Search

In Asia-Pacific region, hepatocellular carcinoma is a serious health threat attributing to over 600,000 deaths each year and account for over 70% of global cases. Clinically, the major unmet needs are recurrence after curative-intent surgery, liver transplantation or local ablation and disease progression in those with hepatocellular carcinoma not eligible for resection or failed locoregional therapy. In the recent few years, new targeted therapy and immune-checkpoint inhibitors have been registered as systemic therapy to address these issues. Notably, new forms of systemic therapy, either as first-line or second-line therapy for unresectable hepatocellular or those not eligible for locoregional therapy, are now available. New data is also emerging with the use of systemic therapy to prevent hepatocellular carcinoma recurrence after curative-intent resection or local ablation therapy and to retard disease progression after locoregional therapy. In the future, further implementation of immune-checkpoint inhibitors and other forms of immunotherapy are expected to bring a new paradigm to the management of hepatocellular carcinoma. New insight related to immune-related adverse events with the use of immunotherapy has allso enabled optimization of the therapeutic approach to patients with hepatocellular carcinoma. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia-Pacific key opinion leaders in the field of hepatocellular carcinoma. Three key questions will be addressed, namely: (1) Which patients with hepatocellular carcinoma should be considered for systemic therapy? (2) Which systemic therapy should be used? (3) How should a patient planned for immune checkpoint-based systemic therapy be managed and monitored?, Competing Interests: Declarations. Conflict of interest: George LAU reported lecture fees from AstraZeneca. Shuntaro OBI reported research grants from Eisai, Otsuka pharmaceutical, and Mochida pharmaceutical. Ryosuke TATEISHI reported lecture fees from Abbvie, AstraZeneca, Chugai, Eisai, Gilead Sciences, MSD and Takeda. Sadahisa OGASAWARA reported honoraria from Bayer, Eisai, Eli Lilly, consulting or advisory fees from Bayer, Eisai, Merck & Co. Inc., Chugai Pharma, Eli Lilly, and research grants from Bayer and Eisai. Naoya KATO reported honoraria payment from Bayer and Chugai; research funding from Bayer, Chugai, and Roche. Stephen L CHAN reported consulting or advisory board fees from AstraZeneca, Eisai, and MSD; reports being an invited speaker for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, IPSEN, MSD, and Roche; and research funding from Bayer, Eisai, IPSEN, MSD, and Sirtex Medical. Yoshiyuki UENO reported honoraria payment from Chugai and Eisai. Ann-Lii CHENG reported consulting or advisory board fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Eisai, Genentech/Roche, Ipsen, IQVIA, MSD, Ono Pharmaceutical, and Roche; and honoraria from AstraZeneca, Bayer, Eisai, and Genentech/Roche. Yock Young DAN reported consulting or advisory board fees from Boehringer Ingelheim, MSD, Norvo Nordisk, Roche, and research grants from MSD, Norvo Nordisk, Perspectum, Siemens. Jeong Min LEE reported lecture fees from Samsung Medison, GE Healthcare, Philips Healthcare, Starmed, and research grants from Samsung Medison, Siemens Healthineers, Philips Healthcare, GE Healthcare, Bayer, Guerbet, CMS, Canon Healthcare, Dongkuk Pharma. Diana A. Payawal reported lecture, consulting or advisory board fees from Gilead Sciences, Mylan Pharmaceuticals, Echosense, Getz and Abbott. Ekaphop SIRACHAINAN reported honoraria payment from MSD, Sanofi/Aventis, Merck, Amgen, Roche, Mundipharma, AstraZeneca, LF Asia, Diethelm Keller Group, Bristol Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Dr Reddy's Laboratories, Zuellig Pharma, Meda Pharmaceuticals, Pfizer, Novo Nordisk, Novartis. Tawesak Tanwandee reported research grants from Bristol Myers Squibb and Merck. Masao Omata reported lecture, consulting or advisory board fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Otsuka, Astellas, Gilead Sciences, Chugai, Mitsubishi Tanabe, Kyorin, Merck Sharp and Dohme, Dainippon Sumitomo, Vertex Pharmaceuticals, Takeda, Merck Serono, and Zeria. Jian ZHOU, Shukui QIN, Haitao ZHAO, Motoyuki OTSUKA, Jacob GEORGE, Pierce KH CHOW, Jianqiang CAI, Shuichiro SHIINA, Osamu YOKOSUKA, Kyoko OURA, Thomas YAU, Ming KUANG, Minshan CHEN, Gregory CHENG, Wan-Long CHUANG, Oidov BAATARKHUU, Feng BI, Rino A GANI, Atsushi TANAKA, Wasim JAFRI, Ji-Dong JIA, Jia-Horng KAO, Kiyoshi HASEGAWA, Patrick LAU, Jun LIANG, Zhenwen LIU, Yinying LU, Hongming PAN, Salimur RAHMAN, Jinsil SEONG, Feng SHEN, Gamal SHIHA, Tianqiang SONG, Hui-Chuan SUN, Tsutomu MASAKI, Lai WEI, Jin Mo YANG, Jose D SALLANO, Yanqiao ZHANG,, A Kadir DOKMECI, Shu-sen ZHENG, Jia FAN, Sheung-Tat FAN and Shiv Kumar Sarin reported that they have no conflict of interest. Ethical approval: Not applicable. Informed consent: Not applicable., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background: Tri-weekly cisplatin and radiotherapy (CDDP + RT) is a standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) but is sometimes challenging to complete in older patients. Weekly CDDP + RT has shown mild toxicity compared to tri-weekly CDDP + RT for LA-HNSCC and is a promising option for older adults. We aimed to report the treatment outcomes and prognostic factors in patients with LA-HNSCC treated with weekly CDDP + RT., Methods: We analyzed patients aged ≥ 70 years who started weekly CDDP + RT for LA-HNSCC between July 2006 and October 2022. LA-HNSCC includes cancer in the oropharynx, hypopharynx, or larynx with a clinical stage of 3 or 4 without distant metastases based on the Union for International Cancer Control staging system 8th edition. The radiation dose of 70 Gy was delivered in 35 fractions by 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy. The primary endpoint was the 3-year overall survival (OS), and the secondary endpoints were the 3-year progression-free survival (PFS) and 3-year cause-specific survival (CSS). The Kaplan-Meier method was used to calculate survival rates, and the log-rank test was used to evaluate statistical significance. A Cox proportional hazards model was used for the multivariate analysis of prognostic factors., Results: The median age of the 49 patients was 72 (range: 70-78) years. The median CDDP dose was 200 (40-280) mg/ m 2 , and 47 patients completed scheduled radiotherapy. Forty-eight patients (98.0%) had a performance status of ≥ 1 at the initial visit. The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval [CI]: 64.8-90.7), 68.3% (95% CI 51.8-81.2), and 85.0% (95% CI 68.7-93.4), respectively. In the multivariate analysis, the cumulative CDDP dose (< 200 or ≥ 200 mg/m 2 ) was a significant factor for OS (hazard ratio: 0.29 [95% CI 0.08-0.97], p = 0.044). There was one case of early mortality. Grade 3 or higher late adverse events were observed in four patients (8.2%)., Conclusions: Weekly CDDP + RT in older patients led to good survival outcomes with an acceptable rate of adverse events. CDDP should be administered at a dose of at least 200 mg/m 2 in older patients. Trial registration Retrospectively registered., (© 2023. The Author(s).)

Background/purpose: Primary sclerosing cholangitis (PSC) is a rare chronic liver disease. The mechanisms and prediction of PSC progression are unclear. Recent investigations have shown that general conditions, such as oxidative stress, affect the course of chronic diseases. We investigated the clinical course and oxidative stress-related condition of PSC to determine prognostic factors., Methods: We recruited 58 patients with PSC (mean age; 37.4 years, mean observation period; 1382 days) who visited our department from 2003 to 2021. Clinical characteristics were investigated to define prognostic factors. Oxidative stress status was evaluated using two types of markers: an oxidative stress marker (serum reactive oxygen metabolite; dROM) and an antioxidant marker (serum OXY adsorbent test; OXY)., Results: The revised Mayo risk, Child-Pugh, model for end-stage liver disease-sodium (MELD-Na) scores or fibrosis-related FIB-4 index significantly predicted poor overall survival. High intestinal immunoglobulin A (IgA) levels predicted poor survival. Among patients with high and intermediate revised Mayo risk scores, those with physiologically high dROM levels showed better survival than those with lower dROM levels. In this population, dROM was negatively correlated with AST and IgA, which are both correlated with survival., Conclusions: High and intermediate revised Mayo risk score group predicted a poor clinical course in PSC. Additionally, the Child-Pugh score, MELD-Na score, FIB-4 index, and serum IgA were significantly correlated with survival. In patients with high and intermediate revised Mayo risk scores, physiologically high oxidative stress status correlated with low IgA levels and a good prognosis., (© 2023. The Author(s).)

Silicate ions (SiO 3 2- ), or ionic silica, are known to cause silica scaling in industrial water applications when excess amounts are present; hence, concentrations must be monitored and kept at a constant low level. Ionic silica is conventionally measured by spectrophotometry in the form of its silicomolybdic complex based on the molybdenum blue reaction, but the operation process is complicated and not suitable for on-site detection. To solve these issues, microfluidic paper-based analytical devices (µPADs) have been gaining attention as portable, low-cost analytical devices suitable for on-site detection. The foldable origami type device described in this work enabled silica detection based on the molybdenum blue reaction, in the range of 50-1000 mg/L, with a practically detectable lowest concentration of 50 mg/L. The device showed selectivity for silicate ions and stability over 21 days when stored at 4 °C. The semi-quantitative analytical performance makes the proposed paper-based device attractive for on-site industrial monitoring., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

In this work, we optimized classification algorithms and the hyperparameters for screening falsified and substandard amoxicillin capsules. The distribution of low-quality medical products is a serious problem, especially in low- and middle-income countries. Near-infrared (NIR) spectroscopy has been proposed as the first choice for a screening device. However, preparation of the reference library for the classification training is a highly difficult process. We herein propose a hetero-device classification between training and test devices. In this proposal, Fourier-transform NIR spectrometer and portable wavelength dispersive NIR spectrometer were used as training and test devices, respectively. As the classifier candidates, we examined 13 algorithms and selected 8. We then optimized the hyperparameters for these classifiers by the grid search and cross validation methods. In the final analysis, few classifiers were found to give acceptable prediction results by the hetero-device classification. When using these methods, it is crucial to examine the results by the classification probability, due to the trade-off between sensitivity and specificity. Finally, we suggest that k-nearest neighbors, extra trees, and gradient boosting classifiers are the optimal algorithms with high classification probability for the substandard and falsified amoxicillin capsules., (© 2022. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Purpose: Pulmonary vein (PV) isolation using balloon ablation was developed as a technique for patients with paroxysmal atrial fibrillation (PAF). While most studies examined cryoballoon ablation (CBA), there have also been many reports on hot balloon ablation (HBA). We aimed to evaluate the clinical characteristics and outcomes between HBA and CBA., Methods: In a total of 103 consecutive patients with PAF who underwent catheter ablation, 60 propensity score-matched (30 CBA and 30 HBA) patients were enrolled. The procedural differences and clinical outcomes between the two groups were analyzed., Results: The requirement for additional touch-up ablation was more frequent in the left superior pulmonary vein (LSP) in the HBA group than in the CBA group. Pre-procedural computed tomography (CT) images showed that a thicker left pulmonary vein ridge and larger cross-sectional area of the LSPV were significantly associated with residual PV potentials after HBA. However, post-procedural CT images showed that PV stenosis (> 25%) was higher in the HBA group (33%) than in the CBA group (0%). PV stenosis after HBA was observed most frequently in the right superior PV (50%). The atrial fibrillation/atrial tachycardia-free survival rate during follow-up (365 ± 102 days) was similar between the two groups (CBA vs. HBA, 83% vs. 90%)., Conclusions: Although both balloon modalities can relieve atrial arrhythmia after the procedure, careful attention is required during HBA procedures, especially for the right superior PV, to avoid PV stenosis., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Newly designed pyrrolo[2,1-c][1,4]benzodiazepines tricyclic skeleton has shown potential clusters of cannabinoid receptors CB1/CB2 selective ligands. CB2 plays a critical role in microglial-derived neuroinflammation, where it modulates cell proliferation, migration, and differentiation into M1 or M2 phenotypes. Beginning with computer-based docking studies accounting the recently discovered X-ray crystal structure of CB2, we designed a series of PBD analogs as potential ligands of CB2 and tested their binding affinities. Interestingly, computational studies and theoretical binding affinities of several selected ( S , E )-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction towards CB1 and CB2. Reported here is the discovery of the first representatives of this series of selective binding to CB2. Preliminary data showed that this class of molecules display potential binding efficacy towards the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed K i of 0.49 and 4.7 μM towards CB2 receptors while no binding was observed to CB1. The designed leads have shown remarkable stability pattern at the physiological pH magnifying their therapeutic values. We hypothesize that the PBD tricyclic structure offers the molecule an appropriate three-dimensional conformation to fit snugly within the active site of CB2 receptors, giving them superiority over the reported CB2 agonists/inverse agonists. Our findings suggested that the attachment of heterocyclic ring through the condensation of diazepine hydrazone and S- or N-heterocyclic aldehydes enhances the selectivity of CB2 over CB1., Competing Interests: Conflict of Interest Authors declare no conflict of interest.

Marine natural products have drawn a great deal of attention as a vital source of new drugs for the last five decades. However, marine organisms in the seas surrounding Turkey (the Black Sea, the Aegean Sea and the Mediterranean Sea) haven't been yet extensively explored. In the present study, three marine organisms (Dysidea avara, Microcosmus sabatieri and Echinaster sepositus) were sampled from the Dardanelles (Turkish Straits System, Western Turkey) by scientific divers, transferred to the laboratory and then were extracted with 70% ethanol. The extracts were tested for their cytotoxic effect against K562, KMS-12PE, A549, and A375 cancer cell lines. The sponge extract elicited the most promising cytotoxic activity, thus it was further evaluated against H929, MCF-7, HeLa, and HCT116 cancer cells. Most of the designated cells showed a considerable sensitivity for the sponge extract particularly H929, K562, KMS-12PE and HeLa cells with IC 50 less than 10 μg/mL. On the contrary, the other two extracts exhibited no cytotoxic activity on all cells at 100 μg/mL concentration. The sponge extract was tested for its capacity to induce apoptosis in cancer cells and to inhibit a panel of tyrosine kinases showing remarkable results. The outcome of this study represents a platform for discovery of new chemotherapeutic agents of marine natural origin.

This study characterized the plan complexity of the dual-layer multi-leaf collimator (MLC) performance for volumetric modulated arc therapy (VMAT) in Halcyon. Plan complexity metrics were computed independently for each MLC layer (proximal and distal): modulation complexity score (MCS), plan averaged beam area, irregularity, and modulation (PA, PI, and PM) were obtained. These were investigated when weighted by proportions of the effective proximal MLC and distal MLC (MCS w , PA w , PI w , and PM w ). Conventional plan complexity metrics for the effective 5.0 mm resolution MLC (MCS 5 , PA 5 , PI 5 , PM 5 ), small aperture score (SAS), effective distal MLC score (EDS), and MU were also evaluated. Forty-five consecutive VMAT plans were analyzed retrospectively for treatment sites of the prostate, head and neck (HN), and other parts. The mean values of the metrics for proximal MLC and distal MLC were 0.310 and 0.245 (MCS), 71.09 cm 2 and 55.92 cm 2 (PA), 6.24 and 10.19 (PI), and 0.593 and 0.645 (PM), respectively. The degree of plan complexity in the distal MLC was larger than in the proximal MLC. The percentage of the effective distal MLC was higher than that of the proximal MLC (mean EDS = 0.555). The MCS w , PA w , PI w , and PM w showed significant differences between the prostate and HN groups like the PA 5 , PI 5 , and PM 5 ; however, the MCS 5 did not. Additionally, the MCS 5 correlated with MU and PM 5 , while the MCS w correlated with SAS and PA 5 . The plan complexity for each MLC layer and subsequently combining these complexities might be useful to better understand the dual-layer MLC performance.

Quantitative flow ratio (QFR) is an image-based fractional flow reserve (FFR) computed by three-dimensional quantitative coronary angiography and estimated flow velocity. Several studies have reported that QFR was rapidly computed within approximately 5 min and had a good diagnostic performance as compared with FFR. However, studies comparing QFR with instantaneous wave-free ratio (iFR) as an index with a prognostic value comparable to that of FFR are limited. Thus, we investigated the applicability of QFR with respect to iFR, both being easy-to-measure indices not requiring pharmacological hyperaemic induction. We computed QFR in prospectively enrolled 150 coronary lesions (including 50 lesions for onsite QFR analysis) in consecutive patients with intermediate stenosis evaluated by iFR. The correlation and diagnostic performance of QFR were compared using iFR as a reference. The mean QFR and iFR were 0.81 ± 0.12 and 0.89 ± 0.11, respectively. QFR and iFR exhibited a good correlation in all subjects (R = 0.70, p < 0.0001) and the onsite-analysed vessels (R = 0.74, p < 0.0001). In the receiver-operating characteristics analysis, the area under the curve of QFR predicting iFR ≤ 0.89 was 0.91. Applying the cut-off value of QFR ≤ 0.80 and iFR ≤ 0.89, the sensitivity, specificity, positive and negative predictive values were 85%, 83%, 72%, and 91%, respectively, in all subjects, and 82%, 82%, 78%, and 85%, respectively, in the onsite-analysed vessels. QFR including onsite analysis demonstrated a good correlation with iFR and a diagnostic performance comparable to that of iFR in consecutive patients with intermediate coronary stenosis, suggesting its potential as a rapidly derived index for evaluating myocardial ischaemia in clinical settings.

Background: This study aimed to investigate factors related to improvement of hemodynamics and evaluated the usefulness of intraoperative Doppler for predicting postoperative hemodynamics in patients with cerebrovascular atherosclerotic steno-occlusive disease (CASD) of the internal carotid artery (ICA) or middle cerebral artery (MCA) who were treated with extracranial-intracranial (EC-IC) bypass surgery., Method: Forty-eight patients with CASD of the ICA or MCA who were treated by superficial temporal artery to middle cerebral artery bypass with a follow-up longer than 12 months were enrolled. Repeated transient ischemic attack or completed ischemic stroke was observed under optimal medical therapy in all patients. Intraoperative blood flow velocity of the MCA was evaluated by a Doppler flowmeter. Cerebral blood flow and cerebrovascular reserve (CVR) were evaluated using N-isopropyl-[ 123 I] p-iodoamphetamine (IMP) single photon emission computed tomography (SPECT) preoperatively and 3 months after surgery. Imaging and clinical data were retrospectively reviewed., Results: CVR was significantly increased postoperatively (p = 0.03). One year after the operation, two (4.2%) patients developed cerebral infarction. The change in MCA flow velocity just after anastomosis compared with pre-anastomosis proximal and distal of the anastomosis site was a median of 3.0 and 2.6 times, respectively. However, there was no significant association between changes in intraoperative MCA flow velocity and postoperative CVR. Multivariate analysis showed that the presence of a lower estimated glomerular filtration rate (eGFR) was an independent risk factor for a decrease in CVR (p = 0.036)., Conclusions: A higher eGFR might have prognostic value for improvement in CVR after EC-IC bypass surgery in patients with CASD and misery perfusion.

Although near infrared (NIR) spectra are primarily influenced by undesired variations, i.e., baseline shifts and non-linearity, and many applications of NIR spectroscopy to the real-time monitoring of wet granulation processes have been reported, the granulation mechanisms behind these variations have not been fully discussed. These variations of NIR spectra can be canceled out using appropriate pre-processing techniques prior to spectral analysis. The present study assessed the feasibility of directly using baseline shifts in NIR spectra to monitor granulation processes, because such shifts can reflect changes in the physical properties of the granular material, including particle size, shape, density, and refractive index. Specifically, OPUSGRAN ® , a novel granulation technology, was investigated by in-line NIR monitoring. NIR spectra were collected using a NIR diffuse reflectance fiber optic probe immersed in a high-shear granulator while simultaneously examining the morphology, particle size, density, strength, and Raman images of the mixture during granulation. The NIR baseline shift pattern was found to be characteristic of the OPUSGRAN ® technology and was attributed to variations in the light transmittance, reflection, and scattering resulting from changes in the physicochemical properties of the samples during granulation. The baseline shift also exhibited an inflection point around the completion of granulation, and therefore may be used to determine the endpoint of the process. These results suggest that a specific pattern of NIR baseline shifts are associated with the unique OPUSGRAN ® granulation mechanism and can be applied to monitor the manufacturing process and determine the endpoint.

Some studies have suggested that radial access (RA) for percutaneous coronary intervention (PCI) reduces vascular complications and bleeding compared to femoral access (FA). The purpose of this study was to investigate the routine use of hemostatic devices and bleeding complications among RA, brachial access (BA), and FA. Between January 2015 and December 2015, 298 patients treated for PCI with RA were compared with 158 patients using BA and 206 patients using FA. The radial sheath was routinely removed with ADAPTY, the brachial sheath with BLEED SAFE, and the femoral sheath with Perclose ProGlide. In-hospital bleeding complications were investigated. Cardiogenic shock was most frequent in patients in the femoral group (RA 1.3%, BA 2.5%, FA 9.2%, p < 0.0001). The rate of major bleeding was highest in the femoral group (RA 1.0%, BA 2.5%, FA 5.3%, p = 0.01). Blood transfusion rates were highest in the femoral group (RA 0.7%, BA 1.3%, FA 4.4%, p = 0.01). Retroperitoneal bleeding was observed in 1.9% of patients in the femoral group. Patients in the brachial group had large hematomas (RA 0.7%, BA 4.4%, FA 1.5%, p = 0.01). Pseudoaneurysm formation needing intervention occurred most frequently in the brachial group (RA 0%, BA 1.3%, FA 0%, p = 0.04). In conclusion, compared to the brachial and femoral approaches, the radial approach appears to be the safest technique to avoid local vascular bleeding complications. The brachial approach has the highest risk of large hematoma and pseudoaneurysm formation among the three groups.

Here, we report on near-infrared and ATR/FT-IR spectroscopic measurements of magnesium stearate and potato starch powder blends. In the pharmaceutical and food industries, magnesium stearate is commonly used as a supplement in powder blends or granules for the purpose of lubrication and to minimize aggregation and adherence. However, excessive blending of magnesium stearate (MgSt) may lead to unwanted effects, and more particularly during the manufacturing of products. Upon blending, the IR bands due to both CH symmetric and anti-symmetric stretching modes decreased and displayed a frequency shift to higher wavenumber as the blending duration increased. The NIR and the auto-correlation spectra were collected during the duration of blending in real-time. The auto-correlation spectra indicated the disaggregation of starch particles and a following effect of excessive blending. We suggest that the disaggregation of starch and the following process can be monitored by NIR and the auto-correlation spectra.

Resonant acoustic ® mixing (RAM) technology is a system that performs high-speed mixing by vibration through the control of acceleration and frequency. In recent years, real-time process monitoring and prediction has become of increasing interest, and process analytical technology (PAT) systems will be increasingly introduced into actual manufacturing processes. This study examined the application of PAT with the combination of RAM, near-infrared spectroscopy, and chemometric technology as a set of PAT tools for introduction into actual pharmaceutical powder blending processes. Content uniformity was based on a robust partial least squares regression (PLSR) model constructed to manage the RAM configuration parameters and the changing concentration of the components. As a result, real-time monitoring may be possible and could be successfully demonstrated for in-line real-time prediction of active pharmaceutical ingredients and other additives using chemometric technology. This system is expected to be applicable to the RAM method for the risk management of quality.

Purpose: Liver transplantation is currently the only curative therapeutic option for end-stage liver cirrhosis. However, due to the limitations of donor liver availability and occasional rejection, it cannot always be successfully applied. In this study, we determined whether fibroblasts can be transdifferentiated into hepatocyte-like cells by transcription factors that initiate and maintain hepatocyte differentiation., Methods: Fibroblasts were transduced with retrovirus vectors carrying FOXA2, HNF4α, and C/EBPβ. To enhance the efficiency of transdifferentiation, cMyc was also expressed., Results: Transdifferentiation was successful using both neonatal fibroblasts and human forehead fibroblasts. The transdifferentiated cells produced hepatocyte-specific proteins such as albumin and cytochrome, and had important hepatocyte-specific functions, such as glycogen storage and indocyanine green uptake, suggesting that the cells function at least as partial hepatocytes., Conclusions: These results provide a novel method of generating differentiated hepatocyte-like cells, and may represent an alternative source of cells for future cell-based therapeutics for end-stage liver diseases.

Near-infrared spectroscopy (NIR) was applied to the quantitative analysis of the concentration of alpha-mangostin (aM) in mangosteen pericarp powder (MP). The predicted results from the partial least squares chemometric method of various pretreatment data were compared to obtain the best calibration model. Two different types of containers (transparent capsules and glass vials) filled with the same samples were measured. For MP mixture in vials, the calibration model involving nine principal components (PC) could predict the amount of aM most accurately based on non-pretreatment spectral data. For MP mixture in capsules, the calibration model involving nine PC could predict the amount of aM most accurately based on first-derivative pretreatment spectra. The relationships of the calibration models for both samples had sufficiently linear plots. The standard error of cross-validation for the MP mixture in vials was lower and the R(2) values of validation were higher compared to the MP mixture in capsules. The equation for prediction of the concentration of aM in MP mixtures in vials is y = 0.9775x + 0.0425 with R(2) = 0.9950 and for those in capsules is y = 1.0264x + 0.0126 with R(2) = 0.9898. Both validation results indicated that the concentrations of aM in MP mixtures were predicted with sufficient accuracy and repeatability. NIR can be a useful tool for the quality control of herbal medicine in powder form without any sample preparation. The type and the shape of the container should be considered to obtain more accurate data.

In this paper, hybrid inorganic-organic core-shell hollow microspheres, made of poly(L-lactic acid) (PLLA) and biomimetic nano apatites (HA), were prepared from biodegradable and biocompatible substances, suitable for bone tissue applications. Preparation is started from Pickering emulsification, i.e., solid particle-stabilized emulsions in the absence of any molecular surfactant, where solid particles adsorbed to an oil-water interface. Stable oil-in-water emulsions were produced using biomimetic 20 nm sized HA nanocrystals as particulate emulsifier and a dichloromethane (CH(2)Cl(2)) solution of PLLA as oil phase. Hybrid hollow PLLA microspheres at three different HA nanocrystals surface coverage, ranging from 10 to 50 μm, were produced. The resulting materials were completely characterized with spectroscopic, calorimetric and microscopic techniques and the cytocompatibility was established by indirect contact tests with both fibroblasts and osteoblasts and direct contact with these latter. They displayed a high level of cytocompatibility and thus represent promising materials for drug delivery systems, cell carriers and scaffolds for regeneration of bone useful in the treatment of orthopaedic, maxillofacial and dental fields.

Highly soluble amorphous calcium phosphate powder (ACP) was added to the alginate gel as a buffering agent, in an attempt to enable widely controlled release while avoiding an acidification of the gel-environment. Therapeutic effects of the ACP-containing alginate gel which slowly releases a drug, simvastatin, on osteoporosis model rats were examined. A model drug, simvastatin, incorporated in the alginate gel with ACP up to 0.5%, was continuously released for a long time under the acidic condition. The release rate was controlled by the amount of ACP, serving as a buffer to suppress acidity. When the alginate solution intramuscularly injected in the rat, a soft gel was formed in the injected site. Simvastatin released from the gel containing 0.5% of ACP showed high therapeutic effect on osteoporosis rat. Thus, the present injectable long-sustained release system is expected to be a novel drug delivery controlling device.

Near-infrared (NIR) spectroscopy combined with chemometrics has been utilized in predictions of natural medicine content without destroying samples. Suppositories (oren powdered extract content 0, 0.5, 1.0, 2.5, 10, 12.5, and 15%) were produced by mixing oren powdered extract with macrogol mixture consisting of 1 part macrogol 1500 and 2.5 parts macrogol 4000 at 54°C, and pouring the melt mixture into a plastic container. NIR spectra of the 10 prepared samples were recorded 10 times, and a total of 100 spectra were randomly divided into two data sets, one for calibration and the other for validation. The calibration model for the oren content of the suppository was calculated based on NIR spectra using a partial least-squares regression analysis after pre-treatment (smoothing and the multiplicative scatter correction). The relationship between the actual and predicted values for calibration and validation models had a straight line with correlation coefficients of 0.9936 and 0.9898, respectively. The regression vector result of the calibration model indicates that the peaks at 6945, 5747, and 5160 cm(-1) in the regression vector were consistent with those in oren powder extracts. NIR spectroscopy combined with chemometrics offers promise as a method of predicting the oren powder content in suppositories without destroying the samples.

Purpose: Development of improved protocols for differentiating induced pluripotent stem (iPS) cells into hepatic cells is an important step toward their use in the field of hepatology. Specifically, the number of different cytokines should be reduced to limit undesired effects and to reduce the cost of the process. In this report, we describe a simple method for directing human iPS cells to differentiate into hepatic cells using only two cytokines and a short incubation time., Methods: A two-step protocol for differentiating iPS cells into hepatic cells was developed. A high dose of activin A was applied for 3 days to induce definitive endoderm formation. Subsequently, cells were treated with hepatocyte growth factor (HGF) for 5 days to generate hepatic cells. Differentiation was confirmed by immunostaining for differentiation markers. Albumin mRNA levels in differentiated hepatic cells generated using a previously tested three-step protocol that uses activin A, fibroblast growth factor (FGF)/bone morphogenetic protein (BMP), and HGF, and our new protocol were compared to determine the efficiency of differentiation., Results: Our two-step protocol induced the differentiation of iPS cells into hepatic cells and required a shorter differentiation period than the previous three-step protocol. The differentiation efficiencies of the two protocols were comparable and the induced hepatic cells were functional., Conclusions: Developing efficient induction and culture methods to generate more highly matured hepatocytes is essential for regenerative cell-based therapies. Our protocol provides a simple, cost-effective, and time-saving approach for generating hepatic cells from iPS cells.

A 46-year-old woman presented herself at the hospital with progressive effort dyspnea and lower limbs edema which she had had for 3 months. She had a history of surgical ligation of patent ductus arteriosus (PDA) at the age of 25-year-old. A transthoracic cardiac ultrasonography showed left ventricular dilatation, severe functional mitral regurgitation, and a recurrent shunt of PDA. Percutaneous coil closure of PDA was performed and 6 months after the procedure, resolution of functional mitral regurgitation and normalization of left atrial and ventricular sizes were achieved.

Alpha-tricalcium phosphate (alpha-TCP) ceramic is a bioresorbable material that degrades in bone tissue after implantation, since it exhibits higher solubility than beta-tricalcium phosphate (beta-TCP) ceramics. The high solubility of alpha-TCP in an aqueous solution causes its transformation into hydroxyapatite (HAp) through hydrolysis. While one expects the formation of hydroxyapatite after exposure to an aqueous solution mimicking a body environment, we occasionally find variation in HAp formation in the simulated body fluid (SBF). In the present study, HAp formation resulting from exposure to SBF was investigated for some types of alpha-TCP ceramics with different porosities and specific surface area. Reduced porosity and large surface area of porous specimens may increase the local density of Ca2+ in the surrounding SBF to increase the degree of supersaturation with respect to HAp. Thus, the porosity and specific surface area are significant parameters for determining not only bioabsorbability but also the ability to form HAp.

The purpose of this study was to establish a calibration model to predict the hydrate content in powder materials consisting of anhydrate (theophylline anhydrate (THA)) and theophylline monohydrate (THM) by using various kinds of X-ray powder diffraction (XRPD) analytical methods. XRPD profiles were measured five times each for 11 standard samples containing of THA and THM. THM content in the standard samples was evaluated based on XRPD profiles by the diffraction peak height and area methods, and the Wakelin's and principal component regression (PCR) methods, respectively. Since THA and THM were cube- and rod-shaped particles, the standard samples consisted of THA and THM showed crystal orientation due to THM crystal shape. THA showed reproducible XRPD profiles, but THM showed fluctuating intensities in some specific peaks in the profiles. The linear calibration models were evaluated based on calibration XRPD datasets of the standard materials by various methods. In the result based on validation XRPD datasets, the order of the mean bias and the mean accuracy were peak height > peak area > Wakelin's > PCR, indicating that PCR was the best method to correct sample crystal orientation. The effectiveness of the PCR method in construction of calibration models was discussed by a scientific approach based on regression vectors.

"Hierba santa," a Peruvian herbal medicine, is used to alleviate many symptoms, including headache, hemorrhoids, fever, and rheumatism. Several Cestrum species are said to be the origin of hierba santa. Three lots of hierba santa: Cestrum auriculatum (herb 1 and herb 2) and C. hediundinum (herb 3), which were purchased from Peruvian markets at Cuzco (Andes area) and Equitos (Amazon area), respectively, were examined for their pharmacological activities and active components. Herbs 1-3 showed anti-inflammatory and analgesic activities in the in vivo writhing inhibition test in mouse and inhibited prostaglandin E(1)-, E(2)-, or ACh-induced contractions of guinea pig ileum in the Magnus method. Activity-based separation of each extract yielded cestrumines A and B, cestrusides A and B, a mixture of (+)- and (-)-pinoresinol glucosides, nicotiflorin, rutin, sinapoyl glucose, ursolic acid, beta-sitosteryl glucoside, and 2-sec-butyl-4,6-dihydroxyphenyl-beta-D: -glucopyranoside. Among them, cestrumine A and cestrusides A and B are new compounds. All three lots of hierba santa do not contain exactly the same active components.

Data from X-ray powder diffraction (XRD) were subjected to a partial least-squares regression analysis (PLS) to build a calibration model for predicting the polymorphic content of carbamazepine (CBZ). The effectiveness of the PLS method in the construction of calibration models was analyzed by a scientific approach based on a regulation vector. CBZ forms I and III were characterized by differential scanning calorimetry (DSC) and XRD. Powder mixtures of forms I and III at various ratios (0-100% w/w; form III) were subjected to XRD. Five diffraction peaks were used for the peak-area method to compare with PLS. The results obtained by PLS had a better predictive accuracy compared to those of the peak-area method. The XRD-PLS method was established as a non-destructive, non-contact way to avoid the particle orientation effect based on statistical theory.

Objectives: Multislice computed tomography (MSCT) has been currently utilized as a non-invasive diagnostic modality to detect coronary artery disease. We sought to investigate whether preprocedural lesion assessment by MSCT could offer strategic guidance in the setting of elective complex percutaneous coronary intervention (PCI)., Methods and Results: Twenty-six complex coronary artery lesions in 23 patients were evaluated using 16-row MSCT scanner and an off-line image analysis workstation prior to the PCI. Procedural strategies of PCI were planned based on the morphologic and geometric analysis of the target lesion and vessel. MSCT provided valuable strategic information, which was useful for subsequent PCI procedure. The three-dimensional computed tomography (CT) images allowed us to determine optimal working view angle that best demonstrated the target lesion with least foreshortening. Furthermore, the thin-slab maximum intensity projected CT images of the target lesion served as a preprocedural road map depicting the bends of complex luminal path, vessel geometry and occluded segment of the vessel. As results, procedural success was achieved in all cases with complex lesions including chronic total occlusion., Conclusions: Our preliminary results showed that preprocedural lesion and vessel assessment by MSCT provided important additive strategic information that led to successful complex PCI procedures.

In order to clarify the theoretical basis of the variability in the measurement of tablet hardness by compression pressure, NIR spectroscopic methods were used to predict tablet hardness of the formulations. Tablets (200 mg, 8 mm in diameter) consisting of berberine chloride, lactose, and potato starch were formed at various compression pressures (59, 78, 98, 127, 195 MPa). The hardness and the distribution of micropores were measured. The reflectance NIR spectra of various compressed tablets were used as a calibration set to establish a calibration model to predict tablet hardness by principal component regression (PCR) analysis. The distribution of micropores was shifted to a smaller pore size with increasing compression pressure. The total pore volume of tablets decreased as the compression pressure increased. The hardness increased as the compression pressure increased. The hardness could be predicted using a calibration model consisting of 7 principal components (PCs) obtained by PCR. The relationship between the predicted and the actual hardness values exhibited a straight line, an R(2) of 0.925. In order to understand the theoretical analysis (scientific background) of calibration models used to evaluate tablet hardness, the standard error of cross validation (SEV) values, the loading vectors of each PC and the regression vector were investigated. The result obtained with the calibration models for hardness suggested that the regression vector might involve physical and chemical factors. In contrast, the porosity could be predicted using a calibration model composed of 2 PCs. The relationship between the predicted and the actual total pore volume showed a straight line with R(2) = 0.801. The regression vector of the total pore volume might be due to physical factors.

Innate immunity is part of the antiviral response. Interferon (IFN)-beta plays a leading role in this system. To investigate the influence of hepatitis C virus (HCV) on innate immunity, we examined the effect of viral proteins on IFN-beta induction. HepG2 cells were co-transfected with plasmids for seven HCV proteins (core protein, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) and the IFN-beta promoter luciferase. Toll-like receptor (TLR) 3 and Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF) play key roles in dsRNA-mediated activation of interferon regulatory factor (IRF)-3 and IFN-beta; therefore, the participation of TLR3/TRIF in NS5B-mediated IFN induction was examined. Among seven HCV proteins, only NS5B, a viral RNA-dependent RNA polymerase (RdRp), activated the IFN-beta promoter. However, mutant NS5B without RdRp activity or template/primer association did not activate the IFN-beta promoter. Activation of the IFN-beta promoter by NS5B required the positive regulatory domain III, a binding sequence for IRF-3. Moreover, IRF-3 was phosphorylated by NS5B. Both inhibition of TLR3 expression by small interfering RNA and expression of the dominant negative form of TRIF significantly reduced NS5B-induced activation of IFN-beta. Of the six other HCV proteins, NS4A, NS4B, and NS5A efficiently inhibited this activation. HCV NS5B is a potent activator of the host innate immune system, possibly through TLR3/TRIF and synthesis of dsRNA. Meanwhile, NS4A, NS4B, and NS5A block IFN-beta induction by NS5B, which may contribute toward the persistence of this virus.

The effects of compression and pulverization on the dehydration kinetics and hardness of creatine monohydrate tablets were studied using a variety of kinetic equations and physical models. The dehydration behavior of unpulverized and pulverized tablets was investigated by using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The hardness of both unpulverized and pulverized monohydrate tablets was significantly decreased after dehydration. The relationship between the degree of dehydration and the tablet hardness of both unpulverized and pulverized monohydrate tablets formed a straight line. The results suggest that the reduction in tablet hardness is dependent on the dehydration of crystal water, and the values of the slopes indicate that the bonding energy of the unpulverized sample was stronger than that of the pulverized sample. The dehydration kinetics of the unpulverized and pulverized monohydrate tablets were evaluated by analyzing the fit of the isothermal DSC data using a variety of solid-state kinetic models. The dehydration of the unpulverized tablets at various levels of compression pressure followed the 3-dimensional growth of nuclei mechanism. In contrast, although the dehydration kinetics of pulverized monohydrate tablets compressed at 500 and 750 kg/cm2 followed the 3-dimensional diffusion mechanism, those compressed at 1000 kg/cm2 followed the 3-dimensional growth of nuclei mechanism. The PXRD analysis indicated that the diffraction intensity of the pulverized monohydrate powder was significantly lower than that of the unpulverized powder. The diffraction peaks of the (h00) planes and the micropore structure of the unpulverized monohydrate tablets were affected by pulverization and compression force, respectively.

Nuclear Factor-kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, and is sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB can exist in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of stimuli including viral products, and oxidative stress, leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (KB sites in the DNA) to initiate transcription. These kappaB sites are also present in the Long Terminal Repeat (LTR) of HIV-1, and hence NF-kappaB (p50 subunit) binding to LTR-DNA is critical in viral replication. Targeting direct p50-DNA binding, in this regard, is a novel approach to design anti-HIV gene expression inhibitors, which do not have the problem of resistance unlike in other anti-HIV strategies. The present study is a part of our search for leads for the specific inhibition of p50-DNA binding. We have been experimentally studying different types of these inhibitors, and in this work, we attempted to get a common definition of their structural mechanism onto p50-DNA binding. Using three different classes of inhibitors, we modelled their association with the DNA-Binding Region (DBR) of the p50 subunit of NF-kappaB. Docking studies were carried out using a genetic algorithm based program (GOLD). Further, to compare electrostatic complementarity in the association of the inhibitors with the DBR, Molecular Electrostatic Potentials (MEPs) were generated for the DBR and each inhibitor. The results of docking revealed a strong network of hydrogen bonding interactions for every active inhibitor, and the contrary for the less active ones. Further, the MEPs revealed that the DBR of p50 represents a surface of electropositive potential, and the active inhibitors represent a complementary electronegative surface. With the present modelling study we conclude that the principal properties to be possessed by the new leads against p50-DNA binding should be that of having the ability to make a strong network of hydrogen bonds with the DBR of p50, and preferably, having electronegative potentials in their peripheral surface.

The structure of 7,8-dihydroxy-4-methylcoumarin was determined by an X-ray diffraction method. The compound crystallized in the triclinic space group P1, Z = 2, with a = 7.631(2), b = 9.456(5), c = 7.075(3)A, alpha = 103.13(3), beta = 91.84(3), gamma= 68.21(3) degrees, and V= 460.9(3)A3. The X-ray crystal structure was also compared with those of 5,7-dihydroxy-4-methylcoumarin and 7-hydroxy-4-methylcoumarin.

The purpose of this research was to apply near-infrared (NIR) spectroscopy with chemometrics to predict the change of pharmaceutical properties of antipyrine granules during granulation by regulation of the amount of water added. The various kinds of granules (mean particle size, 70-750 microm) were obtained from the powder mixture (1 g of antipyrine, 6 g of hydroxypropylcellulose, 140 g of lactose, and 60 g of potato starch) by regulation of the added water amount (11-19 wt/wt%) in a high-speed mixer. The granules were characterized by mean particle size, angle of repose, compressibility, tablet porosity, and tablet hardness as parameters of pharmaceutical properties. To predict the pharmaceutical properties, NIR spectra of the granules were measured and analyzed by principal component regression (PCR) analysis. The mean particle size of the granules increased from 81 micro m to 650 micro m with an increase in the amount of water, and it was possible to make larger spherical granules with narrow particle size distribution using a high-speed mixer. Angle of repose, compressibility, and porosity of the tablets decreased with an increase of added water, but tablet hardness increased. The independent calibration models to evaluate particle size, angle of repose, and tablet porosity and hardness were established by using PCR based on NIR spectra of granules, respectively. The correlation coefficient constants of calibration curves for prediction of mean particle size, angle of repose, tablet porosity, and tablet hardness were 0.9109, 0.8912, 0.7437, and 0.8064, respectively. It is possible that the pharmaceutical properties of the granule, such as mean particle size, angle of repose, tablet porosity, and tablet hardness, could be predicted by an NIR-chemometric method.

The purpose of this research was to improve the stability of carbamazepine (CBZ) bulk powder under high humidity by surface modification. The surface-modified anhydrates of CBZ were obtained in a specially designed surface modification apparatus at 60 degrees C via the adsorption of n-butanol, and powder x-ray diffraction, Fourier-Transformed Infrared spectra, and differential scanning calorimetry were used to determine the crystalline characteristics of the samples. The hydration process of intact and surface-modified CBZ anhydrate at 97% relative humidity (RH) and 40 +/-C 1 degrees C was automatically monitored by using isothermal microcalorimetry (IMC). The dissolution test for surface-modified samples (20 mg) was performed in 900 mL of distilled water at 37 +/-C 0.5 degrees C with stirring by a paddle at 100 rpm as in the Japanese Pharmacopoeia XIII. The heat flow profiles of hydration of intact and surface-modified CBZ anhydrates at 97% RH by using IMC profiles showed a maximum peak at around 10 hours and 45 hours after 0 and 10 hours of induction, respectively. The result indicated that hydration of CBZ anhydrate was completely inhibited at the initial stage by surface modification of n-butanol and thereafter transformed into dihydrate. The hydration of surface-modified samples followed a 2-dimensional phase boundary process with an induction period (IP). The IP of intact and surface-modified samples decreased with increase of the reaction temperature, and the hydration rate constant (k) increased with increase of the temperature. The crystal growth rate constants of nuclei of the intact sample were significantly larger than the surface-modified sample's at each temperature. The activation energy (E) of nuclei formation and crystal growth process for hydration of surface-modified CBZ anhydrate were evaluated to be 20.1 and 32.5 kJ/mol, respectively, from Arrhenius plots, but the Es of intact anhydrate were 56.3 and 26.8 kJ/mol, respectively. The dissolution profiles showed that the surface-modified sample dissolved faster than the intact sample at the initial stage. The dissolution kinetics were analyzed based on the Hixon-Crowell equation, and the dissolution rate constants for intact and surface-modified anhydrates were found to be 0.0102 +/-C 0.008 mg(1/3) x min(-1) and 0.1442 +/-C 0.0482 mg(1/3) x min(-1). The surface-modified anhydrate powders were more stable than the nonmodified samples under high humidity and showed resistance against moisture. However, surface modification induced rapid dissolution in water compared to the control.

The purpose of this research was to develop a rapid chemometrical method based on near-infrared (NIR) spectroscopy to determine indomethacin (IMC) polymorphic content in mixed pharmaceutical powder and tablets. Mixed powder samples with known polymorphic contents of forms alpha and gamma were obtained from physical mixing of 50% of IMC standard polymorphic sample and 50% of excipient mixed powder sample consisting of lactose, corn starch, and hydroxypropylcellulose. The tablets were obtained by compressing the mixed powder at 245 MPa. X-ray powder diffraction profiles and NIR spectra were recorded for 6 kinds of standard materials with various polymorphic contents. The principal component regression analysis was performed based on normalized NIR spectra sets of mixed powder standard samples and tablets. The relationships between the actual and predicted polymorphic contents of form g in the mixed powder measured using x-ray powder diffraction and NIR spectroscopy show a straight line with a slope of 0.960 and 0.995, and correlation coefficient constants of 0.970 and 0.993, respectively. The predicted content values of unknown samples by x-ray powder diffraction and NIR spectroscopy were reproducible and in close agreement, but those by NIR spectroscopy had smaller SDs than those by x-ray powder diffraction. The results suggest that NIR spectroscopy provides a more accurate quantitative analysis of polymorphic content in pharmaceutical mixed powder and tablets than does conventional x-ray powder diffractometry.

The effect of humidity on the physicochemical properties of amorphous forms of cimetidine was investigated using differential scanning calorimetry, isothermal microcalorimetry, and x-ray diffraction analysis. Amorphous forms were obtained by the melting (amorphous form M [AM]) and the cotton candy (amorphous form C [AC]) methods. Thermal behaviors of AM and AC with or without seed crystals were measured using an isothermal microcalorimeter under various conditions of relative humidity (RH) and temperature, respectively. The crystallization kinetics of amorphous solids was analyzed based on 10 kinds of solid-state reaction models. AM transformed into form A at 11% RH, 50 degrees C but transformed into a mixture of form A and monohydrate at 51% and 75% RH at 25 degrees C. The mean crystallization times (MCTs) of the heat flow curve of AM and AC at 11% RH, 50 degrees C were 47.82 and 32.00 hours, respectively, but at 11% RH, 25 degrees C both were more than 4320 hours. In contrast, AC transformed into form A under all storage conditions. The MCTs of AC at 51% and 75% RH were 29.61 and 11.81 hours, respectively; whereas the MCTs of AM were 46.79 and 15.52 hours, respectively. The crystallization of amorphous solids followed the three-dimensional growth of nuclei (Avrami equation) with an induction period (IP). The IP for AM at 11% RH, 50 degrees C was more than 2 times that for AC, but the difference in the crystal growth rate constant (CR) between AC and AM was within 10%. The IP for AM at 75% RH, 25 degrees C was reduced to only 10% of the IP at 51% RH with increasing humidity, but the CR did not change significantly. In contrast, the IP for AC was slightly reduced at 75% RH compared with 51% RH, but the CR was about 5 times greater. At 75% RH, 25 degrees C, the IP and CR of AM were about one-fourth the values of AC. This result suggests that the crystallization process consists of an initial stage during which the nuclei are formed and a final stage of growth.

The effect of the amount of a water-soluble, lactose, on cephalexin (CEX) release from bioactive bone cement consisting of bisphenol-alpha-glycidyl methacrylate (bis-GMA), triethylene-glycol dimethacrylate (TEGDMA) resin and apatite- and wollastonite-containing glass-ceramic (A-W GC) powder was investigated. A-W GC powder containing 5% CEX and lactose powders hardened within 5 min after mixing with bis-GMA/TEGDMA resin, and furthermore its compressive strength was expected to be higher than that of polymethylmethacrylate cement. In vitro CEX release from bioactive bone cement pellets in a simulated body fluid at pH 7.25 and 37 degrees C continued for more than 2 wk. The drug-release rate increased with increasing amount of lactose powder in the mixture. CEX release profiles followed the Higuchi equation in the initial stage, but not in later stages. As hydroxyapatite was precipitated out on the cement surface, the CEX release rate decreased. The micropore distribution of the cements measured by mercury porosimetry also supported the variation in drug release due to cement porosity being mainly a result of the dissolution of lactose in the cements. These results suggest that the rate of CEX release from bioactive bone cement could be controlled by varying the amount of lactose in the cement system., (Copyright 1999 Kluwer Academic Publishers)

1. To study physiological roles of substance P (SP), gamma-aminobutyric acid (GABA), enkephalins and other endogenous substances, we developed several kinds of isolated spinal cord preparations of newborn rats. 2. In these preparations, various slow responses of spinal neurons evoked by stimulation of primary afferent C fibers were depressed by a tachykinin antagonist, spantide. These results together with many other lines of evidence suggest that SP and neurokinin A serve as pain transmitters in a subpopulation of primary afferent C fibers. 3. Some C-fiber responses in various isolated spinal cord preparations were depressed by GABA, muscimol, and opioid peptides. In contrast, bicuculline (GABA antagonist) and naloxone (opioid antagonist) potentiated the "tail pinch potential," i.e., a nociceptive response of the ventral root evoked by pinch stimulation of the tail in isolated spinal cord-tail preparation of the newborn rat. The latter results support the hypothesis that some primary afferents activate inhibitory spinal interneurons which release GABA and enkephalins as transmitters to modulate pain inputs.