fit for pathologic analysis. Diagnostic failure was found for eight (11.3%) masses; the 63 masses diagnosed successfully included thymic carcinoma (n=17), lung cancer (n=14), thymoma (n=12), malignant lymphoma (n=11), germ cell tumor (n=3), and others (n=6). Using a thinner needle (i.e., a 20-gauge needle) was the sole significant risk factor for diagnostic failure (P=0.039). CONCLUSION: CT fluoroscopy-guided biopsy of anterior mediastinal masses was safe and had a high diagnostic yield; however, using a thinner biopsy needle significantly increased the risk of a failed diagnosis.

Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload.

It is known that long-standing volume overload on the left ventricle due to mitral regurgitation eventually leads to contractile dysfunction. However, it is unknown whether or not correction of the volume overload can lead to recovery of contractility. In this study we tested the hypothesis that depressed contractile function due to volume overload in mitral regurgitation could return toward normal after mitral valve replacement. Using a canine model of mitral regurgitation which is known to produce contractile dysfunction, we examined contractile function longitudinally in seven dogs at baseline, after 3 mo of mitral regurgitation, 1 mo after mitral valve replacement, and 3 mo after mitral valve replacement. After 3 mo of mitral regurgitation (regurgitant fraction 0.62 +/- 0.04), end-diastolic volume had nearly doubled from 68 +/- 6.8 to 123 +/- 12.1 ml (P less than 0.05). All five indices of contractile function which we examined were depressed. For instance, maximum fiber elastance (EmaxF) obtained by assessment of time-varying elastance decreased from 5.95 +/- 0.71 to 2.25 +/- 0.18 (P less than 0.05). The end-systolic stiffness constant (k) was also depressed from 4.2 +/- 0.4 to 2.1 +/- 0.3. 3 mo after mitral valve replacement all indexes of contractile function had returned to or toward normal (e.g., EmaxF 3.65 +/- 0.21 and k 4.2 +/- 0.3). We conclude that previously depressed contractile function due to volume overload can improve after correction of the overload.