Ten-year territory-wide trends in the utilisation and clinical outcomes of extracorporeal membrane oxygenation in Hong Kong.

INTRODUCTION: The utilisation of extracorporeal membrane oxygenation (ECMO) has been rapidly increasing in Hong Kong. This study examined 10-year trends in the utilisation and clinical outcomes of ECMO in Hong Kong. METHODS: We retrospectively reviewed the records of all adult patients receiving ECMO who were admitted to the intensive care units (ICUs) of public hospitals in Hong Kong between 2010 and 2019. Temporal trends across years were assessed using the Mann-Kendall test. Observed hospital mortality was compared with the Acute Physiology and Chronic Health Evaluation (APACHE) IV-predicted mortality. RESULTS: The annual number of patients receiving ECMO increased from 18 to 171 over 10 years. In total, 911 patients received ECMO during the study period: 297 (32.6%) received veno-arterial ECMO, 450 (49.4%) received veno-venous ECMO, and 164 (18.0%) received extracorporeal cardiopulmonary resuscitation. The annual number of patients aged ≥65 years increased from 0 to 47 (27.5%) [P for trend=0.001]. The median (interquartile range) Charlson Comorbidity Index increased from 1 (0-1) to 2 (1-3) [P for trend<0.001] while the median (interquartile range) APACHE IV score increased from 90 (57-112) to 105 (77-137) [P for trend=0.003]. The overall standardised mortality ratio comparing hospital mortality with APACHE IV-predicted mortality was 1.11 (95% confidence interval=1.01-1.22). Hospital and ICU length of stay both significantly decreased (P for trend=0.011 and <0.001, respectively). CONCLUSION: As ECMO utilisation increased in Hong Kong, patients put on ECMO were older, more critically ill, and had more co-morbidities. It is important to combine service expansion with adequate resource allocation and training to maintain quality of care.

Admission triage tool for adult intensive care unit admission in Hong Kong during the COVID-19 outbreak.

Intensive care is expensive, and the numbers of intensive care unit (ICU) beds and trained specialist medical staff able to provide services in Hong Kong are limited. The most recent increase in coronavirus disease 2019 (COVID-19) infections over July to August 2020 resulted in more than 100 new cases per day for a prolonged period. The increased numbers of critically ill patients requiring ICU admission posed a capacity challenge to ICUs across the territory, and it may be reasonably anticipated that should a substantially larger outbreak occur, ICU services will be overwhelmed. Therefore, a transparent and fair prioritisation process for decisions regarding patient ICU admission is urgently required. This triage tool is built on the foundation of the existing guidelines and framework for admission, discharge, and triage that inform routine clinical practice in Hospital Authority ICUs, with the aim of achieving the greatest benefit for the greatest number of patients from the available ICU resources. This COVID-19 Crisis Triage Tool is expected to provide structured guidance to frontline doctors on how to make triage decisions should ICU resources become overwhelmed by patients requiring ICU care, particularly during the current COVID-19 pandemic. The triage tool takes the form of a detailed decision aid algorithm based on a combination of established prognostic scores, and it should increase objectivity and transparency in triage decision making and enhance decision-making consistency between doctors within and across ICUs in Hong Kong. However, it remains an aid rather than a complete substitute for the carefully considered judgement of an experienced intensive care clinician.

Favorable outcomes of culture-based Helicobacter pylori eradication therapy in a region with high antimicrobial resistance.

BACKGROUND: The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. To overcome resistance-associated treatment failure, the efficacy of culture-based, susceptibility-guided therapy was demonstrated as the first-line eradication therapy for H pylori infection. AIMS: To evaluate the efficacy of culture-based therapy as the first-line eradication therapy in regions with high levels of antimicrobial resistance. METHODS: Helicobacter pylori-positive patients without previous eradication treatment history were recommended to undergo culture to determine the minimal inhibitory concentration (MIC). If they consented, 7-day clarithromycin-containing PPI triple; 7-day esomeprazole, moxifloxacin, and amoxicillin (MEA) therapy; or 7- or 14-day esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapy were administered based on the agar dilution-determined MIC. Eradication, treatment compliance, and adverse events were examined. RESULTS: In total, 74 patients were enrolled, and 69 patients completed the protocols. The overall resistance rates to amoxicillin, clarithromycin, metronidazole, and moxifloxacin were 6.7%, 31.0%, 41.8%, and 39.2%, respectively. The patients were allocated to the PPI triple (n = 50), MEA (n = 8) or quadruple (n = 16) therapy. The eradication rate in the intention-to-treat analysis was 93.1% (69 of 74 patients). The eradication rates in the per-protocol analysis were 100.0% (69 of 69 patients). Epigastric pain, nausea, and vomiting were less common than those of other empirical therapies. CONCLUSIONS: Culture-based, susceptibility-guided therapy is effective first-line eradication therapy, especially in regions with high levels of antimicrobial resistance.

Upregulated microRNA-193a-3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells.

Cisplatin is a well-known anticancer drug used to treat various cancers. However, development of cisplatin resistance has hindered the efficiency of this drug in cancer treatment. Development of chemoresistance is known to involve many signaling pathways. Recent attention has focused on microRNAs (miRNAs) as potentially important upstream regulators in the development of chemoresistance. CD44 is one of the gastric cancer stem cell markers and plays a role in regulating self-renewal, tumor initiation, metastasis and chemoresistance. The purpose of the present study was to examine the mechanism of miRNA-mediated chemoresistance to cisplatin in CD44-positive gastric cancer stem cells. We sorted gastric cancer cells according to level of CD44 expression by FACS and analyzed their miRNA expression profiles by microarray analysis. We found that miR-193a-3p was significantly upregulated in CD44(+) cells compared with CD44(-) cells. Moreover, SRSF2 of miR-193a-3p target gene was downregulated in CD44(+) cells. We studied the modulation of Bcl-X and caspase 9 mRNA splicing by SRSF2 and found that more pro-apoptotic variants of these genes were generated. We also found that downstream anti-apoptotic genes such as Bcl-2 were upregulated, whereas pro-apoptotic genes such as Bax and cytochrome C were downregulated in CD44(+) cells compared to CD44(-) cells. In addition, we found that an elevated level of miR-193a-3p triggered the development of cisplatin resistance in CD44(+) cells. Inhibition of miR-193a-3p in CD44(+) cells increased SRSF2 expression and also altered the levels of multiple apoptotic genes. Furthermore, inhibition of miR-193a-3p reduced cell viability and increased the number of apoptotic cells. Therefore, miR-193a-3p may be implicated in the development of cisplatin resistance through regulation of the mitochondrial apoptosis pathway. miR-193a-3p could be a promising target for cancer therapy in cisplatin-resistant gastric cancer.

Solid-state colloidal CuInS2 quantum dot solar cells enabled by bulk heterojunctions.

Colloidal copper indium sulfide (CIS) nanocrystals (NCs) are Pb- and Cd-free alternatives for use as absorbers in quantum dot solar cells. In a heterojunction with TiO2, non-annealed ligand-exchanged CIS NCs form solar cells yielding a meager power conversion efficiency (PCE) of 0.15%, with photocurrents plummeting far below predicted values from absorption. Decreasing the amount of zinc during post-treatment leads to improved mobility but marginal improvement in device performance (PCE = 0.30%). By incorporating CIS into a porous TiO2 network, we saw an overall drastic improvement in device performance, reaching a PCE of 1.16%, mainly from an increase in short circuit current density (Jsc) and fill factor (FF) and a 10-fold increase in internal quantum efficiency (IQE). We have determined that by moving from a bilayer to a bulk heterojunction architecture, we have reduced the trap-assisted recombination as seen in changes in the ideality factor, the intensity dependence of the photocurrent and transient photocurrent (TPC) and photovoltage (TPV) characteristics.

The PR status of the originating cell of ER/PR-negative mouse mammary tumors.

Progesterone receptor (PR) is usually co-localized with estrogen receptor (ER) in normal mammary cells. It is not known whether ER/PR-negative human breast cancer arises from an ER/PR-negative cell or from an ER/PR-positive cell that later lost ER/PR. Using intraductal injection of a lentivirus to deliver both an oncogene (ErbB2) and a floxed green fluorescent protein (GFP) in PR(Cre/+)mice, whose Cre gene is under the control of the PR promoter, we were able to trace the PR status of the infected cells as they progressed to cancer. We found that the resulting early lesions stained negative for PR in most of the cells and usually retained GFP. The resulting tumors lacked ER and PR, and 75% (15/20) of them retained the GFP signal in all tumor cells, suggesting PR was never expressed throughout the evolution of a majority of these tumors. In conclusion, our data demonstrate that ErbB2-initiated ER/PR-negative mammary tumors primarily originate from the subset of the mammary epithelium that is negative for PR and probably ER as well. These findings also provide an explanation for why antihormonal therapy fails to prevent ER-negative breast cancers.

A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study.

Treatment of carriers of the CYP2C19*2 allele and ABCB1 TT genotype with clopidogrel is associated with increased ischemic complications after percutaneous coronary intervention (PCI). We sought to evaluate a pharmacogenomic strategy among patients undergoing PCI for ST-elevation myocardial infarction (STEMI), by performing a randomized trial, enrolling 102 patients. Point-of-care genetic testing for CYP2C19*2, ABCB1 TT and CYP2C19*17 was performed with carriers of either the CYP2C19*2 allele or ABCB1 TT genotype randomly assigned to a strategy of prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg daily for 6 days then 75 mg daily). The primary end point was the proportion of at-risk carriers exhibiting high on-treatment platelet reactivity (HPR), a marker associated with increased adverse cardiovascular events, after 1 month. Fifty-nine subjects (57.8%) were identified as carriers of at least one at-risk variant. Treatment with prasugrel significantly reduced HPR compared with clopidogrel by P2Y12 reaction unit (PRU) thresholds of >234 (0 vs 24.1%, P=0.0046) and PRU>208 (3.3 vs 34.5%, P=0.0025). The sensitivity of point-of-care testing was 100% (95% CI 88.0-100), 100% (86.3-100) and 96.9% (82.0-99.8) and specificity was 97.0% (88.5-99.5), 97.1% (89.0-99.5) and 98.5% (90.9-99.9) for identifying CYP2C19*2, ABCB1 TT and CYP2C19*17, respectively. Logistic regression confirmed carriers as a strong predictor of HPR (OR=6.58, 95% CI 1.24-34.92; P=0.03). We confirmed that concurrent identification of three separate genetic variants in patients with STEMI receiving PCI is feasible at the bedside. Among carriers of at-risk genotypes, treatment with prasugrel was superior to an augmented dosing strategy of clopidogrel in reducing HPR.

Clinical trial transparency and orphan drug development: recent trends in data sharing by the pharmaceutical industry.

BACKGROUND: Data sharing from clinical trials can be key to the development and approval of medicines for rare diseases. Many events during the first half of 2013 have contributed to the movement for increased transparency. These include the development of the European Medicines Agency's new data publication policy, the creation of the AllTrials petition and GlaxoSmithKline's choice to sign it, the launch of GlaxoSmithKline's system for access to patient-level clinical trial data and Roche's commitment to create a similar system, the release of results from the Yale University Open Data Access project's first medicine analysis for Medtronic, and the creation of the Reg4All website. AIMS/OBJECTIVES: This paper summarises major developments in clinical trial transparency between January and June 2013 and analyses the composition of datasets released by GlaxoSmithKline. METHODS: GlaxoSmithKline's database of available trials was tabulated and graphs of relevant trial characteristics were produced. RESULTS/CONCLUSIONS: Due to current transparency initiatives, it is likely that much more data will be made available over the next few years through systems similar to GlaxoSmithKline's. Although some aspects of GlaxoSmithKline's model could limit its usefulness, the data currently listed is diverse and could be promising for researchers interested in rare disease treatment.

ST segment resolution in patients with tenecteplase-facilitated percutaneous coronary intervention versus tenecteplase alone: Insights from the Combined Angioplasty and Pharmacological Intervention versus Thrombolysis ALone in Acute Myocardial Infarction (CAPITAL AMI) trial.

BACKGROUND: Compared with fibrinolysis alone, fibrinolysis followed by immediate percutaneous coronary intervention (PCI) reduced clinical events in the Combined Angioplasty and Pharmacological Intervention versus Thrombolysis ALone in Acute Myocardial Infarction (CAPITAL AMI) study. It is unclear whether the benefits go beyond achieving epicardial reperfusion. OBJECTIVES: To determine the differences in ST segment resolution (STR) among patients treated with tenecteplase (TNK)-facilitated PCI compared with patients treated with TNK alone. METHODS AND RESULTS: A formal ST segment analysis was conducted on the 170 patients with ST elevation myocardial infarction in the CAPITAL AMI trial: 86 patients treated with TNK-facilitated PCI were compared with 84 patients who were treated with TNK alone. Epicardial flow measured by percentage with Thrombolysis In Myocardial Infarction (TIMI) 3 flow improved from 52% (pre-PCI) to 89% (post-PCI) in those assigned to facilitated PCI. ST segment resolution was stratified by complete (70% or greater), partial (less than 70% to 30%) or no (less than 30% to 0%) resolution. The baseline mean ST segment elevation was 11.3+/-7.5 mm in the facilitated PCI patients and 11.8+/-7.1 mm in patients with TNK alone (P=0.66). Complete STR in the facilitated PCI patients versus the TNK-alone patients was present in 55.6% versus 54.6%, respectively (P=0.58) at 180 min and 62.0% versus 55.3% (P=0.64), respectively at day 1. The mean STR at 180 min and day 1 were similar in patients who experienced death, reinfarction, recurrent unstable ischemia or stroke at six months compared with patients who remained event free: 56.3% versus 64.6% at 180 min (P=0.40); and 67.7% versus 67.6% at day 1 (P=0.99), respectively. CONCLUSIONS: TNK-facilitated PCI did not demonstrate differences in ST segment resolution compared with TNK alone, despite improvement in epicardial flow after PCI. Further studies are required to clarify these findings.

Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients.

BACKGROUND: Serum thyroglobulin (Tg) is the marker of differentiated thyroid cancer after initial treatment and TSH stimulation increases its sensitivity for the diagnosis of recurrent disease. AIM: The goal of the study is to compare the diagnostic values of seven methods for serum Tg measurement for detecting recurrent disease both during L-T4 treatment and after TSH stimulation. METHODS: Thyroid cancer patients who had no evidence of persistent disease after initial treatment (total thyroidectomy and radioiodine ablation) were studied at 3 months on L-T4 treatment (Tg1) and then at 9-12 months after withdrawal or recombinant human TSH stimulation (Tg2). Sera with anti-Tg antibodies or with an abnormal recovery test result were excluded from Tg analysis with the corresponding assay. The results of serum Tg determination were compared to the clinical status of the patient at the end of follow-up. RESULTS: Thirty recurrences were detected among 944 patients. A control 131I total body scan had a low sensitivity, a low specificity, and a low clinical impact. Assuming a common cutoff for all Tg assays at 0.9 ng/ml, sensitivity ranged from 19-40% and 68-76% and specificity ranged from 92-97% and 81-91% for Tg 1 and Tg2, respectively. Using assays with a functional sensitivity at 0.2-0.3 ng/ml, sensitivity was 54-63% and specificity was 89% for Tg1. Using the two methods with a lowest functional sensitivity at 0.02 and 0.11 ng/ml resulted in a higher sensitivity for Tg1 (81% and 78%), but at the expense of a loss of specificity (42% and 63%); finally, for these two methods, using an optimized functional sensitivity according to receiver operating characteristic curves at 0.22 and 0.27 ng/ml resulted in a sensitivity at 65% and specificity at 85-87% for Tg1. CONCLUSION: Using an assay with a lower functional sensitivity may give an earlier indication of the presence of Tg in the serum on L-T4 treatment and may be used to study the trend in serum Tg without performing any TSH stimulation. Serum Tg determination obtained after TSH stimulation still permits a more reliable assessment of cure and patient's reassurance.

Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors.

EpCam is an epithelial adhesion molecule expressed in a broad range of carcinomas. Clinical trials with specific humanized anti-EpCam antibodies have shown promising results and have been inaugurated in renal cell carcinoma (RCC) therapy. To study the EpCam expression profile, primary renal cell neoplasms as well as corresponding metastases were evaluated by immunohistochemistry in tissue microarrays. EpCam expression in oncocytomas and chromophobe RCCs was determined on conventional large sections. Moderate or strong EpCam expression was found in eighteen percent of clear cell (n=147), 75% of chromophobe (n=12), and 55% of papillary RCCs (n=20), but not in oncocytomas (n=3). On large sections, 90% of chromophobe RCCs (n=20) showed a strong and homogeneous positivity, whereas oncocytomas (n=15) revealed EpCam positivity in single tumor cells or small clusters. Fourteen percent of RCC metastases (n=97) showed EpCam expression. Patients with EpCam expressing clear cell RCC showed a trend toward a better prognosis in a Cox regression analysis including stage, grade, and necrosis. The data suggest EpCam as a potential therapeutic target in a subset of patients with RCC. In addition, expression patterns of EpCam could become a helpful tool in the discrimination of chromophobe RCC and oncocytoma.

Relevance of nuclear and cytoplasmic von hippel lindau protein expression for renal carcinoma progression.

Alterations of the von Hippel-Lindau tumor-suppressor gene (VHL) on 3p25-p26 are frequent in clear-cell renal-cell carcinoma (RCC). The VHL protein (pVHL) is implicated in cell-cycle control and gene regulation, and requires transcription-dependent nuclear-cytoplasmic trafficking for its function. There are two biologically active VHL protein isoforms: pVHL(30) and pVHL(19). To study prevalence, subcellular expression and biological significance of pVHL in renal tumors, tissue microarrays with renal-cell carcinomas were immunohistochemically examined for pVHL expression. Antibodies against both protein isoforms (anti-pVHL(30)/pVHL(19)) and against pVHL(30) (anti-pVHL(30); Ig33) were used. The anti-pVHL(30)/pVHL(19) antibody showed nuclear and cytoplasmic pVHL expression, whereas the anti-pVHL(30) antibody (Ig33) detected cytoplasmic pVHL expression, suggesting that the distribution of VHL protein isoforms varies in the nuclear and cytoplasmic compartments of renal tumors. There were 175 of 398 primary clear-cell RCCs (44%) with both nuclear and cytoplasmic pVHL expression. Seventy-seven clear-cell RCCs (19%) showed only nuclear, 22 (6%) showed only cytoplasmic, and 124 tumors (31%) showed no pVHL expression. Notably, combined nuclear and cytoplasmic pVHL expression was associated with low histological grade (P < 0.0001), early tumor stage (P < 0.01), and better prognosis (P < 0.01). These results imply that alteration of subcellular pVHL trafficking is of potential relevance for the biological behavior of clear-cell RCC.

NQ-Y15 inhibits the calcium mobilization by elevation of cyclic AMP in rat platelets.

2-1(4-Cyanophenyl)aminol-3-chloro-1,4-naphthalenedione (NQ-Y15) is a dual action drug which acts as a thromboxane A2 (TXA2) synthase inhibitor and TXA2/PGH2 receptor antagonist. In the present study, we examined the effects of NQ-Y15 on Ca2+ mobilization, which is the common event in various types of platelet activation, in arachidonic acid (AA)-stimulated rat platelets. The elevation of cytosolic Ca2+ concentration ([Ca2+]i) induced by AA was inhibited by NQ-Y15 in a concentration-dependent manner. This inhibition-effect of NQ-Y15 was found to be based on the suppression of the rise in [Ca2+]i by the inhibition of both Ca2+ release from internal stores and Ca2+ influx from the extracellular space. Our successive trial was focused on the role of cyclic AMP (cAMP) in the action of NQ-Y15, because cAMP was reported to be increased by dual action drugs such as picotamide and to inhibit the increase in [Ca2+]i. NQ-Y15 was confirmed to increase cAMP in AA-stimulated rat platelets. These results suggested that NQ-Y15 might inhibit the rise in [Ca2+]i in AA-treated rat platelets by increasing cAMP, which is involved in the inhibition of platelet activation.

Brazilin augments cellular immunity in multiple low dose streptozotocin (MLD-STZ) induced type I diabetic mice.

Brazilin, an active principle of Caesalprenia sappan, was examined for its immunopotentiating effects in multiple low dose streptozotocin (MLD-STZ) induced type diabetic mice. Brazilin was intraperitoneally administered for 5 consecutive days to MLD-STZ induced type I diabetic mice. Delayed type hypersensitivity, Con A-induced proliferation of splenocytes and mixed lymphocyte reaction, which had been decreased in diabetic mice, were significantly recovered by the administration of brazilin. Brazilin increased IL-2 production without affecting suppressor cell activity. Con A-induced and IL-2-induced expression of high affinity IL-2 receptors were also enhanced by brazilin. These results indicate that brazilin augments cellular immune responses, which are suppressed in the MLD-STZ induced type I diabetic mice, by increasing IL-2 production and responsiveness of immune cells to IL-2.

Effects of brazilin on GLUT4 recruitment in isolated rat epididymal adipocytes.

The effects of brazilin on glucose transport into isolated rat epididymal adipocytes were investigated. Brazilin increased [3H]2-deoxy-D-glucose uptake, which was characterized by an increase in Vmax with no effect on the Km value. Phenylarsine oxide, which inhibits the translocation of glucose transporters, decreased brazilin-stimulated glucose transport to the basal level. The inhibition of phosphatidylinositol 3-kinase (PI3-kinase) with wortmannin also blocked brazilin-stimulated glucose transport. Western blot analysis with an anti-GLUT4 antibody revealed that brazilin increased the translocation of GLUT4 from intracellular pools to the plasma membrane. Brazilin, in combination with phorbol ester, showed an additive effect on glucose transport. The stimulating effect of phorbol ester on glucose transport was inhibited by staurosporine, but the effect of brazilin remained unchanged. Protein kinase C activity was not influenced by brazilin treatment. The inhibition of protein synthesis showed no effect on brazilin-stimulated glucose transport, and GLUT4 content in the total membrane fraction was not altered as a result of treatment with brazilin for 4 hr. Metabolic labeling of GLUT4 with [35S]methionine showed that de novo synthesis of GLUT4 was not induced by brazilin. These data suggest that brazilin may increase glucose transport by recruitment of GLUT4 from intracellular pools to the plasma membrane of adipocytes via the activation of PI3-kinase. However, the effect of brazilin may not be mediated by GLUT4 synthesis and protein kinase C activation.

Effects of Brazilin on induction of immunological tolerance by sheep red blood cells in C57BL/6 female mice.

Brazilin was examined for its effects on the induction of immunological tolerance. Brazilin was administered to C57BL/6 female mice for 2 consecutive days before the immunization with high dose SRBC (10(9) cells) which can produce immunological tolerance. Delayed type hypersensitivity, IgM plaque forming cells, ConA induced IL-2 production and mitogen- or antigen-induced proliferation of lymphocytes were measured as evaluation parameters. Administration of brazilin prior to immunization could keep the DTH and IL-2 production almost optimally immunized levels. Brazilin also inhibited the elevation of non-specific suppressor cell activity. ConA induced proliferation of splenocytes in high dose SRBC immunized mice was significantly decreased by pretreatment of brazilin. And this might be one of the reason for augmentation of DTH by brazilin. However, IgM plaque forming cells were not affected by the treatment of brazilin. These results indicate that brazilin prevents the induction of immunological tolerance caused by high dose SRBC by suppressing the elevation of suppressor cell activity and by inhibiting the decrease in IL-2 production in C57BL/6 female mice.

Effects of Brazilin on the phospholipase A2 activity and changes of intracellular free calcium concentration in rat platelets.

Brazilin (7,11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6 H)-tetrol) inhibited thrombin-,collagen- and ADP-induced aggregation of washed rat platelets. Thrombin- and collagen-induced ATP release were also inhibited by brazilin in a concentration-dependent manner. Brazilin inhibited the formation of platelet thromboxane A2 caused by thrombin, whereas it had no effect on the prostaglandin D2 formation. Brazilin inhibited [3H]-arachidonic acid liberation from membrane phospholipids of thrombin-stimulated platelets. Brazilin inhibited the rise of intracellular free calcium caused by thrombin. These results indicate that the inhibition of phospholipase (PLA2) activity and [Ca2+]i elevation might be at least a part of antiplatelet mechanism of brazilin.

Brazilin inhibits activities of protein kinase C and insulin receptor serine kinase in rat liver.

Hypoglycemic action of brazilin was found to be based on the improvement of peripheral glucose utility, and this action might be correlated with the insulin action pathway. In the present study we investigated the effect of brazilin on the insulin receptor autophosphorylation, protein kinase C (PKC), protein phosphatase and insulin receptor serine kinase in order to confirm whether the hypoglycemic mechanism is concerned with insulin action pathway. Brazilin was found to inhibit PKC and insulin receptor serine kinase, which are involved in the regulation of insulin signal pathway. But any significant effect was not shown on insulin receptor tyrosine kinase activity, autophosphorylation and phosphatase activity. These findings suggest that brazilin might enhance insulin receptor function by decreasing serine phosphorylation, which might mediate hypoglycemic effect of brazilin.

Effects of brefeldin-A on Golgi morphology in human cultured fibroblasts observed in three-dimensional stereo scanning electron microscopy.

Brefeldin A (BFA) has been reported to cause disassembly of the Golgi. We have used three-dimensional (3-D) high-resolution scanning electron microscopy (HRSEM) to investigate these effects in human skin fibroblast cells. The spontaneous reassembly during prolonged exposure to BFA and some effects of forskolin were observed. A BFA concentration of 5 micrograms/ml caused Golgi complexes to become vesicular, resulting in a progressive decrease in the size of the Golgi. Morphologic changes were visible within 2 min of BFA incubation, and by 30 min no identifiable Golgi could be found. Spontaneous reassembly of the Golgi apparatus upon the removal of the BFA or with continued long-term exposure with BFA could not be confirmed. Preliminary experiments with forskolin were not effective in reversing or inhibiting the effects of BFA in human fibroblast cells grown in culture. This inability for spontaneous reassembly and nonreversal by forskolin may reflect a differential effect of BFA in various cell types. HRSEM has proven to be useful for observing 3-D morphologic effects of BFA in Golgi.

Thin-film grating polarizer.

The deexcitation of guided modes in a thin-film planar dielectric waveguide is considered. On the film-cover interface is etched an ordinary diffraction grating whose wave number is such that one radiation beam in the substrate alone is generated. For a specified radiation direction the p-polarized radiation vanishes selectively. This phenomenon is used in the development of a polarizer whose output is predominantly in the p polarization. The sensitivity of the performance of the polarizer to small deviations in the design parameters is also investigated.