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In compression coil springs subjected to cyclic load, fatigue cracks can sometimes initiate and propagate from scratch-like small defects produced during the manufacturing process and degrade the fatigue strength. In this study, torsional and rotating bending fatigue tests were conducted to examine the fatigue behavior of a high-strength spring steel (JIS G 3561, SWOSC-V) in the presence of small scratches. The sensitivity of the HCF and VHCF strength to small scratches was evaluated based on the √area parameter model. [ABSTRACT FROM AUTHOR]

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime. [ABSTRACT FROM AUTHOR]

Background: Robotic surgery is the most advanced development in minimally invasive surgery. However, the number of reports on robot-assisted endoscopic gastrointestinal surgery is still very small. In this article, we describe total laparoscopic pancreaticoduodenectomy (PD) undertaken using the da Vinci Surgical System® (Intutive Surgical). Methods: Three patients underwent robotic PD between November 2009 and February 2010. Following resection of the pancreatic head, duodenum, and the distal stomach, intracorporeal anastomosis was accomplished by Child's method of reconstruction, which includes a two-layered end-to-side pancreaticojejunostomy, an end-to-side choledochojejunostomy, and a side-to-side gastrojejunostomy. Results: The time required for surgery was 703 ± 141 min, and blood loss was 118 ± 72 mL. The average hospital stay period was 26 ± 12 days. As a postoperative complication, pancreatic juice leak occurred in one case, but it was managed with conservative treatment. Of the three patients, one had cancer of the papilla of Vater, one had cancer of the pancreatic head, and one had a solid pseudopapillary neoplasm. In all cases, the surgical margin was negative for tumor. Conclusions: Robot-assisted PD required a long time, but organ removal with less bleeding was able to be safely performed owing to the high degree of freedom associated with the forceps manipulation and the magnified view. Similarly, pancreatojejunostomy could certainly be conducted. No major postoperative complications were found. Accumulation of da Vinci PD experience in the future will lead to safer and faster PD. [ABSTRACT FROM AUTHOR]

Background/purpose: During a pancreatoduodenectomy (PD) it is important that the anatomy of the arcade of blood vessels in the head of the pancreas is fully understood before the surgery in order to reduce intraoperative bleeding. In most of the patients our group has treated, the inferior pancreaticoduodenal artery (IPDA), one of the efferent arteries of the head of the pancreas, has formed a short common trunk with the first jejunal artery (FJA). Thus, by first locating the origin of the FJA, it was easier to locate the IPDA. There are two ways to locate the IPDA: (1) by measuring the distance between the origin of the superior mesenteric artery (SMA) and that of the FJA; (2) by measuring the distance between the origin of the middle colic artery (MCA) and that of the FJA. Here, we report our measurements of both distances using three-dimensional (3D) models of arteries constructed with multidetector-row computed tomography (MD-CT) images and discuss which is the better measurement to determine the location of the IPDA during PD. Methods: A total of 140 patients underwent 64-MD-CT imaging to acquire early and late arterial phase scans. The distance between the origin of the SMA and that of the FJA and the distance between the origin of the MCA and that of the FJA origin were measured. Results: In patients whose IPDA formed either a common trunk with the FJA or arose directly from the SMA, the IPDA or the common truck was located in parallel with the SMA at a very short distance of approximately 18 mm from the MCA origin towards the center. The distance between the SMA origin and the IPDA was significantly longer (approximately 36 mm). Therefore, locating the MCA origin during PD helped determine the location of the IPDA. However, in patients whose anterior inferior pancreaticoduodenal artery (AIPDA) and posterior inferior pancreaticoduodenal artery (PIPDA) arose separately, the distance between the AIPDA origin and the MCA origin was approximately 18 mm, the distance between the AIPDA origin and the PIPDA origin was approximately 19 mm, and the distance between the PIPDA origin and the SMA origin was 19 mm. Thus, locating the SMA helped determine the location of the IPDA during PD in these patients. Conclusion: Based on our findings that the distance between the IPDA origin and the MCA origin was short, we have shown that it is effective to locate the MCA origin in order to determine the location of the IPDA. [ABSTRACT FROM AUTHOR]

The goal of our study was to examine the effects of amiloride on distal renal tubule calcium and sodium absorption at low and high luminal pH. In vivo microperfusion of distal convoluted tubules were performed on rats. Total Ca and Na concentrations in perfusion and collected fluids were measured by atomic absorption spectrometry. When tubules were perfused with low pH perfusate (pH = 5.6), net calcium absorption (JCa) averaged 5.4 pmol/min. With high pH perfusate (pH = 7.1), JCa was significantly higher averaging 8.9 pmol/min. (P < 0.01). In contrast, net sodium absorption (JNa) was not affected by luminal pH (231 pmol/min. versus 237 pmol/min.). At low luminal pH, 10-4 M amiloride analogue (5-N-methyl-N-isobutyl amiloride) (MIA) inhibited sodium absorption but stimulated calcium absorption. At high luminal pH MIA still inhibited Na absorption but it had no effect on calcium absorption. Thus, the natriuretic effect of amiloride appears to be independent of luminal pH, while the amiloride-stimulated distal calcium absorption is observed at low but not at high luminal pH. [ABSTRACT FROM AUTHOR]

A letter to the editor on immunoexpression of human epidermal growth factor receptor-2 is presented.

The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T-025 treatment. MYC activation, which altered pre-mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti-tumor efficacy of T-025 in an allograft model of spontaneous, MYC-driven breast cancer, at well-tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC-driven cancer patients., (© 2018 Takeda Pharmaceutical Company Published under the terms of the CC BY 4.0 license.)

Pachydermoperiostosis is a rare hereditary disease, which presents with the cutaneous manifestations of pachydermia and cutis verticis gyrata. Histological findings in pachydermia frequently include dermal edema, mucin deposition, elastic fiber degeneration, dermal fibrosis and adnexal hyperplasia. However, the severity of these findings varies between clinical reports, and a systematic multiple-case clinicopathological correlative analysis has not been performed to date. In the present study, we reviewed the skin biopsy specimens obtained from the pachydermia of six pachydermoperiostosis patients. The severity of the characteristic histological features was semiquantitatively evaluated and correlated with the grade of pachydermia. Dermal edema, mucin deposition and elastic fiber degeneration were observed in all cases. Patients with severe pachydermia had sebaceous gland hyperplasia and fibrosis. These results suggest that the triad of mucin deposition, dermal edema and elastic fiber degeneration are found from very early stage pachydermia, and could be considered diagnostic findings. To ensure an earlier diagnosis of pachydermoperiostosis, a biopsy should be taken when a patient has grade 1 pachydermia to determine the presence of this histological triad., (© 2015 The Authors. The Journal of Dermatology published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Dermatological Association.)

Aptamers, which are folded DNA or RNA molecules, bind to target molecules with high affinity and specificity. An RNA aptamer specific for the Fc fragment of human immunoglobulin G (IgG) has recently been identified and it has been demonstrated that an optimized 24-nucleotide RNA aptamer binds to the Fc fragment of human IgG and not to other species. In order to clarify the structural basis of the high specificity of the RNA aptamer, it was crystallized in complex with the Fc fragment of human IgG1. Preliminary X-ray diffraction studies revealed that the crystals belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 83.7, b = 107.2, c = 79.0 A. A data set has been collected to 2.2 A resolution.

Objective: To investigate the roles of tumor necrosis factor alpha(TNFalpha) and the CD40-CD154 interaction in interleukin-12 (IL-12) production by rheumatoid synovial cells (SC)., Methods: Levels of IL-12 (p40 and p70) in synovial tissue and culture supernatants of SC from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS) were assayed by enzyme-linked immunosorbent assay. Effects of anti-CD154 and anti-TNFalpha antibody on spontaneous and lipopolysaccharide (LPS)-stimulated IL-12 production by SC were examined. Effects of immobilized anti-CD3 treatment and depletion of CD4+ T cells on IL-12 production were also tested. CD154 expression by synovial T cells and intracellular IL-12 production during culture were analyzed by flow cytometry., Results: IL-12 p40 and p70 levels in RA synovial tissue and spontaneous IL-12 p40 production by SC from RA patients were significantly higher than the levels in OA and AS patients. Spontaneous IL-12 production by SC from RA patients significantly decreased after depletion of CD4+ T cells from SC or after application of anti-CD154 antibody, but not by treatment with anti-TNFalpha antibody. Anti-CD3 antibody stimulation increased spontaneous IL-12 p40 production and CD154 expression by synovial T cells. The increment of IL-12 p40 production by anti-CD3 was abrogated by anti-CD154 antibody. IL-12 p40 production was also increased by LPS stimulation. LPS-stimulated IL-12 production was inhibited by anti-TNFalpha antibody, but not by T cell depletion and anti-CD154 antibody treatment. The TNFalpha inhibitor rolipram inhibited LPS-stimulated IL-12 p40 production by RA SC more strongly than spontaneous production. TNFalpha restored LPS-stimulated IL-12 production that had been inhibited by rolipram., Conclusion: IL-12 production in RA is regulated by 2 different pathways. One pathway is T cell dependent, predominantly through a CD40-CD154 interaction, while the other is T cell independent, mediated through TNFalpha. Inhibition of IL-12 production by interference with CD40-CD154 interaction and TNFalpha production may be a potential therapeutic strategy for treating RA.

Photoallergy to vitamin B6 is very rare; only a few cases of contact dermatitis and one case of photosensitive dermatitis due to pyritinol have been reported. We report here the first case of photoallergic drug eruption due to pyridoxine hydrochloride. A 71-year-old man developed papulo-squamous erythemata which were confined to sun-exposed sites. Photopatch testing, together with the clinical course, was helpful in reaching the initial diagnosis; this was confirmed by an oral challenge test. Photoallergic drug eruption due to vitamin B6 should be considered a rare cause of photosensitive dermatitis.

We report a case of a 74-year-old male with a trichilemmal tumor arising in a seborrheic keratosis on the buttock and the results of a cell kinetic study of this tumor using a BrdU staining method. The incidence of trichilemmal tumor arising in a seborrheic keratosis seems to be extremely rare. The labeling index of this tumor was 12.0%; this was a level intermediate between normal epidermis and a variety of hyperproliferative skin diseases such as squamous cell carcinoma, Bowen's disease, and psoriasis vulgaris. DNA replicating cells were present in the germinative layers in normal epidermis and the benign hyperproliferative skin diseases, psoriasis vulgaris. In contrast, DNA replicating cells were found throughout the entire epidermis in premalignant and malignant tumors such as in Bowen's disease and squamous cell carcinoma. In this case, DNA replicating cells were localized mainly in the basal and parabasal cell layers, but also seen in the upper squamous layers. These findings suggest that this trichilemmal tumor had a malignant tendency, though it was slow-growing and relatively benign in nature.

Escherichia coli easily developed resistance to a new antimicrobial agent of the sideromycin group, No. 216, by spontaneous mutation. Most of the No. 216-resistant mutants tested proved not to be cross-resistant to E. coli phages T1, T5, and ø80. On the other hand, these phage-resistant mutants were cross resistant to No. 216. The initial site for binding of No. 216 to the sensitive cells was located, at the ton A gene product (Ton A-protein) of the outer membrane. However, unlike the phage-resistant mutants, ton A protein (78K-protein) in most No. 216-resistant mutants was intact and these mutants were possessed a particular 87K protein in the outer membrane. It is suggested that No. 216 is taken up by ton A protein and then penetrates into the cell by way of a particular transport system and that a highly mutable portion may exist in this reaction system.