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Osteocyte network architecture is closely associated with bone turnover. The cellular mechanosensing system regulates osteocyte dendrite formation by enhancing focal adhesion. Therefore, titanium surface nanotopography might affect osteocyte network architecture and improve the peri-implant bone tissue quality, leading to strengthened osseointegration of bone-anchored implants. We aimed to investigate the effects of titanium nanosurfaces on the development of osteocyte lacunar-canalicular networks and osseointegration of dental implants. Alkaline etching created titanium nanosurfaces with anisotropically patterned dense nanospikes, superhydrophilicity, and hydroxyl groups. MLO-Y4 mouse osteocyte-like cells cultured on titanium nanosurfaces developed neuron-like dendrites with increased focal adhesion assembly and gap junctions. Maturation was promoted in osteocytes cultured on titanium nanosurfaces compared to cells cultured on machined or acid-etched micro-roughened titanium surfaces. Osteocytes cultured in type I three-dimensional collagen gels for seven days on nano-roughened titanium surfaces displayed well-developed interconnectivity with highly developed dendrites and gap junctions compared to the poor interconnectivity observed on the other titanium surfaces. Even if superhydrophilicity and hydroxyl groups were maintained, the loss of anisotropy-patterned nanospikes reduced expression of gap junction in osteocytes cultured on alkaline-etched titanium nanosurfaces. Four weeks after placing the titanium nanosurface implants in the upper jawbone of wild-type rats, osteocytes with numerous dendrites were found directly attached to the implant surface, forming well-developed lacunar-canalicular networks around the nano-roughened titanium implants. The osseointegration strength of the nano-roughened titanium implants was significantly higher than that of the micro-roughened titanium implants. These data indicate that titanium nanosurfaces promote osteocyte lacunar-canalicular network development via nanotopographical cues and strengthen osseointegration. The clinical stability of bone-anchoring implant devices is influenced by the bone quality. The osteocyte network potentially affects bone quality and is established by the three-dimensional (3D) connection of neuron-like dendrites of well-matured osteocytes within the bone matrix. No biomaterials are known to regulate formation of the osteocyte network. The present study provides the first demonstration that titanium nanosurfaces with nanospikes created by alkali-etching treatment enhance the 3D formation of osteocyte networks by promoting osteocyte dendrite formation and maturation by nanotopographic cues, leading to strengthened osseointegration of titanium implants. Osteocytes attached to the titanium nanosurfaces via numerous cellular projections. The success of osteocyte regulation by nanotechnology paves the way for development of epoch-making technologies to control bone quality. [Display omitted] [ABSTRACT FROM AUTHOR]

The predictive value of echocardiographic parameters for early worsening heart failure (WHF), worsening of symptoms of heart failure requiring intensification of therapy during an admission for acute decompensated heart failure (ADHF), has not been elucidated. Sixteen centers in Japan prospectively enrolled 303 ADHF hospitalized patients who did not receive positive inotropic agents as an initial therapy. Physical and Doppler echocardiographic examinations were performed before the initial therapy and the association of low output findings and occurrence of early WHF were tested. Early WHF occurred in 63 patients with a median duration of 6 (IQR: 2–23) hours from the administration of the initial therapy. In patients with left ventricular (LV) ejection fraction <40% (N = 153), echocardiographic stroke volume index, and cardiac index showed greater c-index [95% confidence interval, 0.71 (0.61–0.79) and 0.72 (0.63–0.80), respectively] compared to single low perfusion finding (symptomatic hypotension, reduced pulse pressure, and impaired mentation) other than cool extremities. When physical findings were combined (low perfusion score), the predictive ability improved to the similar levels of echocardiographic LV output parameters [c-index: 0.69 (0.60–0.76)]. However, addition of cardiac index significantly improved the prognostic ability when added to low perfusion score [0.82 (0.74–0.87), p < 0.001]. In contrast, in patients with LV ejection fraction ≥40% (N = 150), low perfusion score, rather than LV output parameters, was predictive of early WHF [c-index: 0.73 (0.56–0.85)]. We demonstrated the predictive value of echocardiographic LV output indices for early WHF in ADHF patients with LV systolic dysfunction. These data support the motivation for routine use of echocardiography for initial assessment of ADHF. [Display omitted] • Predictive value of echocardiographic LV output parameters for early WHF was tested. • Echocardiographic CI well predicted early WHF in ADHF HFrEF patients. • Association of echocardiographic CI was independent of clinically relevant parameters in HFrEF. • Data of PREDICT encourages routine use of Doppler echocardiography in ADHF management. [ABSTRACT FROM AUTHOR]

Continuing education is essential for pharmacists to acquire latest knowledge. Our previously established educational program for pharmacists on the systematic and extensive palliative care of cancer patients was evaluated for its educational effectiveness in one urban prefecture. However, whether the same learning effect can be achieved when a program is expanded from one urban prefecture to multiple rural prefectures is unclear. In this study, we examined whether the continuing education program would be useful to pharmacists, even if the scale was expanded. With the aim of correcting educational disparities in the region, pharmacists living in nine prefectures in the Kyushu area underwent a systematic and extensive palliative care educational program for six days (with 24 topics in total). They were administered a questionnaire before and after each topic to evaluate their level of understanding. The level of understanding of the 24 topics in the program that palliative care pharmacists underwent, from "basic knowledge" to "clinical application," significantly improved (P <.01). The educational program for pharmacists is useful even when implemented on a larger scale. We believe that our efforts are important for improving community-based care. [ABSTRACT FROM AUTHOR]

Definitive prevention of inflammatory osteolysis around peri-implant bone tissue remains unestablished. M1 macrophages play a key role in the host defense against inflammatory osteolysis, and their polarization depends on cell shape. Macrophage polarization is controlled by environmental stimuli, particularly physicochemical cues and hence titanium nanosurface might tune macrophage polarization and function. This study determined whether titanium nanosurfaces with anisotropically patterned nanospikes regulates macrophage polarization for inhibiting osteoclast differentiation of osteoclast precursors. Alkaline-etching treatment with different protocols created two types of titanium nanosurfaces that had anisotropically patterned nanospikes with high or low distribution density, together with superhydrophilicity and the presence of hydroxyl groups. J774A.1 cells (mouse macrophage-like cell line), cultured on both titanium nanosurfaces, exhibited truly circulated shapes and highly expressed M1, but less M2, markers, without loss of viability. M1-like polarization of macrophages on both titanium nanosurfaces was independent of protein-mediated ligand stimulation or titanium surface hydrophilic or chemical status. In contrast, other smooth or micro-roughened titanium surfaces with little or no nanospikes did not activate macrophages under any culture conditions. Macrophage culture supernatants on both titanium nanosurfaces inhibited osteoclast differentiation of RAW264.7 cells (mouse osteoclast precursor cell line), even when co-incubated with osteoclast differentiation factors. The inhibitory effects on osteoclast differentiation tended to be higher in macrophages cultured on titanium nanosurfaces with denser nanospikes. These results showed that titanium nanosurfaces with anisotropically patterned nanospikes tune macrophage polarization for inhibiting osteoclast differentiation of osteoclast precursors, with nanotopographic cues rather than other physicochemical properties. Peri-implant inflammatory osteolysis is one of the serious issues for dental and orthopedic implants. Macrophage polarization and function are key for prevention of peri-implant inflammatory osteolysis. Macrophage polarization can be regulated by the biomaterial's surface physicochemical properties such as hydrophilicity or topography. However, there was no titanium surface modification to prevent inflammatory osteolysis through immunomodulation. The present study showed for the first time that the titanium nanosurfaces with anisotropically patterned nanospikes, created by the simple alkali-etching treatment polarized macrophages into M1-like type producing the inhibitory factor on osteoclast differentiation. This phenomenon attributed to nanotopographic cues, but not hydrophilicity on the titanium nanosurfaces. This nanotechnology might pave the way to develop the smart implant surface preventing peri-implant inflammatory osteolysis through immunomodulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Attitudes, experience, and knowledge of healthcare professionals guide the care they provide and are particularly important factors affecting the quality of palliative care. Palliative care education for pharmacists is crucial for improving quality of care and effective participation on the palliative care team. We previously developed and reported a systematic and multifaceted pharmacist education program for cancer-related palliative care. We compared 12 behavioral changes immediately (August 2017) and two years after (October 2019) participation in this systematic education program (SEP) to evaluate if participants were performing pharmaceutical management appropriately and to assure that behaviors had not deteriorated. Of 88 participants in the SEP, 36 responded to the survey (response rate 40.9%). There was no significant difference in the behavioral change items of pharmacists immediately after participating in the SEP (2017) and two years later (2019) (4.47 vs. 4.58, P =.47). We confirmed that behavioral changes developed by the SEP were maintained over a significant time. This indicates that knowledge was firmly established in the participants such that they could continue utilizing it long after participating in the SEP. Our study showed that participating in this SEP not only enabled participants to acquire knowledge regarding palliative medicine but also led to continued behavioral changes based on this knowledge. [ABSTRACT FROM AUTHOR]

• Splanchnic venous thrombosis caused by superior mesenteric vein thrombosis is rare. • Delayed diagnosis and/or treatment can result in acute intestinal infarction. • Protein C deficiency is rare. • Insufficient awareness can result in mismanagement of splanchnic venous thrombosis. • Coagulation disorders contribute to acute intestinal infarction of unknown cause. Splanchnic venous thrombosis (SVT) originating in the superior mesenteric vein (SMV) is rare and may cause acute intestinal infarction (AII). Protein C deficiency (PCD) results in thrombophilia. Acute unexplained SVT originating in the SMV and portal vein was detected in 68-year-old man. Pan-peritonitis and AII were diagnosed and emergency surgery performed. Part of the small intestine was necrotic and partial resection without anastomotic reconstruction was performed. Heparin was administered intravenously continuously from postoperative day (POD) 1. Hereditary, heterozygous, type 1 PCD was diagnosed postoperatively. The anastomosis was reconstructed on POD 16. Warfarin was substituted for heparin on POD 22. No recurrent thrombosis occurred during 2 years of follow-up. Patients with the rare condition of SVT require prompt diagnosis and treatment and may have underlying disease. PCD can cause SVT even in intact veins and anticoagulation therapy should be administered immediately postoperatively. Misdiagnosis and/or delayed treatment of SVT can result in AII, a life-threatening condition with a high mortality rate. Insufficient clinician awareness can result in serious mismanagement of patients with PCD and SVT; emergency patients with AII caused by unexplained SVT should therefore be further investigated for prothrombotic states and assessment of coagulation–fibrinolysis profiles to clarify the underlying mechanism. We here present a thought-provoking emergency case of AII associated with acute SVT caused by underlying PCD that was successfully treated by two-stage surgery and anticoagulation therapy. This case provides a timely reminder for emergency clinicians and gastrointestinal surgeons. [ABSTRACT FROM AUTHOR]

Abstract Oxidative stress on transplanted bone marrow-derived mesenchymal stem cells (BMSCs) during acute inflammation is a critical issue in cell therapies. N-acetyl-L cysteine (NAC) promotes the production of a cellular antioxidant molecule, glutathione (GSH). The aim of this study was to investigate the effects of pre-treatment with NAC on the apoptosis resistance and bone regeneration capability of BMSCs. Rat femur-derived BMSCs were treated in growth medium with or without 5 mM NAC for 6 h, followed by exposure to 100 μM H 2 O 2 for 24 h to induce oxidative stress. Pre-treatment with NAC significantly increased intracellular GSH levels by up to two fold and prevented H 2 O 2 -induced intracellular redox imbalance, apoptosis and senescence. When critical-sized rat femur defects were filled with a collagen sponge containing fluorescent-labeled autologous BMSCs with or without NAC treatment, the number of apoptotic and surviving cells in the transplanted site after 3 days was significantly lower and higher in the NAC pre-treated group, respectively. By the 5th week, significantly enhanced new bone formation was observed in the NAC pre-treated group. These data suggest that pre-treatment of BMSCs with NAC before local transplantation enhances bone regeneration via reinforced resistance to oxidative stress-induced apoptosis at the transplanted site. [ABSTRACT FROM AUTHOR]

Background Rapid and accurate diagnosis of acute myocardial infarction (AMI) are critical for the initiation of effective medical treatment. Recently, a high-sensitivity cardiac troponin I (hs-cTnI) assay was developed as a biochemical marker for the early diagnosis of AMI. Current guidelines recommend that serial measurements of cardiac troponin should be performed in patients who present symptoms suggestive of acute coronary syndrome. The aim of this study was to evaluate the diagnostic performance of 30-minute serial measurements of hs-cTnI for the detection of AMI. Methods We prospectively enrolled patients presenting with suspected AMI within 12 h from symptom onset. We measured hs-cTnI levels at presentation and 30 min later to calculate the “30-minute-delta”. The diagnostic performance was determined by the area under the receiver operating characteristic curve (AUC). Results Among the 71 patients enrolled in this study, 55 (77%) were diagnosed with AMI. The hs-cTnI level at presentation was significantly greater in the patients with AMI than in those without AMI [306.2 (77.3–1809.9) pg/mL versus 22.5 (7.2–115.5) pg/mL, p < 0.01]. The “30-minute-delta” was also significantly greater in patients with AMI [54.6 (13.5–288.0) pg/mL versus 1.9 (0.6–6.3) pg/mL, p < 0.01]. The AUC of the “30-minute-delta” was significantly greater than that of a single measurement at presentation (0.911 versus 0.829, p < 0.05). Conclusions The “30-minute-delta” of hs-cTnI presents improved diagnostic performance for AMI compared with a single measurement. [ABSTRACT FROM AUTHOR]

This paper quantitatively evaluates the cost and risk of banks trading at the Forex London fixing, and examines the impact of the reform of February 2015. Based on the model calibration, we find that (1) the widening of the fixing time window, a main reform agenda, did not reduce the cost for banks but increased the risk of using pre-hedge; (2) the path of the actual trading volume pattern after the reform is consistent with theoretical predictions in a case of not being able to influence the fixing price. [ABSTRACT FROM AUTHOR]

Background The wearable cardioverter-defibrillator (WCD) has been expected to play a role as an effective bridge therapy to implantable cardioverter-defibrillator (ICD) implantation in patients at high risk of ventricular tachyarrhythmias (VA). Although WCD has been available since April 2014 in Japan, its usefulness remains unclear. Methods and results During the early period after hospitalization, patients at high risk of VA after excluding some elderly patients were prescribed WCD. The consecutive 50 patients with WCD use (median age 56 years, 38 for secondary prevention) were studied. We analyzed clinical efficacy and safety of WCD, and examined its potential roles. Of the 50 patients, 38 used WCD only during hospitalization. During WCD use [median 16 (IQR 8–33) days], all patients wore WCD for 98% of a day regardless of in or out-of-hospital use. Sustained VA was detected in 4 patients (8%; for primary prevention in 1) with 7 episodes, and 6 of 7 episodes required shock therapy. Of the 6 shock therapies, 4 were for sustained ventricular tachycardia with the median rate of 236 beats/min (IQR 203–250), and the other 2 for ventricular fibrillation. Subsequently, only 27 patients (54%) of all underwent ICD implantation following the WCD use, because of reduced risk of VA after optimal pharmacological therapy or improvement in the left ventricular function. Conclusions The WCD use for the acute phase care of patients at high risk of VA can be safe and effective, and may be useful for evaluating indication of ICD implantation. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to evaluate if residual thrombus burden after aspiration thrombectomy affects the outcomes of primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI). Background Recent studies failed to show clinical benefit of aspiration thrombectomy in STEMI patients. This might be due to insufficient removal of thrombus at the culprit lesion. Methods A total of 109 STEMI patients who underwent aspiration thrombectomy followed by stenting within 24 h from symptom onset were included. Optical coherence tomography was performed after thrombectomy to measure residual thrombus burden. Patients were divided into tertiles based on the amount of residual thrombus and the outcomes were compared. Results Myocardial no reflow, defined as TIMI (Thrombolysis In Myocardial Infarction) flow grade of ≤2 and/or myocardial blush grade of ≤1 after stenting, was more observed frequently in patients in the highest tertile compared with those in the lowest tertile (44.4% vs. 16.7%; p = 0.001). Patients in the highest tertile also had greater myocardial damage measured by creatine kinase MB compared with those in the lowest tertile (p = 0.002). Conclusions STEMI patients with greater residual thrombus burden after aspiration thrombectomy had worse microvascular dysfunction and greater myocardial damage compared with those with smaller residual thrombus burden. [ABSTRACT FROM AUTHOR]

Purpose To assess target localization errors (TLEs) from implanted fiducial markers by three different centers of gravity (CG) and three different multiple regression analysis (MRA) approaches. Methods The three-dimensional (3D) positions of the markers were detected on the fluoroscopic images of 15 lung cancer patients, and the marker closest to the tumor was then assumed to be the target ( P t ). The estimated target position ( P e ) was calculated from three markers adjacent to the target ( P i , 1 ≤ i ≤ 3) using the equation P e = aP 1 + bP 2 + cP 3 + d . P e was then calculated using three different CGs and three different MRAs. The TLE was calculated as the root-mean-square error of the difference between P t and P e calculated for each fraction. First, we compared the TLE of the first fraction to assess the intrafraction TLE of the six approaches tested. Second, interfraction TLEs were calculated to evaluate the robustness of the coefficients obtained in the first fraction. The interfraction TLE was defined as the difference between the TLE of a later and the first fraction. Results The mean plus two times the standard deviation of the intrafraction TLE was up to 4.3 mm in the CG approaches, while the MRA approaches provided TLEs within 1.5 mm. The mean plus two times the standard deviation of the interfraction TLE did not exceed 1.7 mm in any direction using either approach. Conclusions The MRA approach was superior to the CG approach in terms of estimating the target position based on the implanted fiducial markers. [ABSTRACT FROM AUTHOR]

Objectives This study sought to evaluate the incidence of plaque rupture (PR), plaque erosion (PE), and calcified nodule (CN) using optical coherence tomography (OCT) in patients with ST-segment elevation myocardial infarction (STEMI); to compare detailed morphologic plaque characteristics of PR, PE, and CN with optical coherence tomography and intravascular ultrasound; and to compare the post-procedure outcomes among PR, PE, and CN. Background The incidence and detailed morphologic characteristics of PR, PE, and CN in STEMI patients and their outcome after percutaneous coronary intervention (PCI) are unknown. Methods A total of 112 STEMI patients who underwent PCI within 12 h from symptom onset were included. Both optical coherence tomography and intravascular ultrasound were performed following aspiration thrombectomy. Results The incidence of PR, PE, and CN was 64.3%, 26.8%, and 8.0%, respectively. PE and CN, compared with PR, had more fibrous plaque (p < 0.001 and p < 0.001) and less thin-cap fibroatheroma (p < 0.001 and p < 0.001) as well as smaller plaque burden (p = 0.003 and p = 0.001) and remodeling index (p = 0.003 and p < 0.001). PE had greater plaque eccentricity index than PR and CN (p < 0.001 and p < 0.001). CN had greater calcified arc and shallower calcium than PR (p < 0.001 and p < 0.001) or PE (p < 0.001 and p < 0.001). More than one-half of CN had negative remodeling. PE had a lower incidence of no-reflow phenomenon after PCI than PR (p = 0.011). Conclusions PE was the underlying mechanism in one-fourth of STEMI. PE was characterized by eccentric fibrous plaque. CN was characterized by superficial large calcium and negative remodeling. PE was associated with less microvascular damage after PCI. [ABSTRACT FROM AUTHOR]

Purpose To assess the utility of 10 s and 20 s modeling periods, rather than the 40 s currently used, in the clinical construction of practical correlation models (CMs) in dynamic tumor tracking irradiation using the Vero4DRT. Methods The CMs with five independent parameters (CM parameters) were analyzed retrospectively for 10 consecutive lung cancer patients. CM remodeling was performed two or three times per treatment session. Three different CMs trained over modeling periods of 10, 20, and 40 s were built from a single, original CM log file. The predicted target positions were calculated from the CM parameters and the vertical displacement of infrared markers on the abdomen ( P IR ) during the modeling. We assessed how the CM parameters obtained over modeling periods of T s ( T = 10, 20, and 40 s) were robust to changes in respiratory patterns after several minutes. The mimic-predicted target positions after several minutes were computed based on the previous CM parameters and P IR during the next modeling. The 95th percentiles of the differences between mimic-predicted and detected target positions over 40 s ( E95 robust,T : T = 10, 20, and 40 s) were then calculated. Results Strong correlations greater than 0.92 were observed between the E95 robust,20 and E95 robust,40 values. Meanwhile, irregular respiratory patterns with inconsistent amplitudes of motion created differences between the E95 robust,10 and E95 robust,40 values of ≥10 mm. Conclusions The accuracies of CMs derived using 20 s were almost identical to those obtained over 40 s, and superior to those obtained over 10 s. [ABSTRACT FROM AUTHOR]

• On average, high-frequency traders (HFTs) make profits against non-HFTs by taking liquidity during large price shocks in individual stocks • HFTs' trading profits are decreasing in the relative tick size of stocks • HFTs provide liquidity when the relative tick size is large and the price shock is idiosyncratic Using tick data identifying high-frequency traders (HFTs), this paper studies the trading profits and liquidity provision of HFTs during large price shocks. Previous studies report mixed evidence on whether HFTs provide or take liquidity in such events. Empirical findings in this paper suggest that relative tick size matters: HFTs provide liquidity when the shock is idiosyncratic and the relative tick size is large, but in this case, they do not earn profits from trading. On average, HFTs can earn profits against non-HFTs because they aggressively take liquidity and trade in the direction of the shocks for stocks of small relative tick sizes. [ABSTRACT FROM AUTHOR]

Abstract: Bone regeneration often requires cues from osteogenesis-inducing factors for successful outcome. N-acetyl cysteine (NAC), an anti-oxidant small molecule, possibly modulates osteoblastic differentiation. This study investigated the potential of NAC as an osteogenesis-enhancing molecule in vitro and in vivo. Various concentrations of NAC (0, 2.5, 5.0, and 10 mm) were added to rat bone marrow stromal cell or osteoblastic cell culture in media with or without dexamethasone. The results showed marked enhancement of alkaline phosphatase activity and mineralized matrix formation together with consistent upregulation of bone-related gene markers such as collagen I, osteopontin, and osteocalcin in the osteoblastic culture with addition of 2.5 or 5.0 mm NAC regardless of the presence of dexamethasone. Micro-CT-based analysis and histological observation revealed that addition of NAC to a collagenous sponge implanted in a critical size cortical bone defect (3.0 mm × 5.0 mm) in rat femur yielded acceleration and completion of defect closure, with thick, compact, and contiguous bone after 6 weeks of healing. In contrast, with sponge alone, only sparse and incomplete bone regeneration was observed during the matching healing period. These results indicate that NAC can function as an osteogenesis-enhancing molecule to accelerate bone regeneration by activating differentiation of osteogenic lineages. [Copyright &y& Elsevier]

Abstract: In a bubbly flow, the mass transfer from bubble swarms to the surrounding liquid and the concentration of dissolved gas transported in the liquid are deeply related to time-spatial structures of the gas and liquid phases. Various techniques to measure bubble characteristics or solution concentration in gas-liquid two-phase flows have been developed. However, detailed discussions about the gas absorption process in consideration of the above relations are not found, because there was no instrument to enable simultaneous measurement of bubble characteristics and concentrations of the surrounding liquid. The purpose of the present study was to develop a new type of probe that enables the simultaneous measurement of these features. We have developed a platinum (Pt)-plated optical fiber probe (POFP: Photoelectric Optical Fiber Probe), which can perform the functions of an optical fiber probe and an electrical probe. The POFP is able to simultaneously measure a CO2-included bubble chord length, velocity, and time-series void fraction as well as the liquid-phase local CO2 concentration. The bubble velocities and chord lengths measured via the POFP method satisfactorily agreed with those obtained with high-speed visualization. Based on the theoretical analysis and primary experimental results, the POFP was considered to possess satisfactory accuracy and response speed for the simultaneous measurement of a bubble velocity, a bubble chord length, a void fraction and a CO2 concentration in the surrounding water. We demonstrated the performance of the POFP by examining it in a bubble column. The CO2 concentration fluctuation at the bottom zone of the bubble column correlated rationally with the void fraction fluctuation. The correlation faded out toward the upper zone. The POFP is considered a useful tool for revealing the relations between flow structures of a bubbly flow and concentration transportation. [Copyright &y& Elsevier]

Abstract: The role of nanofeatured titanium surfaces in a number of aspects of in vivo bone–implant integration, and, in particular, their potential advantages over microfeatured titanium surfaces, as well as their specific contribution to osteoconductivity, is largely unknown. This study reports the creation of a unique nanobimorphic titanium surface comprised of nanotrabecular and nanotuft-like structures and determines how the addition of this nanofeature to a microroughened surface affects bone–implant integration. Machined surfaces without microroughness, sandblasted microroughened surfaces, and micro–nano hybrid surfaces created by sandblasting and alkali and heat treatment of Ti–15Mo–5Zr–3Al alloy were subjected to biomechanical, interfacial and histological analyses in a rat model. The presence of microroughness enabled accelerated establishment of biomechanical implant fixation in the early stages of healing compared to the non-microroughened surfaces; however, it did not increase the implant fixation at the late stages of healing. The addition of nanobimorphic features to the microroughened surfaces further increased the implant fixation by as much as 60–100% over the healing time. Bone area within 50μm of the implant surface, but not beyond this distance, was significantly increased by the presence of nanobimorphic features. Although the percentage of bone–implant contact was also significantly increased by the addition of nanobimorphic features, the greatest improvement was found in the soft tissue intervention between the bone and the implant, which was reduced from >30% to <5%. Mineralized tissue densely deposited with calcium-binding globular proteins was observed in an extensive area of nanobimorphic surfaces after biomechanical testing. This study clearly demonstrates the nanofeature-enhanced osteoconductivity of titanium by an alkali- and heat-treated nanobimorphic surface compared to that by microfeatured surfaces, which results not only in an acceleration but also an improvement of bone–implant integration. The identified biological parameters that successfully detect the advantages of nanofeatures over microfeatures will be useful in evaluating new implant surfaces in future studies. [Copyright &y& Elsevier]

Abstract: Prevention of local infection from wound pathogens such as Staphylococci and Streptococci is crucial for tissue regeneration. N-acetyl cysteine (NAC), an anti-oxidant amino acid derivative, has anti-microbial potential against various species. This in vitro study evaluated whether NAC prevented bacterial infection of gingival fibroblasts and osteoblasts on a scaffold. N-acetyl cysteine delayed growth of Staphylococcus aureus and Streptococcus pyogenes cultured in brain heart infusion (BHI) broth for 12 h in an almost dose-dependent manner (2.5, 5.0 or 10.0 mm). The number of rat gingival fibroblasts on collagen scaffolds with bacterial co-incubation was less than 30% of that in cultures without bacterial co-incubation at day 7. However, pre-addition of NAC to the scaffold yielded a number comparable with that in culture without bacteria. Fibroblasts on the scaffold with bacterial co-incubation were small, rounded and filled with bacteria and reactive oxygen species. Pre-addition of NAC, however, resulted in fibroblasts similar to those observed in culture without bacterial co-incubation. N-acetyl cysteine completely prevented devastating suppression of alkaline–phosphatase activity and extracellular matrix mineralization in osteoblastic culture on scaffolds with bacterial co-incubation. These results indicate that NAC can functionalize a scaffold with anti-infective capabilities, thus assisting healing of soft and hard tissues. [Copyright &y& Elsevier]

Abstract: Titanium surfaces with micro-nano hybrid topography (nanoscale nodules in microscale pits) have been recently demonstrated to show higher biological capability than those with microtopography alone. On the other hand, UV treatment of titanium surfaces, which is called UV photofunctionalization, has recently been introduced to substantially increase the biological capability and osteoconductivity of titanium surfaces. However, synergistic effects of these two advanced surface modification technologies and regulatory factors to potentially modulate the mutual effects have never been addressed. In this study, utilization of a recently discovered controllable self-assembly of TiO2 nanonodules has enabled the exploration of the relative contribution of different sizes of nanostructures to determine the biological capability of titanium surfaces and their relative responsiveness to UV photofunctionalization. Rat bone marrow-derived osteoblasts were cultured on titanium disks with either micropits alone, micropits with 100-nm nodules, micropits with 300-nm nodules, or micropits with 500-nm nodules, with or without UV treatment. Although UV treatment increased the attachment, spread, proliferation, and mineralization of these cells on all titanium surfaces, these effects were more accentuated (3–5 times) on nanonodular surfaces than on surfaces with micropits alone and were disproportionate depending on nanonodule sizes. For instance, on UV-treated micro-nano hybrid surfaces, cell attachment correlated with nanonodule sizes in a quadratic approximation with its peak for 300-nm nodules followed by a decline for 500-nm nodules, while cell attachment exponentially correlated with surface roughness with its plateau achieved for 300-nm nodules without a subsequent decline. Moreover, cell attachment increased in a linear correlation with the surface area, while no significant effect of the inter-irregularities space or degree of hydrophilicity was observed on cell attachment. These results suggest that the effect of UV photofunctionalization can be multiplied on micro-nano hybrid titanium surfaces compared with the surfaces with micropits alone. This multiplication is disproportionately regulated by a selected set of topographical parameters of the titanium surfaces. Among the nanonodules tested in this study, 300-nm nodules seemed to create the most effective morphological environment for responding to UV photofunctionalization. The data provide a systematic platform to effectively optimize nanostructures on titanium surfaces in order to enhance their biological capability as well as their susceptibility to UV photofunctionalization. [Copyright &y& Elsevier]

Abstract: Introduction: The purpose of this study was to evaluate the cytotoxicity of mineral trioxide aggregate (MTA) and its potential detoxification by an antioxidant amino acid, N-acetylcysteine (NAC). Methods: Rat dental pulp cells extracted from rat maxillary incisors were directly cultured on MTA with or without NAC in culture me-dium. The number of cells and their spreading behavior were both assessed 24 hours after seeding. The intracellular levels of reactive oxygen species (ROS) and glutathione (GSH) were also assessed after 24 hours of culture. Results: The number of cells attached to MTA was 60% greater when NAC was added to the culture medium. In addition, the area and perimeter of the cells were found to be 2-fold greater in the culture containing NAC. Cells cultured on MTA alone showed large ROS concentrations, which disappeared when the medium was supplemented with NAC. The intracellular GSH level, however, increased 3.5-fold with NAC addition. Conclusions: This study demonstrated that the presence of NAC in environments can substantially improve attachment and spreading behaviors of dental pulp cells on MTA. This biological effect was associated with an im-provement in the cellular redox system by NAC and warrants further exploration of NAC for determining its therapeutic value in improving the biocompatibility of MTA. [Copyright &y& Elsevier]

Abstract: Current dental restorative materials are only used to fill the defect of hard tissues, such as dentin and enamel, because of their cytotoxicity. Therefore, exposed dental pulp tissues in deep cavities must be first covered by a pulp capping material like calcium hydroxide to form a layer of mineralized tissue. However, this tissue mineralization is based on pathological reaction and triggers long-lasting inflammation, often causing clinical problems. This study tested the ability of N-acetyl cysteine (NAC), amino acid derivative, to reduce cytotoxicity and induce mineralized tissue conductivity in resin-modified glass ionomer (RMGI), a widely used dental restorative material having dual cure mechanism. Rat dental pulp cells were cultured on untreated or NAC-supplemented RMGI. NAC supplementation substantially increased the percentage of viable cells from 46.7 to 73.3% after 24-h incubation. Cell attachment, spreading, proliferative activity, and odontoblast-related gene and protein expressions increased significantly on NAC-supplemented RMGI. The mineralization capability of cells, which was nearly suppressed on untreated RMGI, was induced on NAC-supplemented RMGI. These improved behaviors and functions of dental pulp cells on NAC-supplemented RMGI were associated with a considerable reduction in the production of intracellular reactive oxygen species and with the increased level of intracellular glutathione reserves. These results demonstrated that NAC could detoxify and functionalize RMGIs via two different mechanisms involving in situ material detoxification and antioxidant cell protection. We believe that this study provides a new approach for developing dental restorative materials that enables mineralized tissue regeneration. [ABSTRACT FROM AUTHOR]

Abstract: Recently, UV photofunctionalization of titanium has been shown to be effective in enhancing osteogenic environment around this functional surface, in particular for the use of endosseous implants. However, the underlying mechanism remains unknown and its potential application to other tissue engineering materials has never been explored. We determined whether adhesion of a single osteoblast is enhanced on UV-treated nano-thin TiO2 layer with virtually no surface roughness or topographical features. Rat bone marrow-derived osteoblasts were cultured on UV-treated or untreated 200-nm thick TiO2 sputter-coated glass plates. After an incubation of 3 h, the mean critical shear force required to initiate detachment of a single osteoblast was determined to be 1280 ± 430 nN on UV-treated TiO2 surfaces, which was 2.5-fold greater than the force required on untreated TiO2 surfaces. The total energy required to complete the detachment was 37.0 ± 23.2 pJ on UV-treated surfaces, 3.5-fold greater than that required on untreated surfaces. Such substantial increases in single cell adhesion were also observed for osteoblasts cultured for 24 h. Osteoblasts on UV-treated TiO2 surfaces were larger and characterized with increased levels of vinculin expression and focal contact formation. However, the density of vinculin or focal contact was not influenced by UV treatment. In contrast, both total expression and density of actin fibers increased on UV-treated surfaces. Thin layer TiO2 coating and UV treatment of Co–Cr alloy and PTFE membrane synergistically resulted in a significant increase in the ability of cell attachment and osteoblastic production of alkaline phosphatase. These results indicated that the adhesive nature of a single osteoblast is substantially enhanced on UV-treated TiO2 surfaces, providing the first evidence showing that each individual cell attached to these surfaces is substantially more resistant to exogenous load potentially from blood and fluid flow and mechanical force in the initial stage of in vivo biological environment. This enhanced osteoblast adhesion was supported synergistically but disproportionately by enhancement in focal adhesion and cytoskeletal developments. Also, this study demonstrated that UV treatment is effective on nano-thin TiO2 depositioned onto non-Ti materials to enhance their bioactivity, providing a basis for TiO2-mediated photofunctionalization of biomaterials, a new method of developing functional biomaterials. [Copyright &y& Elsevier]

Abstract: In this study, we tested the potential of UV-photofunctionalized titanium surfaces to overcome compromised bone–titanium integration in a gap healing model. Titanium in rod and disk forms was acid etched and then stored for 4 weeks under dark ambient conditions. Titanium rods with and without UV pretreatment were placed into a rat femur with (contact healing) or without (gap healing) contact with the innate cortical bone. The titanium implants were subjected to a biomechanical push-in test, micro-CT bone morphometry, and surface elemental analysis after 2 weeks of healing. The strength of bone–titanium integration in the gap healing model was one-third of that in the contact healing model. However, UV-treated implants in the gap healing condition produced a strength of bone–titanium integration equivalent to that of untreated implants in the contact healing condition. Bone volume around UV-treated implants was 2- to 3-fold greater than that around the untreated implants in the gap healing model. A bone generation profile drawn along the long axis of the implant exhibited greater contrast between the untreated and UV-treated surfaces in the cortical area than in the bone marrow area. The bone tissue formed on UV-treated implants showed a higher Ca/P ratio than that formed on untreated titanium. The rate of cell proliferation, alkaline phosphatase activity, and calcium deposition in femoral periosteal cells and in bone marrow-derived osteoblasts were greater in cultures on UV-treated titanium disks than in cultures on untreated disks. The UV-enhanced function in periosteal cells was more pronounced when they were co-cultured with bone marrow-derived osteoblasts, indicating a synergistic effect of UV-treated titanium with biological signals from bone marrow-derived osteoblasts. Within the limitation of the model used in this study, UV-photofunctionalized titanium surfaces may overcome the challenging condition of bone–titanium integration without cortical bone support. UV treatment of implants induced marked improvements in the behavior of bone formation and quantity and quality of bone tissue around the implants. These effects may be related to the promoted function of both periosteum- and bone marrow-derived osteogenic cells at the local level around UV-treated titanium surfaces. [Copyright &y& Elsevier]

Abstract: Improving the osteoconductive potential of titanium implants has been of continuing interest in the fields of dentistry and orthopedic surgery. This study determined the bioactivity of ultraviolet (UV) light-treated titanium. Human mesenchymal stem cells (MSCs) were cultured on acid-etched microtopographical titanium surfaces with and without 48h pretreatment with UVA (peak wavelength of 360nm) or UVC (peak wavelength of 250nm). The number of cells that migrated to the UVC-treated surface during the first 3h of incubation was eight times higher than those that migrated to the untreated surface. After 24h of incubation, the number of cells attached to the UVC-treated surface was over three times more than those attached to the untreated surface. On the UVC-treated surface, the cellular spread was expedited with an extensive and intensive expression of the focal adhesion protein vinculin. The cells on the UVC-treated surface exhibited a threefold higher bromodeoxyuridine incorporation, a doubling of the alkaline phosphatase-positive area and the up-regulated expression of bone-related genes, indicating the accelerated proliferation and differentiation. The UVC-treated surface did not adversely affect the viability of the cells. These biological effects were not seen after UVA treatment, despite the generation of superhydrophilicity. Thus, we discovered a novel photofunctionalization of titanium dioxide that substantially enhances its bioactivity in human MSCs. Further studies are required to investigate the universal effectiveness of this surface modification for different titanium-containing materials, with varying chemistries and textures, as well as to understand its significance in enhancing in vivo osteoconductivity. [Copyright &y& Elsevier]

Abstract: Methyl methacrylate (MMA)-based bone cement monomer is cytotoxic. N-Acetyl cysteine (NAC), a cysteine derivative, may alleviate this toxicity by inactivating the monomer components with its sulfhydryl moiety. This study examined the chemical interaction dynamics between bone cement monomer and NAC resulting in detoxification of the monomer. A monomer/NAC mixture was prepared by mixing and incubating a commercially available MMA-based bone cement monomer with NAC for various time periods of 1min, 1h, 6h and 24h. Rat bone marrow-derived osteoblastic cells were cultured with either the monomer/NAC mixture or the monomer alone. Only 17% of the cells were viable 24h after seeding in the culture containing the monomer alone. The proliferation rate and alkaline phosphatase activity of the cells were substantially reduced under this condition. In contrast, when cultured with the monomer/NAC mixture, the viability and function of the cells were improved with increasing time of monomer/NAC incubation. For instance, the monomer/NAC mixture that was pre-reacted for 1min increased cell viability from 17% to 55%. The monomer/NAC mixture that was pre-reacted for 24h nearly completely restored cell viability, proliferation and ALP activity to the level of an untreated control culture. The DPPH radical-scavenging capacity of monomer/NAC mixture decreased with an increase in their reaction time, indicating time-dependent depletion of the NAC anti-oxidant moiety. Within the limit of this experimental condition, these data demonstrate the immediate initiation and rapid completion of bone cement monomer/NAC interaction, resulting in abrogation of the monomer’s cytotoxicity. [Copyright &y& Elsevier]

Abstract: Currently used poly(methyl methacrylate) (PMMA)-based bone cement lacks osteoconductivity and induces osteolysis and implant loosening due to its cellular and tissue-toxicity. A high percentage of revision surgery following the use of bone cement has become a significant universal problem. This study determined whether incorporation of the amino acid derivative N-acetyl cysteine (NAC) in bone cement reduces its cytotoxicity and adds osteoconductivity to the material. Biocompatibility and bioactivity of PMMA-based bone cement with or without 25mm NAC incorporation was examined using rat bone marrow-derived osteoblastic cells. Osteoconductive potential of NAC-incorporated bone cement was determined by μCT bone morphometry and implant biomechanical test in the rat model. Generation of free radicals within the polymerizing bone cement was examined using electron spin resonance spectroscopy. Severely compromised viability and completely suppressed phenotypes of osteoblasts on untreated bone cement were restored to the normal level by NAC incorporation. Bone volume formed around 25mm NAC-incorporated bone cement was threefold greater than that around control bone cement. The strength of bone–bone cement integration was 2.2 times greater for NAC-incorporated bone cement. For NAC-incorporated bone cement, the spike of free radical generation ended within 12h, whereas for control bone cement, a peak level lasted for 6 days and a level greater than half the level of the peak was sustained for 20 days. NAC also increased the level of antioxidant glutathione in osteoblasts. These results suggest that incorporation of NAC in PMMA bone cement detoxifies the material by immediate and effective in situ scavenging of free radicals and increasing intracellular antioxidant reserves, and consequently adds osteoconductivity to the material. [Copyright &y& Elsevier]

[Display omitted] A comprehensive approach is proposed to systematically determine the optimal mode of operation between continuous and batch injectable manufacturing considering product and market conditions. At the core of this approach are two integrated complete mathematical modules for discrete and continuous injectable manufacturing, which are supplemented with an economic evaluation module that can then be used to explore the impact of all relevant process parameters (e.g., lot-size, number of operators, solubility, product demand, raw material costs). When the developed approach was applied to two case studies, it was found that batch production was preferred at low to moderate solution (raw material) costs. In contrast, at higher solution costs, the preference for batch and continuous production processes changed back and forth as the annual product demand changed. The study also found that continuous production processes became increasingly preferred at medium to large final dosage volumes and a competitive alternative even at moderate solution costs. From a decision-making point of view, batch injectable manufacturing will be preferred over the novel continuous manufacturing technology unless there is a significant economic incentive to overcome the perceived technology risk. The proposed approach is intended as a decision-support tool for pharmaceutical process engineers. [ABSTRACT FROM AUTHOR]

Abstract: Despite the proven cytotoxicity, poly(methylmethacrylate) (PMMA) resin is one of the most frequently and extensively used materials in medical and dental fields. The study examined the potential detoxification of the resin material and restoration of the resin-induced suppression of cellular function using an antioxidant amino acid derivative, N-acetyl cysteine (NAC). Oral fibroblasts extracted from rat oral mucosa were cultured on the resin material with or without incorporation of NAC into the material. Twenty-four hour after incubation, less than 2% of the cells were viable on the untreated control resin, while up to 35% of the cells were viable on the resin with incorporation of NAC. At day 7 of culture, the expression of collagen I and III genes was downregulated on the untreated resin, while the cells on NAC-supplemented resin showed the expression levels similar to those in polystyrene culture. The cells produced three times greater amount of collagen on the NAC-supplemented resin than on the untreated resin. The data demonstrated that the cytotoxicity of PMMA resin was substantially lower when the material contains NAC. The potential usefulness of this principle should be explored with a view of developing biocompatible polymer-based materials in a broad range of dental and medical resin materials and tissue engineering scaffolds. [Copyright &y& Elsevier]

Abstract: Emulsion copolymerizations of styrene and methacrylic acid with polyoxyethylene nonylphenyl ether nonionic emulsifiers having various hydrophilic–lipophilic balance (HLB) values (13.7, Emulgen 911; 15.5, Emulgen 920; 17.2, Emulgen 931) were performed. The incorporation behavior of the nonionic emulsifiers, comprising polydisperse poly(ethylene oxide) (PEO) chain lengths, inside the particles was investigated. At the completion of the polymerization, the incorporated percentage of the lowest HLB emulsifier was 61%, much higher than that of the highest HLB one (10%). In both polymerizations, the amounts of the incorporated emulsifiers increased with conversion, and shorter PEO chain (i.e., lower molecular weight) components were predominantly incorporated over longer PEO chain components. [Copyright &y& Elsevier]

Abstract: The zinc coated steel sheet has been mostly used for automobile and other industries because of its high corrosion resistance. This paper deals with the development of new ceramics support roll used for a continuous galvanizing pot to manufacture stable galvanizing steel sheet. Usually stainless steel rolls coated by tungsten carbide are used to support and stabilize the strip in a continuous galvanizing pot, which is filled with molten zinc. However, corrosion and abrasion arise on the roll surface only in a few weeks, and causing the deterioration of quality of plating. Although developing all-ceramics rolls is most desirable, risk of fracture has to be reduced when the ceramic roll dips into molten metal. In this paper, therefore, how to reduce the thermal stress is considered when the ceramic rolls are installed in molten metal using finite volume method and finite element method. The usefulness of silicon nitride having extremely high conductivity is also discussed. [Copyright &y& Elsevier]

Abstract: The abdominal sympathetic system is unique in that its postganglionic axons do not directly innervate gastrointestinal smooth muscle layers but exert their effects through the enteric nervous system. The purpose of the present study was to examine the ability of neurons in abdominal sympathetic ganglia to regenerate after axonal injury and to determine whether reinnervation occurs after the removal of ganglia. Axons from the celiac ganglion and superior mesenteric ganglion complex (CG/SMG) of adult female BALB/c mice were crushed or the ganglion complex was removed. Immunohistochemistry, western blotting and in situ hybridization were performed to examine the changes in tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP-43) in the duodenum and the sympathetic ganglia. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and injection of the tracer dye, fluorogold were also performed. After crushing the nerve, TH in the duodenum disappeared and reappeared within 90 days. In the CG/SMG, TH decreased and increased as in the duodenum, while the expression of GAP-43 changed in the opposite direction. Nerve crushing caused cell death to limited number of neurons in the CG/SMG. The removal of CG/SMG decreased TH in the duodenum and stomach, but 180 days later TH-positive innervation was recovered. Fluorogold injection revealed that the inferior mesenteric ganglion reinnervated the stomach. Therefore, postganglionic sympathetic nerves in the abdomen are able to regenerate and reinnervation occurs even after the removal of sympathetic ganglia. [Copyright &y& Elsevier]

• We showed a simple manipulation of verbal cues affected performance accuracy in Fitts' Law task. • Directing attention to an intended effect improved performance accuracy relative to directing attention to body movements. • Body-oriented attention affected performance when subjects' attention was directed to a 'virtual' body. The effects of attentional focus (AF) instruction were examined in a reciprocal aiming task implemented in a 3-dimensional, fully immersive virtual environment (VE). Within the VE, participants (N = 19) moved a cube between two targets at two paces (750 ms and 500 ms) while being asked to focus externally (EXF) and internally (INF). Performance accuracy was measured as two-dimensional error and its variability between the center of the target to the center of the cube and one-dimensional bias (undershooting/overshooting behavior in the anteroposterior and mediolateral directions). The results indicated better performance, specifically greater accuracy and lower one-dimensional bias in the anteroposterior direction when adopting an EXF compared to an INF. Our findings reveal that the beneficial effects of an EXF on motor performance are not restricted movements within physical environments only but also work in VE. This has implications for rehabilitation and training protocols in VE. [ABSTRACT FROM AUTHOR]

The most common liver malignancies are hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and metastatic tumors. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma may invade the portal vein (PV). An association between diffuse large B-cell lymphoma (DLBCL) and primary biliary cholangitis (PBC) remains unclear. We herein report a thought-provoking case of a difficult-to-diagnose liver tumor with PV thrombosis in a PBC patient. A 66-year-old woman had PBC, systemic sclerosis, diabetes, and osteoporosis. A solitary liver tumor accompanied by macrovascular thrombosis in the PV was detected incidentally. Based on dynamic imaging findings, we considered the tumor to be intrahepatic cholangiocarcinoma, and right lobectomy with lymphadenectomy was performed. Unexpectedly, pathological assessment made a definitive diagnosis of DLBCL that did not invade the vessels and bile duct. In fluorine-18-fluorodeoxyglucose positron emission tomography, abnormal accumulations were clearly observed in the breast tissue and peritracheal, parasternal, mediastinal, and pericardial lymph nodes. The patient achieved complete remission after systemic chemotherapy, and there has been no recurrence 3 years after surgery. Primary lymphoma in the liver is rare, and we did not consider our patient's tumor as primary liver lymphoma. Our case actually showed no tumor thrombosis in the PV. Although autoimmune disorders may increase the risk of non-Hodgkin's lymphoma, an association between DLBCL and PBC is still unclear, and we must remember that DLBCL may develop rarely in a PBC patient. Our case report provides a timely reminder for clinicians and surgeons in the fields of hepatology and hematology. • The most frequent liver neoplasms are HCC, ICC, and metastatic tumors. • HCCs often cause portal thrombosis. • Primary liver lymphoma is rare, and generally does not invade the vessels. • An association between diffuse large B-cell lymphoma and PBC remains unclear. • We describe a thought-provoking case of a difficult-to-diagnose liver tumor in PBC. [ABSTRACT FROM AUTHOR]

• Diagnosis of functioning neuroendocrine neoplasms (NENs) in the pancreas is challenging. • Adrenocorticotropic hormone (ACTH) regulates adrenal cortisol production. • Functioning NENs may cause hypercortisolism as a result of ectopic ACTH secretion. • Systematic endocrine examination and functional imaging studies are vital. • Making a precise diagnosis enables appropriate treatment of NENs. Definitive diagnosis of functioning neuroendocrine neoplasms (NENs) in the pancreas is challenging. Adrenocorticotropic hormone (ACTH) regulates adrenal cortisol production. Ectopic ACTH secretion by functioning NENs may cause hypercortisolism. A 62-year-old woman who was receiving medications for hypertension and hyperlipidemia was referred to our hospital because of abnormal blood tests. Diabetes mellitus was initially diagnosed. Dynamic computed tomography and endoscopic ultrasound revealed a 35-mm diameter hypovascular tumor in the distal pancreas and multiple liver metastases. Endoscopic ultrasound-guided fine-needle aspiration resulted in a diagnosis of neuroendocrine carcinoma. The patient developed pancreatic leakage progressing to peritonitis, abscess formation, pleural effusion, and ascites after the fine-needle aspiration biopsy. Her clinical condition deteriorated to a septic state, necessitating emergency surgery comprising distal pancreatectomy, intraperitoneal lavage, and drainage. Wound healing was protracted and accompanied by ongoing high white blood cell counts and neutrophilia. She also developed a gastric ulcer postoperatively. Systematic endocrine investigations were performed because hypercortisolism caused by a functioning NEN was suspected. Eventually, a definitive diagnosis of an ACTH-producing NEN in the pancreas was made. Systemic chemotherapy was proposed; however, the patient and her family opted for palliative treatment only. She died 42 days after the initial diagnosis. We here present a patient with ACTH-dependent hypercortisolism attributable to a pancreatic NEN who died of progressive cancer after a delay in definitive diagnosis. Detailed investigation, including systematic endocrine examination and functional imaging studies, are important for precise diagnosis of, and appropriate treatment for, NENs. [ABSTRACT FROM AUTHOR]