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The purpose of this report was to develop biodegradable balloon-expandable self-locking poly(ε-caprolactone) (PCL) stents for the treatment of retinal detachment. To create the biodegradable stents, polycaprolactone components were first fabricated by a laboratory-scale microinjection molding machine. The components were then assembled into mesh-like stents of 6 and 8 mm in diameter. A special geometry of the components was designed to self-lock the assembled stents after being expanded by balloons. Characterization of the biodegradable PCL stents was carried out. PCL stents exhibited comparable mechanical properties with that of silicone sponge. Neither significant amount of collapse pressure reduction nor weight loss of the stents was observed after being submerged in phosphate buffered saline for 30 days. In addition, the stents were also implanted in the episcleral space of 10 New Zealand white rabbits. The stents were placed in radial direction and left unsutured after balloon expansion. The stents achieved an efficient buckling effect in echographic and fundus photographic examinations. The ocular pressure was significantly elevated after stent implantation and gradually normalized after the second week. The computed tomography studies verified the hypothesis of minimal migration of the PCL stents. The in vivo result suggests that balloon-expandable biodegradable stents can potentially serve as an ideal indenting biomaterial in retinal detachment surgery., (Copyright © 2012 Wiley Periodicals, Inc.)

BJ-B11 is a selective heat shock protein 90 (Hsp90) inhibitor that has been reported to possess significant antitumor activity in multiple types of cancer cells; however, the mechanism of action needs to be further clarified. We investigated, for the first time, the antitumor activity and the molecular mechanism underlying growth inhibition in Eca-109 cells. The results revealed that BJ-B11 inhibited the proliferation of Eca-109 cells in a time- and concentration-dependent manner, with 50% inhibitory concentration (IC(50)) values of 0.31±0.01 µM after 48-h incubation. BJ-B11 induced concentration-dependent G2/M cell cycle arrest and apoptosis. The cleavage of caspase 3 and PARP signals detected might originate from mitochondrial dysfunction, which was supported by the results of reactive oxygen species (ROS) production, cytochrome c release and the mitochondrial membrane potential (MMP) reduction. The general caspase inhibitor Z-VAD-fmk did not completely abolish BJ-B11-induced cell death. Furthermore, inhibition of the Akt/mTOR/p70S6K signaling pathway might be involved in the process of BJ-B11-induced autophagy, which was characterized by the production of autophagic vacuoles and upregulation of LC3-II protein in a time- and concentration-dependent manner. Meanwhile, the general autophagy inhibitor 3-MA decreased the apoptotic ratio. Furthermore, BJ-B11 induced the polymerization of cytoskeleton β-tubulin and F-actin. Taken together, our results suggest that the growth inhibition of Eca-109 cells induced by BJ-B11 may result from the induction of G2/M cell cycle arrest, apoptosis and autophagy.

Objectives: Withdrawal of opioids is usually associated with intolerable aversive symptoms. Our objective was to evaluate the efficacy of phenothiazine-type antipsychotics for reducing withdrawal symptoms during morphine abstinence., Methods: Adult NRL mice were rendered physically dependent on morphine by escalating the doses of subcutaneous morphine for 3 days. Withdrawal jumping was precipitated by a subcutaneous injection of naloxone (50 mg/kg) on day 4. In study I, on an equimolar basis, we compared the efficacy of six phenothiazine antipsychotics in saline on reducing morphine withdrawal symptoms. One hour before naloxone injection, the mice were assigned to receive intramuscular (i.m.) saline or one of the six phenothiazine-type antipsychotics (0.3 μmol/kg). After naloxone injection, the tested mouse was immediately placed in a transparent acrylic cylinder, and the severity of withdrawal symptoms was assessed, via a computer connected to the floor of the cylinder, by counting the number of the withdrawal jumps over a 30-minute interval. In study II, we performed a dose-response test in these six phenothiazine antipsychotics (0.03, 0.3, and 3 μmol/kg, i.m., for each test drug) on the inhibition of naloxone-precipitated morphine withdrawal jumping., Results: We found that all six phenothiazine-type antipsychotics attenuated the morphine withdrawal jumps, as compared with saline (p < 0.05). The effect is dose-dependent, with the potency ranking order as follows: fluphenazine ＝ triflupromazine > chlorpromazine ＝ perphenazine > promazine ＝ thioridazine (p < 0.05)., Conclusions: All six phenothiazine-type antipsychotics could attenuate morphine withdrawal symptoms; in particular, fluphenazine and triflupromazine may potentially be the more appropriate candidates for the treatment of morphine withdrawal symptoms., (Copyright © 2012. Published by Elsevier B.V.)

Rab3 interacting molecules (RIMs) are evolutionarily conserved scaffolding proteins that are located at presynaptic active zones. In the mammalian nervous system, RIMs have two major activities that contribute to the fidelity of baseline synaptic transmission: they concentrate calcium channels at the active zone and facilitate synaptic vesicle docking/priming. Here we confirm that RIM has an evolutionarily conserved function at the Drosophila neuromuscular junction and then define a novel role for RIM during homeostatic synaptic plasticity. We show that loss of RIM disrupts baseline vesicle release, diminishes presynaptic calcium influx, and diminishes the size of the readily-releasable pool (RRP) of synaptic vesicles, consistent with known activities of RIM. However, loss of RIM also completely blocks the homeostatic enhancement of presynaptic neurotransmitter release that normally occurs after inhibition of postsynaptic glutamate receptors, a process termed synaptic homeostasis. It is established that synaptic homeostasis requires enhanced presynaptic calcium influx as a mechanism to potentiate vesicle release. However, despite a defect in baseline calcium influx in rim mutants, the homeostatic modulation of calcium influx proceeds normally. Synaptic homeostasis is also correlated with an increase in the size of the RRP of synaptic vesicles, although the mechanism remains unknown. Here we demonstrate that the homeostatic modulation of the RRP is blocked in the rim mutant background. Therefore, RIM-dependent modulation of the RRP is a required step during homeostatic plasticity. By extension, homeostatic plasticity appears to require two genetically separable processes, the enhancement of presynaptic calcium influx and a RIM-dependent modulation of the RRP.

Objective: Our aim was to investigate the effects of Spirulina on BV-2 microglial cell cytotoxicity and inflammatory genes expression., Methods: BV-2 microglial cells were treated with lipopolysaccharide (LPS) (1 µg/ml) and various concentrations of Spirulina platensis water extract or its active component (C-phycocyanin (C-PC)) for 24 hours. Cytotoxicity (lactate dehydrogenase (LDH) release) and expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNAs were assayed., Results: LPS increased LDH production and up-regulated expression of iNOS, COX-2, TNF-α, and IL-6 by BV-2 microglial cells. However, Spirulina platensis water extract and C-PC significantly reduced LPS-induced LDH release, and expression of iNOS, COX-2, TNF-α, and IL-6 mRNAs., Conclusion: Spirulina can reduce the cytotoxicity and inhibit expression of inflammation-related genes of LPS-stimulated BV-2 microglial cells.

Objective: Genetic variation of cadheri23 (cdh23; 753G>A in exon 7) has been implicated with age-related hearing impairment (ARHI) in mice. This study aimed to test the association of the CDH23 tag single nucleotide polymorphism (SNP) in intron 7 with ARHI in Han Chinese., Study Design: Individual cohort study., Setting: Tertiary medical center., Subjects and Methods: A total of 1175 Han Chinese subjects were divided into the case group (n = 310, 26% with poorest hearing) and the control group (n = 308, the 26% with best hearing) according to the Z(high) score converted from the original frequency-specific hearing thresholds. The CDH23 SNP locus (rs7087735: C/T) in intron 7 (coordinate: 72996763) shown in the HapMap was genotyped with correlation to the hearing phenotype., Results: The genotype distributions of CDH23 (CC/CT/TT) were not significantly different between the case and control group (P = .489). Compared with genotype CC, the odds ratios of the genotypes CT and TT for ARHI were not significantly different after adjustment for other environmental factors (P = .299 for CT; P = .610 for TT)., Conclusions: Despite that the Ahl allele of Cdh23 had been implicated with ARHI in mice, we found no positive association of the CDH23 tag SNP in intron 7 with ARHI in Han Chinese.

Objective: To investigate the diagnostic value of histopathological changes in the liver of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)., Methods: Liver specimens from 10 cases of NICCD were evaluated by hematoxylin-eosin stain, histochemistry and immunohistochemistry (EnVision method). SLC25A13 mutation analysis was performed to correlate with histopathology., Results: Most specimens showed varying degrees of fat deposition in hepatocytes, necrotic inflammation, cholestasis and fibrosis (so-called tetralogy). The combination of the above four histological changes was highly characteristic for NICCD. With the progression of the disease, hepatic fibrosis deteriorated and ultimately led to cirrhosis., Conclusions: NICCD should be suspected in the presence of cholestasis during infancy. A liver biopsy must be performed to rule out other liver diseases. The tetralogy of the hepatic histopathological changes has a highly diagnostic value for NICCD, which is also practical for accurately assessing the degree of inflammation and fibrosis, and similarly the progression of hepatic cirrhosis.

Background: Hyperuricemia is frequently present in patients with heart failure. Many pathological conditions, such as tissue ischemia, renal function impairment, cardiac function impairment, metabolic syndrome, and inflammatory status, may impact uric acid (UA) metabolism. This study was to assess their potential relations to UA metabolism in heart failure., Methods: We retrospectively assessed clinical characteristics, echocardiological, renal, metabolic and inflammatory variables selected on the basis of previous evidence of their involvement in cardiovascular diseases and UA metabolism in a large cohort of randomly selected adults with congestive heart failure (n = 553). By clustering of indices, those variables were explored using factor analysis., Results: In factor analysis, serum uric acid (SUA) formed part of a principal cluster of renal functional variables which included serum creatinine (SCr) and blood urea nitrogen (BUN). Univariate correlation coefficients between variables of patients with congestive heart failure showed that the strongest correlations for SUA were with BUN (r = 0.48, P < 0.001) and SCr (r = 0.47, P < 0.001)., Conclusions: There was an inverse relationship between SUA levels and measures of renal function in patients with congestive heart failure. The strong correlation between SUA and SCr and BUN levels suggests that elevated SUA concentrations reflect an impairment of renal function in heart failure.

SNX-2112 is a selective heat shock protein 90 (Hsp90) inhibitor which can exert a potent anticancer activity. In this study, we investigated the effects of SNX-2112 on B16 melanoma cells in vitro and in vivo. The 3-(4,5-dimetrylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis demonstrated that SNX-2112 dose-dependently inhibited the growth of B16 cells, and induced G0/G1 cell cycle arrest and apoptosis. Western blotting revealed that SNX-2112 lead to the degradation of Hsp90 client proteins including Akt, IKKα, NF-κB, B-Raf and GSK3β. Furthermore, we assessed the antitumor effect of SNX-2112 in vivo, using a xenograft model in C57BL/6 mice. Oral administration of SNX-2112 significantly inhibited the growth of B16 tumors in mice, with a 47% inhibition observed at dose of 80 mg/kg/day for 15 days, compared to control tumors. Hematoxylin-eosin (H&E) staining of xenograft tissues showed that SNX-2112 also inhibited angiogenesis and lead to a lower blood vessel density in the tumors, compared to the control group. These findings demonstrate that SNX-2112 can exhibit a potent anticancer activity against B16 melanoma cells both in vitro and in vivo, by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis in a mechanism dependent on the degradation of Hsp90 client proteins.

SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated apoptotic pathways, downregulated Bcl-2 and Bcl-xL, upregulated Bid, cleaved caspase-9, caspase-7, caspase-3 and PARP, and activated caspase-8. The general caspase inhibitor, z-VAD-fmk, did not completely abolish SNX-2112-induced cell death. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and autophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

Background: Caramiphen produces spinal anesthesia; caramiphen and carbetapentane have never been tested as infiltrative cutaneous analgesic. The aim of this study was to compare cutaneous analgesia of caramiphen and carbetapentane with bupivacaine and evaluated their central nervous system and cardiovascular toxicity., Methods: After the blockade of cutaneous trunci muscle reflex with subcutaneous drug injections in rats, we evaluated the local anesthetic effect of carbetapentane and caramiphen on infiltrative cutaneous analgesia. After continuous intravenous infusion of equipotent doses of bupivacaine, carbetapentane, caramiphen, and saline, we observed mean arterial blood pressure and heart rate and monitored the onset time of seizure, apnea, and impending death., Results: Carbetapentane and caramiphen acted like bupivacaine and elicited cutaneous analgesia in a dose-related fashion. On a 50% effective dose (ED50) basis, the ranks of potencies were bupivacaine (1.78 [1.52-2.07]) > carbetapentane (2.53 [2.38-2.77]) > caramiphen (3.60 [3.41-3.99]) (P < 0.01). At equianalgesic doses (ED25, ED50, ED75), the duration caused by carbetapentane or caramiphen was similar to that caused by bupivacaine. Under equipotent doses, the infusion time of carbetapentane or caramiphen required to cause seizure, apnea, and impending death was longer than that of bupivacaine (P < 0.05). The decline in mean arterial blood pressure and heart rate was slower with carbetapentane or caramiphen when compared with bupivacaine (P < 0.01 for the differences) at equipotent doses., Conclusions: Carbetapentane and caramiphen were similar to bupivacaine at producing durations of cutaneous analgesia but were less likely than bupivacaine to induce central nervous system and cardiovascular systemic toxicity.

The molecular machinery mediating the fusion of synaptic vesicles (SVs) at presynaptic active zone (AZ) membranes has been studied in detail, and several essential components have been identified. AZ-associated protein scaffolds are viewed as only modulatory for transmission. We discovered that Drosophila Rab3-interacting molecule (RIM)-binding protein (DRBP) is essential not only for the integrity of the AZ scaffold but also for exocytotic neurotransmitter release. Two-color stimulated emission depletion microscopy showed that DRBP surrounds the central Ca(2+) channel field. In drbp mutants, Ca(2+) channel clustering and Ca(2+) influx were impaired, and synaptic release probability was drastically reduced. Our data identify RBP family proteins as prime effectors of the AZ scaffold that are essential for the coupling of SVs, Ca(2+) channels, and the SV fusion machinery.

The purpose of this report was to develop novel biodegradable occlusion devices for closure of atrial septal defects (ASD). To manufacture the biodegradable occluders, polycaprolactone (PCL) components were first fabricated by a lab-scale micro-injection molding machine. They were then assembled and hot-spot welded into double umbrella-like devices of 50 mm in diameter. A special mechanism at the axis of the occluder was designed to self-lock the occluder after the two umbrellas were expanded. Furthermore, a nanofibrous matrix of poly-D-L-lactide-glycolide (PLGA)/type I collagen blend was produced via electrospinning to develop biodegradable and biomimetic anti-shunt membranes for the occluders. Characterization of the biodegradable PCL occluders was carried out. PCL occluders exhibited mechanical properties comparable to that of commercially available Amplatzer occluders. The sealing capability of biodegradable occluders was found superior to that of Amplatzer occluders. In addition, the cell attachment and spreading of endothelial cells seeded on the PLGA/collagen nanofibrous matrix and the interaction between cells and PLGA/collagen nanofibers were studied. The nanofibrous membranes made of PLGA/collagen were very effective in promoting cell proliferation during culture.

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K'), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm(2)/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm(2)/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Klebsiella pneumoniae displaying the hypermucoviscosity (HV) phenotype are considered more virulent than HV-negative strains. Nevertheless, the emergence of tissue-abscesses-associated HV-negative isolates motivated us to re-evaluate the role of HV-phenotype., Results: Instead of genetically manipulating the HV-phenotype of K. pneumoniae, we selected two clinically isolated K1 strains, 1112 (HV-positive) and 1084 (HV-negative), to avoid possible interference from defects in the capsule. These well-encapsulated strains with similar genetic backgrounds were used for comparative analysis of bacterial virulence in a pneumoniae or a liver abscess model generated in either naïve or diabetic mice. In the pneumonia model, the HV-positive strain 1112 proliferated to higher loads in the lungs and blood of naïve mice, but was less prone to disseminate into the blood of diabetic mice compared to the HV-negative strain 1084. In the liver abscess model, 1084 was as potent as 1112 in inducing liver abscesses in both the naïve and diabetic mice. The 1084-infected diabetic mice were more inclined to develop bacteremia and had a higher mortality rate than those infected by 1112. A mini-Tn5 mutant of 1112, isolated due to its loss of HV-phenotype, was avirulent to mice., Conclusion: These results indicate that the HV-phenotype is required for the virulence of the clinically isolated HV-positive strain 1112. The superior ability of the HV-negative stain 1084 over 1112 to cause bacteremia in diabetic mice suggests that factors other than the HV phenotype were required for the systemic dissemination of K. pneumoniae in an immunocompromised setting.

Comamonas testosteroni is a widely distributed aerobic gram-negative bacillus. Infection by C testosteroni is infrequent, and no such cases have been reported in Taiwan. Here, we would like to present a 54-year-old alcoholic patient from Taiwan, and his left leg was injured during a fishing trip, resulting in left leg cellulitis and C testosteroni bacteremia. The patient's fever subsided after initial treatment with extended-spectrum cephalosporin, whereas his erythematous swelling did not resolve until switched to ciprofloxacin. The second patient is a 73-year-old Taiwanese male with chronic hepatitis B infection, liver cirrhosis, and hepatocellular carcinoma. Comamonas testosteroni bacteremia was found after transarterial embolization. Further studies are necessary to determine the best antibiotic(s) for patients infected with C testosteroni., (Copyright © 2011. Published by Elsevier B.V.)

Objective: Despite metallic and silicone stents being effective in treating various airway lesions, many concerns still remain. A bioresorbable stent that scaffolds the airway lumen and dissolves after the remodeling process is completed has advantages over metallic and silicone stents. We designed and fabricated a new mesh-type bioresorbable stent with a backbone of polycaprolactone (PCL), and evaluated its safety and biocompatibility in a rabbit trachea model., Methods: The PCL stent was fabricated by a laboratory-made microinjection molding machine. In vitro mechanical strength of the PCL stents was tested and compared to that of commercial silicone stents. The bioresorbable stents were surgically implanted into the cervical trachea of New Zealand white rabbits (n=6). Animals received bronchoscopic examination at 1, 2, 4, 8, and 12 weeks after surgery. Histological examination was completed to evaluate the biocompatibility of the stents., Results: No animals died during the period of study. Distal stent migration was noted in 1 rabbit. In-stent secretion accumulation was found in 2 rabbits. Histological examination showed intact ciliated epithelium and marked leukocyte infiltration in the submucosa of the stented area at 10 and 28 weeks. Stent degradation was minimal, and the mechanical strength was well preserved at the end of 33 weeks., Conclusions: These preliminary findings showed good safety and biocompatibility of the new PCL stent when used in the airway remodeling. PCL could be a promising bioresorbable material for stent design if prolonged degradation time is required., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The objectives of this study were to compare the incidence of nosocomial infections (NIs) and the distribution of resistant nosocomial pathogens in adult Intensive Care Units (ICUs) and two respiratory care facilities for prolonged mechanically ventilated patients [i.e. the respiratory care centre (RCC) and the respiratory care ward (RCW)] in a 1100-bed tertiary care hospital in Taiwan from 2003 to 2006. The overall incidences of NI for adult ICUs, the RCC and the RCW were 14.0, 10.3 and 5.0 per 1000 patient-days, respectively. Urinary tract infections, bloodstream infections and pneumonias occurred most frequently. The most common reported microorganisms in adult ICUs were non-fermentative Gram-negative bacilli (NFGNB) (33.0%), Enterobacteriaceae (26.5%), Candida spp. (18.2%), Staphylococcus aureus (8.9%), coagulase-negative staphylococci (CoNS) (4.9%) and enterococci (4.5%). In comparison, RCW patients had a higher proportion of NIs caused by S. aureus [odds ratio (OR)=1.9], enterococci (OR=2.2) and Enterobacteriaceae (OR=2.2), but a lower proportion of CoNS (OR=0.3), NFGNB (OR=0.5) and Candida spp. (OR=0.2). RCW patients had higher incidence rates of methicillin-resistant S. aureus (OR=4.91) and extended-spectrum β-lactamase-producing Enterobacteriaceae (OR=4.06) than ICU patients. Further study is needed to delineate the mechanisms responsible for the differences in resistance profile amongst pathogens associated with nosocomial infection in ICUs, RCCs and RCWs., (Copyright © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins.

Background: Marked differences have been found in the characteristics of people dying by suicide in Western and Asian countries. However, there is less information available on possible differences for deliberate self-harm (DSH)., Aims: To compare the characteristics of people presenting to hospital in Hong Kong and Oxford (UK) with DSH, and to assess the outcome of those persons in Hong Kong., Methods: A sample of DSH patients admitted to the accident and emergency (A&E) department of a regional hospital in Hong Kong was assessed and followed up 6 months later to assess the risk of repetition of DSH, and was then compared with such patients in Oxford., Results: The majority of patients in Hong Kong were female (male:female ratio of 1:2.4), young (59% were under 35), and had used self-poisoning (78%). Over one-third were single (37%) and one-fourth unemployed (26%). About half (49%) scored in the high or very high categories of the Beck's Suicide Intent Scale, considerably more so than in Oxford; 44.6% of patients defaulted psychiatric outpatient service during the 6-month follow-up period. The repetition rate within the following 6 months was 16.7%. The number of self-reported adverse life problems, history of childhood sexual and physical abuse, and repetitive self-mutilation were shown to be the factors most strongly correlated with the risk of re-attempt. Alcohol problems were much lower than in Oxford., Conclusions: The findings show that DSH patients in Hong Kong show some marked differences compared to those in Oxford. Implications for the prevention of repeated DSH in Hong Kong are discussed.

Introduction: In trauma patients with chest injuries, traumatic pericardial effusion is an important scenario to consider because of its close linkage to cardiac injury. Even with advances in imaging, diagnosis remains a challenge and use of which surgical approach is controversial. This study reviews the treatment algorithm, surgical outcomes, and predictors of mortality for traumatic pericardial effusion., Patients and Methods: Information on demographics, mechanisms of trauma, injury scores, diagnostic tools, surgical procedures, associated injuries, and hospital events were collected retrospectively from a tertiary trauma center., Results: Between June 2003 and December 2009, 31 patients (23 males and 8 females) with a median age of 31 (range 16-77), who had undergone surgical drainage of pericardial effusion were enrolled in the study. Blunt trauma accounted for 27 (87.1%) insults, and penetrating injury accounted for 4 (12.9%). Patients were diagnosed by Focused Assessment with Sonography for Trauma (FAST) (8 patients), computerized tomography (7 patients), echocardiography (9 patients), and incidentally during surgery (7 patients). Notably, sixteen (51.7%) patients required surgical repair for traumatic cardiac ruptures, including 6 (19.6%) with pericardial defects who presented initially with hemothorax. The surgical approaches were subxiphoid in 8 patients (25.8%), thoracotomy in 7 (22.6%), and sternotomy in 19 (61.2%), including 3 conversions from thoracotomy. The survival to discharge rate was 77.4% (24/31). Concomitant cardiac repair, associated pericardial defects, and initial surgical approach did not affect survival, but the need for massive transfusion, cardiopulmonary cerebral resuscitation (CPCR), trauma score, and incidental discovery at surgery all had a significant impact on the outcome., Conclusions: Precise diagnoses of traumatic pericardial effusions are still challenging and easily omitted even with FAST, repeat cardiac echo and CT. The number of patients with traumatic pericardial effusion requiring surgical repair is high. Standardized therapeutic protocol, different surgical approaches have not impact on survival. Correct identification, prompt drainage, and preparedness for concomitant cardiac repair seem to be the key to better outcomes., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this report was to develop novel balloon-expandable self-lock drug-eluting poly(ε-caprolactone) stents. To fabricate the biodegradable stents, polycaprolactone (PCL) components were first fabricated by a lab-scale micro-injection molded machine. They were then assembled and hot-spot welded into mesh-like stents of 3 and 5 mm in diameters. A special geometry of the components was designed to self-lock the assembled stents and to resist the external pressure of the blood vessels after being expanded by balloons. Characterization of the biodegradable PCL stents was carried out. PCL stents exhibited comparable mechanical property to that of metallic stents. No significant collapse pressure reduction and weight loss of the stents were observed after being submerged in PBS for 12 weeks. In addition, the developed stent was coated with paclitaxel by a spray coating technique and the release characteristic of the drug was determined by an in vitro elution method. The high-performance liquid chromatography analysis showed that the biodegradable stents could release a high concentration of paclitaxel for more than 60 days. By adopting the novel techniques, we will be able to fabricate biodegradable drug-eluting PCL stents of different sizes for various cardiovascular applications.

Background: Postcardiotomy extracorporeal life support (ECLS) is a resource-demanding therapy with varied results among institutions. An organized protocol was necessary to improve the effectiveness of this therapy., Methods and Results: A total of 110 patients received ECLS due to refractory postcardiotomy cardiogenic shock between January 2003 and June 2009, and were eligible for inclusion in this retrospective study. Preoperative, perioperative, and postoperative variables were collected, including the European system for cardiac operative risk evaluation (EuroSCORE) and markers of ECLS-related organ injuries. All variables were analyzed for possible associations with mortality in hospital, and after hospital discharge. The mean age, additive EuroSCORE, and left ventricular ejection fraction (LVEF) for all patients was 60 (+/-14) years, 9 (+/-6), and 43% (+/-20%) respectively. Sixty-seven patients were weaned from ECLS and 46 survived to hospital discharge. The mean duration of ECLS support was 143 h (+/-112 h). Multivariate analysis revealed that an age of >60 years, a necessity for postoperative continuous arteriovenous hemofiltration, a maximal serum total bilirubin >6 mg/dL, and a need for ECLS support for >110 h were independent predictors of in-hospital mortality. In addition, persistent heart failure with LVEF <30% was an independent predictor of mortality after hospital discharge. A risk-predicting score for in-hospital mortality associated with postcardiotomy ECLS was developed for clinical application., Conclusion: Based on the abovementioned findings, a comprehensive protocol for postcardiotomy ECLS was designed. The primary objective was to achieve adequate hemodynamics within the first 24h of initiating ECLS. Other objectives of the protocol included a consistent approach to safe anticoagulation while on ECLS, a process to make decisions within 7 days of initiating ECLS, and patient follow-up after hospital discharge., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Risk factors and outcome in patients who acquire nosocomial infections due to carbapenem-resistant Acinetobacter baumannii (CRAB) are rarely investigated., Methods: A multicenter retrospective study was conducted to analyze the clinical and microbiological data of patients with nosocomial infections due to A. baumannii in 10 hospitals around Taiwan from May 2004 to December 2006. Comparisons were made between patients with infections due to CRAB and patients with infections due to carbapenem-susceptible A. baumannii (CSAB)., Results: One hundred and twenty-one patients carrying CRAB (infections, n=91) and 127 patients carrying CSAB (infections, n=97) were recruited for analysis. Compared with patients with CSAB infections, patients with CRAB infections had a longer duration of hospital stay before A. baumannii was isolated (median 48 vs. 21 days, p<0.001) and were more likely to have had exposure to a carbapenem (adjusted odds ratio (AOR) 2.57, 95% confidence interval (95% CI) 1.43-5.35; p=0.02) and an intensive care unit (ICU) stay (AOR 3.42, 95% CI 1.76-5.26; p=0.008). Risk factors associated with CRAB bacteremia included duration of hospital stay before onset of bacteremia (AOR 1.009 per 1-day longer, 95% CI 1.03-1.24; p=0.049), prior colonization with A. baumannii (AOR 3.27, 95% CI 1.99-5.93; p=0.002), and hospitalization in the ICU (AOR 6.12, 95% CI 1.58-13.68; p=0.009). Patients with CRAB bacteremia had a higher mortality rate than patients with CSAB bacteremia (46.0% vs. 28.3%, p=0.04). Multivariate analysis showed that carbapenem resistance (AOR 5.31, 95% CI 1.88-13.25; p=0.002), central venous catheterization (AOR 3.27, 95% CI 1.55-10.56; p=0.009), and ICU stay (AOR 2.56, 95% CI 1.15-8.85; p=0.04) were independent variables associated with mortality in patients with A. baumannii bacteremia., Conclusions: Patients with CRAB infections have a higher mortality rate than those with CSAB infections. Longer hospital stay, colonization with A. baumannii, and admission to the ICU were associated with the development of CRAB bacteremia., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Rhabdomyalysis is uncommon but potentially life-threatening. We present a 17-year-old patient who developed rhabdomyalysis following pandemic influenza A (H1N1/09) infection. With aggressive hydration her renal function remained normal throughout the entire disease course, and she steadily improved clinically. Although pneumonia and acute respiratory distress syndrome are the most common severe complications of H1N1/09 infection, clinicians should be aware that H1N1/09 infection may be complicated by rhabdomyolysis.

Delivering effective drugs at sufficiently high concentrations to the area of infection is a standard treatment for infectious disease, such as endophthalmitis. This is currently done by empirical trans pars plana intravitreal injection of both antibiotics directed against gram-positive and gram-negative microorganisms and steroids. However, injections by needles repeatedly may increase the risks of intraocular infection and hemorrhage, as well as retinal detachment. This article explores the alternative of using biodegradable polymers as scleral plugs for a long-term drug release in vivo. To manufacture plugs, poly(lactide-glycolide) copolymers were first mixed with vancomycin, amikacin, and dexamethasone. The mixture was compressed and sintered at 55 degrees C to form scleral plugs 1.4 mm in diameter. Biodegradable scleral plugs released high concentrations of antibiotics (well above the minimum inhibitory concentrations, MIC) and steroids in vivo for the period of time needed to treat intraocular infection. In addition, no major complications such as infectious or sterile endophthalmitis, retinal detachment, ocular phthisis, or uvea protrusion at sclerotomy site were observed throughout the experiment. The sclerotomy wound healed after total degradation of the scleral implants without leakage or local necrosis. Antibiotic/steroid-impregnated biodegradable scleral plugs may have a potential role in the treatment of various intraocular infections., ((c) 2010 Wiley Periodicals, Inc.)

Background: The in-hospital mortality of coronary artery bypass grafting (CABG) is low but can be significant if catastrophic complications occur. To increase the safety of CABG, we aimed to establish a predictive model of major postoperative complications that incorporated patient characteristics and operative strategies., Methods: A retrospective study was performed which included all consecutive patients receiving isolated CABG from August 2006 to February 2008 (n = 319). Patient characteristics were quantified by the additive EuroSCORE. Operative strategies were classified as cardioplegic arrest, on-pump beating, and off-pump., Results: Four major complications were identified to be connected to the in-hospital mortality: (1) requirement of mechanical circulatory supports > 72 h (odds ratio [OR] 28.9, 95% confidence interval [CI] 6.0-139.9), (2) requirement of mechanical ventilator supports > 72 h (OR 9.5., 95%, CI 2.2- 42.7), (3) acute renal failure requiring dialysis (OR 9.2, 95% CI 2.2-38.3), (4) major gastrointestinal complications (OR 5.4., 95% CI 1.1-26.7). An increase of additive EuroSCORE (OR 1.2, 95% CI 1.1-1.4) and the cardioplegic strategy (OR 2.7, 95% CI 1.2-6.0) were independent risk factors for major complications. The probability of one or more major complication was > 50% for patients receiving cardioplegic CABG with an additive EuroSCORE > 8., Conclusion: Dependence on the mechanical ventilator or circulatory supports > 72 h, acute renal failure requiring dialysis, and major gastrointestinal complications were major complications of CABG. The individual risk of having at least one of these complications could be predicted by the patient's preoperative EuroSCORE and operative strategy. A surgical plan tailored by institutional experiences on specific risk factors and aggressive therapeutic plans for major complications are helpful in improving the overall results of CABG.

Klebsiella pneumoniae-caused liver abscess (KLA) is an emerging infectious disease. However, factors other than K1-specific loci that contribute to the pathogenesis of this disease have not been identified. pLVPK is a 219,385-bp plasmid of K. pneumoniae CG43, an invasive K2 strain associated with KLA. We aimed in this study to evaluate the involvement of pLVPK in K. pneumoniae virulence and its clinical significance in abscess formation. A pLVPK-cured CG43 was isolated and its virulence was examined in a mouse model. The prevalence of pLVPK-derived loci terW, iutA, rmpA, silS, and repA was investigated in 207 clinical isolates by screening with specific primers. Loss of pLVPK abolished the ability of K. pneumoniae to disseminate into extraintestinal sites and, consequently, attenuated abscess formation in mice. Primary K. pneumoniae abscess isolates (n = 94) were more likely to be terW (+)-iutA (+)-rmpA (+)-silS (+) than those related to non-abscess infections (n = 113) (62% vs. 27%; p < 0.0001). Logistic regression analysis indicated that the presence of the terW-rmpA-iutA-silS loci was a significant risk factor (odds ratio, 4.12; 95% confidence interval, 2.02-8.4; p < 0.0001) for abscess formation. pLVPK is a determinant for K. pneumoniae virulence and infection with strains carrying the pLVPK-derived terW-rmpA-iutA-silS loci may predispose patients to abscess formation.

Background: Although proxymetacaine and oxybuprocaine produce topical ocular and spinal anesthesia, they have never been tested as cutaneous anesthetics. We compared cutaneous analgesia of proxymetacaine and oxybuprocaine with bupivacaine and tested their central nervous system and cardiovascular toxicity., Methods: After blockade of cutaneous trunci muscle reflex with subcutaneous injections, we evaluated the local anesthetic effect of proxymetacaine and oxybuprocaine on cutaneous analgesia in rats. After i.v. infusions of equipotent doses of oxybuprocaine, proxymetacaine, and bupivacaine, we observed the onset time of seizure, apnea, and impending death and monitored mean arterial blood pressure and heart rate., Results: Proxymetacaine and oxybuprocaine acted like bupivacaine and produced dose-related cutaneous analgesia. On a 50% effective dose basis, the ranks of potencies were proxymetacaine > oxybuprocaine > bupivacaine (P < 0.01). Under equipotent doses, the infusion times of proxymetacaine or oxybuprocaine required to cause seizure, apnea, and impending death were longer than that of bupivacaine (P < 0.05). The decrease in mean arterial blood pressure and heart rate was slower with oxybuprocaine and proxymetacaine compared with bupivacaine (P < 0.05 for the differences) at equipotent doses., Conclusions: Oxybuprocaine and proxymetacaine were more potent at producing cutaneous anesthesia but were less potent than bupivacaine at producing central nervous system and cardiovascular toxicity.

This study used nationwide data from the Taiwan Education Panel Survey (TEPS) to examine the longitudinal effects of educational expectations and achievement attributions on the academic achievements of adolescents. The sample included 2,000 Taiwanese secondary school students, each of whom completed three waves of questionnaires and cognitive tests: the first in grade 7 (in 2001), the second in grade 9 (in 2003), and the third in grade 11 (in 2005). Through multilevel longitudinal analysis, the results showed: (1) educational expectations accounted for a moderate amount of the variance in academic achievements; (2) students with high educational expectations and effort attribution exhibited higher growth rates in their academic achievements; and (3) studentswith lower educational expectations and those attributing success to others showed significantly fewer academic achievements and significantly lower growth rates in such achievements. The results demonstrated that adolescents' educational expectations and achievement attributions play crucial roles in the long-term course of academic accomplishments. Implications for educational practice and further studies are also discussed.

The aim of this study was to develop and characterize lipid nanoparticle systems for the transdermal delivery of buprenorphine and its prodrugs. A panel of three buprenorphine prodrugs with ester chains of various lengths was synthesized and characterized by solubility, capacity factor (log K'), partitioning between lipids and water and the ability to penetrate nude mouse skin. Colloidal systems made of squalene (lipid emulsion, LE), squalene + Precirol (nanostructured lipid carriers, NLC) and Precirol (solid lipid nanoparticles, SLN) as the lipid core material were prepared. Differential scanning calorimetry showed that the SLN had a more-ordered crystalline lattice in the inner matrix compared to the NLC. The particle size ranged from 220-300 nm, with NLC showing the smallest size. All prodrugs were highly lipophilic and chemically stable, but enzymatically unstable in skin homogenate and plasma. The in vitro permeation results exhibited a lower skin delivery of drug/prodrug with an increase in the alkyl chain length. SLN produced the highest drug/prodrug permeation, followed by the NLC and LE. A small inter-subject variation was also observed with SLN carriers. SLN with soybean phosphatidylcholine (SLN-PC) as the lipophilic emulsifier showed a higher drug/prodrug delivery across the skin compared to SLN with Myverol, a palmitinic acid monoglyceride. The in vitro permeation of the prodrugs occurred in a sustained manner for SLN-PC. The skin permeation of buprenorphine could be adjusted within a wide range by combining a prodrug strategy and lipid nanoparticles.

Extracorporeal life support (ECLS) is a temporary support of postcardiotomy cardiogenic shock (PCS). Mortality of postcardiotomy ECLS often results from inability to recognize appropriate patients and bridge them to the next therapy before complications. A two-gated strategy for the second bridge transferring was suggested. From January 2003 to January 2008, 72 patients (mean 60 years) received ECLS for PCS. Indicators of cardiac recovery were identified from the physiological responses to ECLS. The optimal ECLS duration for myocardial recovery was defined as the supporting time of survivors. Forty-one patients weaned off ECLS and 29 survived to discharge. The mean duration of ECLS was 130 hours. Twenty- eight of the 29 survivors weaned off ECLS within 7 days. ECLS >100 hours and a refractory phenomenon of persistent hypotension (mean arterial pressure < 70 mm Hg) with a high adrenergic demand (inotropic equivalent score > 35) under a sufficient ECLS (flow > 50 ml x kg x min, SvO(2) > 80%) >24 hours were independent risk factors of ECLS nonweaning. The benefits of adult postcardiotomy ECLS are controversial after a 7-day support. Bridging should be considered in suitable patients having ECLS >7 days or showing instabilities under an adequate ECLS >24 hours. Continuing ECLS poses a higher risk of mortality.

Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN>NLC>LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.

Introduction: Cardiac rupture following blunt thoracic trauma is rarely encountered by clinicians, since it commonly causes death at the scene. With advances in traumatology, blunt cardiac rupture had been increasingly disclosed in various ways. This study reviews our experience of patients with suspected blunt traumatic cardiac rupture and proposes treatment protocols for the same., Methods: This is a 5-year retrospective study of trauma patients confirmed with blunt traumatic cardiac rupture admitted to a university-affiliated tertiary trauma referral centre. The following information was collected from the patients: age, sex, mechanism of injury, initial effective diagnostic tool used for diagnosing blunt cardiac rupture, location and size of the cardiac injury, associated injury and injury severity score (ISS), reversed trauma score (RTS), survival probability of trauma and injury severity scoring (TRISS), vital signs and biochemical lab data on arrival at the trauma centre, time elapsed from injury to diagnosis and surgery, surgical details, hospital course and final outcome., Results: The study comprised 8 men and 3 women with a median age of 39 years (range: 24-73 years) and the median follow-up was 5.5 months (range: 1-35 months). The ISS, RTS, and TRISS scores of the patients were 32.18+/-5.7 (range: 25-43), 6.267+/-1.684 (range: 2.628-7.841), and 72.4+/-25.6% (range: 28.6-95.5%), respectively. Cardiac injuries were first detected using focused assessment with sonography for trauma (FAST) in 4 (36.3%) patients, using transthoracic echocardiography in 3 (27.3%) patients, chest CT in 1 (9%) patient, and intra-operatively in 3 (27.3%) patients. The sites of cardiac injury comprised the superior vena cava/right atrium junction (n=4), right atrial auricle (n=1), right ventricle (n=4), left ventricular contusion (n=1), and diffuse endomyocardial dissection over the right and left ventricles (n=1). Notably, 2 had pericardial lacerations presenting as a massive haemothorax, which initially masked the cardiac rupture. The in-hospital mortality was 27.3% (3/11) with 1 intra-operative death, 1 multiple organ failure, and 1 death while waiting for cardiac transplantation. Another patient with morbid neurological defects died on the thirty-third postoperative day; the overall survival was 63.6% (7/11). Compared with the surviving patients, the fatalities had higher RTS and TRISS scores, serum creatinine levels, had received greater blood transfusions, and had a worse preoperative conscious state., Conclusions: We proposed a protocol combining various diagnostic tools, including FAST, CT, transthoracic echocardiography, and TEE, to manage suspected blunt traumatic cardiac rupture. Pericardial defects can mask the cardiac lesion and complicate definite cardiac repair. Comorbid trauma, particularly neurological injury, may have an impact on the survival of such patients, despite timely repair of the cardiac lesions.

Postcardiotomy right ventricular (RV) failure develops during the perioperative period following pulmonary hypertensive crisis or acute myocardial infarction. This study reports our institutional experience in treating these patients with extracorporeal life support (ECLS). Between June 2002 and July 2005, 46 adults were treated with ECLS for postcardiotomy shock. Acute RV failure was the cause of support in 14 (30%). Patient mean age was 55.7 +/- 15.4 years. Cardiac pathologies were valvular (n = 7), coronary (n = 1), combined coronary and valvular disease (n = 2), complex congenital heart (n = 2), aortic aneurysm (n = 1), and cardiomyopathy post heart transplant (n = 1). The triggers of RV failure were pulmonary hypertension (n = 6), RV infarction (n = 4), and not defined (n = 4). Patients were supported on ECLS for a mean duration of 71 +/- 52 h (range, 10-183 h). Major complications included acute renal failure requiring hemodialysis (n = 4), reexploration for bleeding (n = 2), and acute subdural hematoma (n = 1). Nine (64%) patients were successfully weaned from ECLS, and seven (50%) survived to discharge. Preexisting pulmonary hypertension had a favorable tendency for weaning, and acute renal failure requiring hemodialysis correlated with in-hospital mortality. ECLS is beneficial for treating postcardiotomy RV failure when conventional therapy is exhausted. As it can be deployed rapidly and does not require resternotomy for weaning, ECLS could be regarded as the first choice of mechanical support for postcardiotomy RV failure.

Cocrystallization of 2-amino-benzothia-zole with benzene-1,2,4-tricarboxylic acid in a mixed solvent affords the title ternary cocrystal, C(7)H(7)N(2)S(+)·C(9)H(5)O(6) (-)·H(2)O, in which one of the carboxyl groups of the benzene-tricarboxylic acid is deproton-ated and the heterocyclic N atom of the 2-amino-benzothia-zole is protonated. In the crystal, inter-molecular N-H⋯O and O-H⋯O hydrogen-bonding inter-actions stabilize the packing.

Background: Extracorporeal life support (ECLS) has been applied successfully to patients with acute cardiopulmonary failure. However, ECLS remains controversial for traumatized patients who are prone to bleeding., Patients and Methods: From March 2004 to October 2007, nine patients with post-traumatic respiratory distress refractory to ventilator support were treated with ECLS. Mean patient age was 35.1+/-9.7 (range, 18-47) years, average injury severity score (ISS) was 44.56+/-4.93 (range, 35-50), and Sequential Organ Failure Assessment score (SOFA) score was 12.1+/-3.67 (range, 7-16). Before ECLS, all patients had received thoracic interventions, including four lung resections, with a mean PaO(2) of 49.04+/-9.82 (range, 31-64) mmHg and PaCO(2) of 66.4+/-15.72 (range, 45-86) mmHg. Seven patients were supported in standard veno-venous mode, and the other two were initially supported in veno-arterial mode due to hemodynamic instability., Results: Median interval from trauma to ECLS was 33 (range, 4-384) h, and median duration of ECLS was 145 (range, 69-456) h. Six (66.7%) patients received additional surgeries during ECLS. One died of sepsis from occult colon rupture and the other of acute liver failure, 6 and 13 days respectively after trauma. Seven (77.8%) patients were weaned and discharged., Conclusions: Using ECLS to resuscitate traumatic respiratory distress proved to be safe and effective when conventional therapies had been exhausted. Early deployment of ECLS to preserve systemic organ perfusion, aggressive treatment of coexisting injuries and tailored anticoagulation protocols are crucial to a successful outcome.

Objectives: To determine the effect of finasteride relative to placebo on prostate cancer (PCa) risk at each individual Gleason score in the Prostate Cancer Prevention Trial using a post hoc generalization of a prespecified, exploratory, biopsy sampling density-adjusted analysis., Methods: The Prostate Cancer Prevention Trial enrolled 18 882 men aged >or=55 years with a prostate-specific antigen level of <3.0 ng/mL and normal digital rectal examination findings, and randomized them to finasteride 5 mg daily or placebo. PCa data from evaluable biopsies obtained within 7 years plus

Hulless barley kernels were sequentially abraded to achieve 4%, 8%, 16%, 24%, 32%, and 40% removal. Abraded fines, kernels, and ground kernels were stored at 35 degrees C and 75% relative humidity for 3 wk. Stored samples were extracted and the levels of oil, free phytosterols, tocopherols (Ts), and tocotrienols (T3s) were analyzed and compared with freshly abraded fractions. The results revealed that oil, sterols, and Ts were concentrated in the outer layers, particularly in the germ layer. In whole kernels, homologues of both Ts and T3s showed the same ranking order in concentrations as alpha > gamma > beta > delta. The homologue composition of Ts remained the same but that of T3s changed across the kernel. The %T3 in total tocols increased in fractions with increasing endosperm tissue. Storage caused no change in oil and Ts but significant changes in sterols and T3s. The changes were differential among T3 isomers, with alpha-T3 decreasing and delta-T3 increasing. The degradation of alpha-T3 was accelerated in fractions with more endosperm tissue. Grinding kernel samples before storage accelerated sterol degradation but had a limited effect on changes of T3s. A 2nd experiment using a different hulless barley line and ambient storage for 6 mo confirmed all the findings except that the changing trend for sterols was inconsistent. These results provide practical information to those who wish to produce a barley fraction enriched with a particular functional lipid and maintain stability of their products.

Objective: A key assumption underlying the principle that power increases with sample size is that the standardized effect size is fixed over time. In therapeutic areas where it may be difficult to continually recruit from a homogeneous population, this assumption may not be valid; patients randomized toward the end of enrollment may derive from a more heterogeneous population and negatively impact the power of a study. Post hoc analyses were performed on clinical data from four phase III depression trials with paroxetine to evaluate this possibility., Methods: Each study used a randomized, double-blind, placebo-controlled design and enrolled approximately 150 patients per treatment arm. Plots of observed p-values for the treatment difference between paroxetine and placebo (on the HAM-D17 change from baseline score at week 8) by cumulative enrollment were made for each study., Results: As previously reported, three of the four studies showed an overall significant treatment effect and one did not. In each study, a significant treatment effect was observed before approximately 100 patients had been enrolled per treatment arm. Continuing to enroll additional patients did not maintain the achieved level of significance in most instances, and in one case appeared to alter a potentially positive study into a failed study. Plots of p-values versus cumulative enrollment by patient quarters using combined data from all four studies suggested that late-enrolling patients were more likely to be placebo responders than early-enrolling patients. Hypothesized explanations for this finding include a depleted pool of depressed patients and the rush for patient recruitment at the end of a study in order to meet completion timelines. However, no corroborative evidence could be found to support either possibility., Conclusions: This analysis demonstrates that bigger is not necessarily better for depression trials.

The objective of this study was to develop a three-dimensional leaching method to understand the diffusion behavior of a solidified waste matrix. A cylindrical solidified waste matrix with isotope lead compounds used as a tracer was used to demonstrate the diffusion phenomenon. The leaching test method was coupled with the mathematical diffusion model derived from Duhamel's theorem to control the time-dependent conditions and compute the mass diffusivity and mass generation rate constant of the target pollutants and also simulate the pollutants leached from solidified waste matrix. The simulation value is in fair agreement with experiment.

Background/aim: p27(Kip1) (p27) is a member of the Cip/Kip family of cyclin/cyclin-dependent kinase inhibitors (CKIs), and its CKI-independent function regarding cell motility modulation has been discovered. However, it is controversial whether p27 promotes or inhibits cell migration. This study investigates the migration regulatory role of p27 in metastatic hepatocellular carcinoma (HCC) cells., Methods: RNA interference, RhoA-GTP pull-down assay, Western blots, immunostaining, transwell and wound-healing assays were used., Results: High levels of p27 and phosphorylated p27 (Ser10) were detected in metastatic HCC cells, MHCC97L and MHCC97H, when compared with nonmetastatic HCC cells, PLC and Hep3B. We hypothesized that p27 is responsible for metastasis-related migration in HCC cells and tested the hypothesis by using the p27 RNA interference approach. Increased RhoA activity was observed when p27 was knocked down in MHCC97L cells, which further led to stress fiber formation and decreased cell migration and wound healing. Moreover, high p27 and low stathmin expression of metastatic HCC cells indicated that migration inhibition by p27-stathmin interaction might not be the major regulatory pathway in metastatic HCC cells., Conclusion: p27 promotes cell migration in metastatic HCC cells through the regulation of RhoA activity., ((c) 2008 S. Karger AG, Basel.)

Background: The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the 7-year prevalence of prostate cancer among patients treated with finasteride (5 mg daily) compared with that among patients treated with placebo; however, a 25.5% increase in the prevalence of high-Gleason grade tumors was observed, the clinical significance of which is unknown. One hypothesized explanation for this increase is that finasteride reduced prostate volume, leading to detection of more high-grade tumors due to increased sampling density. This possibility was investigated in an observational reanalysis of the PCPT data, with adjustment for sampling density., Methods: A logistic model for the association of high-grade (Gleason score 7-10) prostate cancer with baseline covariates and/or baseline covariates plus prostate volume and number of cores obtained at biopsy was developed using the placebo group (n = 4775) of the PCPT. This model was then applied to the finasteride group (n = 5123) to compare the predicted and observed numbers of high-grade tumors in that group. In a second approach, odds ratios (ORs) for prostate cancer in the finasteride versus placebo groups calculated from binary and polytomous logistic regression models that contained or excluded covariates for gland volume and number of needle cores were compared., Results: Median prostate volume was 25% lower in the finasteride group (median = 25.1 cm3) than in the placebo group (median = 33.5 cm3). The logistic model developed in the placebo group showed that the likelihood of detection of high-grade prostate cancer decreased as volume increased (for each 10 cm3 increase in prostate volume, OR = 0.81, 95% confidence interval [CI] = 0.74 to 0.90). Based on this model, 239 high-grade prostate cancers were predicted in the finasteride group, whereas 243 were observed, a non-statistically significant difference. Among all participants, the odds ratios for high-grade cancer in the finasteride versus placebo groups decreased from 1.27 (95% CI = 1.05 to 1.54) with adjustment for baseline covariates to 1.03 (95% CI = 0.84 to 1.26) following additional adjustment for gland volume and number of biopsy cores in binary outcome models and from 1.14 (95% CI = 0.94 to 1.38) to 0.88 (95% CI = 0.72 to 1.09) following these adjustments in the polytomous models., Conclusions: Although analyses using postrandomization data require cautious interpretation, these results suggest that sampling density bias alone could explain the excess of high-grade cancers among the finasteride-assigned participants in the PCPT.