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The water and ethanol extracts of Cynanchum Komaroviiu could obviously relieve the cough caused by the irritation of ammonia water in mice, increase secretion of the respiratory tract and promote expectoration. They could also alleviate the asthma induced by histamine and acetylcholine chloride in guinea pigs.
Treatment with glycoprotein (GP) IIb/IIIa inhibitors in combination with aspirin and clopidogrel have become essential therapeutic strategies during invasive procedures and coronary events. However, the ideal monitoring test for the effects of these treatments is still missing. Therefore, we investigated the new Platelet Adhesion Assay (PADA) for its sensitivity in characterizing antiplatelet therapy. Five healthy volunteers were studied before and after a single dose of aspirin (500 mg). Samples were spiked in vitro with increasing doses of abciximab (0, 0.25, 1, 3 microg/mL), eptifibatide (0, 0.25, 1, 2 microg/mL), and AR-C 69931 MX (1 microg/mL) in citrated and hirudinized whole blood. The adhesion index (AI), as the characteristic parameter of the PADA test, decreased in a dose-dependent fashion for abciximab and eptifibatide. Variable effects between the different anticoagulants were shown for eptifibatide. Aspirin showed no additional effect, while inhibition by AR-C 69931 MX was demonstrated in hirudinized blood only. We concluded that different levels of GPIIb/IIIa inhibitors and adenosine diphosphate-receptor inhibition could be assessed with the PADA test, although different anticoagulants led to different results. The suitability of this test for daily use will have to be elucidated in further patient studies.
The aim of the present study was to evaluate the effects of complementary insulin therapy, consisting of a single dose of 1 to 8 units of shortacting insulin before each meal (4-6x daily) and sometimes at 02.30 h, on concentrations of serum lipids, lipoproteins and apoproteins in type 2 (non-insulin-dependent) diabetic patients, unsatisfactorily controlled either by oral hypoglycemic agents (OHA) or by longacting insulin 1-2x daily (INS 1-2). Compared means +/- SD. Patients on INS 1-2 (n = 82) had better baseline glycemic control than patients on OHA (n = 68) (HbAlc: 9.33 +/- 1.76% vs. 10.59 +/- 1.83%, p < 0.001 and fructosamine: 3.34 +/- 0.74 mmol/l vs. 3.85 +/- 0.84 mmol/l, p < 0.001) and serum triglyceride concentrations (3.03 +/- 2.05 mmol/l vs. 4.95 +/- 4.48 mmol/l, p < 0.001), in spite of longer duration of diabetes (13.35 +/- 8.07 years vs. 10.1 +/- 6.9 years, p < 0.001). After 8-10 weeks of complementary insulin therapy, OHA patients (n = 33) improved both the glycemic control (HbA1c: 10.5 +/- 1.78% vs. 9.0 +/- 1.75%, p < 0.001) and fructosamine: 4.0 +/- 0.85 mmol/l vs. 3.5 +/- 0.76 mmol/l, p < 0.001) and most of the lipid parameters (decreased serum triglyceride: 5.8 +/- 5.64 mmol/l vs. 3.6 +/- 4.69 mmol/l, p < 0.001, total cholesterol/HDL-cholesterol: 6.8 +/- 3.13 vs. 5.6 +/- 2.23, p < 0.01 and increased HDL-cholesterol: 1.0 +/- 0.30 mmol/l vs. 1.2 +/- 0.30 mmol/l, p < 0.001, apo AI: 1.6 +/- 0.26 g/l vs. 1.8 +/- 0.28 g/l, p < 0.001, LpAI particles: 0.6 +/- 0.1 g/l vs. 0.7 +/- 0.12 g/l, p < 0.001 and LDL-cholesterol/apo B: 2.1 +/- 0.67 vs. 2.7 +/- 0.67, p < 0.001). In patients previously on INS 1-2x (n = 34), complementary insulin therapy with reduced dose of insulin per day (49.6 +/- 22.5 U/d vs. 36.6 +/- 13.3 U/d, p < 0.001) did not further improve glycemic control but improved the number of proatherogenic and antiatherogenic lipoprotein particles (decreased apo B: 1.7 +/- 0.52 g/l vs. 1.5 +/- 0.94 g/l, p < 0.01, apo AI/Lp AI: 2.9 +/- 1.01 vs. 2.3 +/- 0.98, p < 0.01 and increased Lp AI particles: 0.6 +/- 0.10 g/l vs. 0.7 +/- 0.12 g/l, p < 0.0001); BMI also decreased (29.4 +/- 4.28 kg/m2 vs. 28.9 +/- 4.24 kg/m2, p < 0.05). These results demonstrate that complementary insulin therapy probably induces antiatherogenic lipoprotein changes in NIDDM patients previously treated by either OHA or INS 1-2x. Thus, this type of therapy should be used more often and start earlier, and should be preferred to longacting insulins.
PURPOSE: Androgen-independent prostate cancer (AI-PC) is characterized by a higher invasive potential compared to hormone-responsive prostate cancer. A therapeutic option for AI-PC should thus be targeted to suppress not only cell proliferation, but also the invasive ability of the cells. Here, we investigated the effect of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ('IRESSA', ZD1839) on EGF-stimulated invasion and proliferation in two androgen-independent prostate cancer cell lines PC3 and DU145. In addition, we determined the effect of the compound on EGF-stimulated PI3 K/AKT pathway activation, in view of the key role exerted by this pathway in carcinoma cell invasion. METHODS: Cell proliferation was determined by thymidine incorporation in the nuclei. Cell cycle analysis was performed by flow cytometry. Invasion through matrigel in vitro was measured by using Boyden chambers. PI3 K activity was measured by immunokinase assay and AKT phosphorylation was evaluated by Western blot analysis. RESULTS: Gefitinib inhibits invasion through matrigel and collagen in response to EGF in both cell lines. In addition, we confirm the inhibitory effect of the compound on basal and EGF-induced cell proliferation. Such an effect was accompanied by accumulation of the cells in the G0/G1 phase of the cell cycle. The effect of the compound is due, as expected, to suppression of EGF-induced autotransphosphorylation of EGFR. In addition, we demonstrate here that gefitinib inhibits EGF-induced activation of PI3 K/AKT pathway in both cell lines. CONCLUSION: Overall, our results demonstrate that gefitinib is able to suppress invasion and proliferation of AI-PC cells by suppressing EGF-stimulated activation of the PI3 K/AKT pathway and support a possible use of the drug in the treatment of advanced PC to limit not only proliferation but also invasion to other districts.
Energy optimizations are carried out on the N-terminal fragment of trichorzianine in comparison to that of alamethicin. The results indicate that the helical character of the (Ac...Pro13) sequence of trichorzianine (TA IIIc) is essentially alpha with a bend in the helix axis in the end proline region, a structure comparable to the optimal alpha-helical structure of the corresponding segment (Ac...Pro14) of alamethicin AI. However, two weak n----n + 3 interactions coexist in trichorzianine with the alpha-helical n----n + 4 hydrogen bonds. The possible role of the glutamine side-chains in pairing such segments together is considered.
This work evaluates the degradation of three adhesive/composite systems (Tenure/Marathon One. Scotchbond Multi-Purpose/Z100 and Optibond/Herculite XRV) upon immersion in 75% ethanol solution and in an artificial saliva (Moi-Stir). Shear bond strength (SBS) and diametral tensile strength (DTS) specimens were employed for this study. For the SBS specimens, the bonded interface and composite were exposed to food and oral simulating fluids at 37 degrees C for up to 30 days. A similar control series was stored in air. DTS specimens were stored in 75% ethanol at 37 degrees C for up to 30 days. The SBS specimens were sheared to failure. Small quantities of bonding resin were removed from the tooth side of the fractured surface and from the non-fractured fractured end of the composite for Fourier transform infrared microscopic evaluation. Similar scrapings were taken from DTS specimen surfaces. The infrared absorbance intensity (AI) of the major peaks was measured as a function of storage time and ratioed against the aromatic C = C (1609.4 cm-1) peak. The data were analysed using ANOVA and the Tukey LSD test. The AI of major peaks was similar for the materials stored either in air or in Moi-Stir for all testing periods. Storage in ethanol caused the AI of aliphatic C = C (1638 cm-1) and of O-H (approximately 3500 cm-1) bonds to significantly decrease (30-50%) for specimens of bonding resin while the AI of C = O bonds (1730 cm-1) increased (60-120%).(ABSTRACT TRUNCATED AT 250 WORDS)
A number of trials have studied the value of aromatase inhibitors (AIs) for the adjuvant treatment of early hormone-responsive postmenopausal breast cancer. Three different AIs have been used and they have been compared as initial treatment (two trials) or after 2-3 years of tamoxifen (four trials), in both cases against a standard arm of 5 years of tamoxifen. In addition, two trials have evaluated AIs against no treatment after 5 years of tamoxifen. In all circumstances, the AIs have demonstrated superior efficacy. However, no results are currently available for the key question, that is - is it better to start initially with an AI or use it sequentially after 2 years of tamoxifen? Here, we review the trial results and present two models, which address this issue. The models clearly show that early treatment with an AI is superior to using it after 5 years of tamoxifen. They also favour an upfront strategy to sequencing after 2 years of tamoxifen, but in this case the differences are small and model-dependent. A key question is whether AIs have substantially better efficacy than tamoxifen for ER-positive-PgR-negative tumours, where the data are currently contradictory. A mechanism explaining why greater efficacy might be so is proposed. Further results from ongoing trials will be needed to resolve this issue.
In recent years, several major trials have studied aromatase inhibitors (AIs)/inactivators as adjuvant therapy for postmenopausal women with early-stage breast cancer. The AIs have demonstrated improved efficacy compared with 5 years of tamoxifen when used as initial therapy or when used sequentially after 2-3 years. They also improve outcomes when used after 5 years of adjuvant tamoxifen in this patient population. In all cases, AIs improve disease-free survival compared with the standard 5 years of adjuvant tamoxifen, leading to a reassessment of the optimal adjuvant endocrine therapy for postmenopausal patients with breast cancer. The American Society of Clinical Oncology now recommends the inclusion of an AI into the adjuvant regimen at some point for most postmenopausal patients with hormone receptor-positive early-stage breast cancer. However, the optimal duration of AI therapy and the comparative efficacy and safety of the alternative strategies for their incorporation remain matters of debate. In addition, the long-term impact of AIs on other organs, such as the bone and cardiovascular systems, is not completely understood, and longer follow-up of patients from these original trials as well as carefully planned future trials with appropriate substudies are essential to determine the optimal endocrine treatment strategy.
OBJECTIVE: To study the role of heat shock protein 90 (HSP 90) in the formation of hyperdynamic circulation of portal hypertensive rats. METHODS: Animal model of portal hypertension was established by partial ligation of the portal vein among 20 SD rats (group P). Ten rats underwent sham operation (group S) Four weeks after the operation, the rats were killed and their mesenteric arteries and portal veins were obtained. The expression of HSP 90 in the portal veins and part of the superior mesenteric arteries was detected by Western blotting. Another mesenteric arteries underwent continuous perfusion with methoxamine (MTX, 30 and 100 micro mol/L) or acetylcholine (Ach). The perfusion pressure was monitored by a sensor. The concentration-response curves were examined in response to MTX and Ach infusion respectively. Then geldanamycin (GA) was infused; responses to MTX and ACh were repeated as described above. The endothelia of these arteries was denuded. After endothelial denudation was achieved, response to sodium nitroprusside (SNP) was examined. RESULTS: The expression of HSP 90 was much stronger in the group P than in the group S. The perfusion pressure of the mesenteric artery of the group P was 13.32 mm Hg +/- 0.55 mm Hg, significantly lower than that of the group S (17.33 mm Hg +/- 0.57 mm Hg, n = 10, P < 0.001). After the addition of MTX, the perfusion pressure of the mesenteric artery of the group P was 141.9 mm Hg +/- 7.6 mm Hg, significantly lower than that of the group S (181.1 mm Hg +/- 16.2 mm Hg, n = 8, P < 0.001). GA and 30 micro mol/L or 100 micro mol/L MTX were added successively into the perfusion fluid for the mesenteric superior artery of the group P, then the perfusion pressure became 106.7 mm Hg +/- 7.5 mm Hg or 124.9 mm Hg +/- 5.5 mm Hg, significantly higher than those of the mesenteric superior artery of the group P without addition of GA (60.9 mm Hg +/- 4.3 mm Hg, n = 5, P < 0.05 and 98.7 mm Hg +/- 4.7 mm Hg, n = 5, P < 0.05). GA and 100 micro mol/L MTX were added successively into the perfusion fluid for the mesenteric superior artery of the group S, the perfusion pressure became 151.2 mm Hg +/- 7.1 mm Hg, not significantly different from that of the mesenteric superior artery of the group S without addition of GA (149.8 mm Hg +/- 5.6 mm Hg, P > 0.05). With the addition of GA in advance, the ACh-dependent vasorelaxation of the isolated perfused rat mesenteric artery was significantly attenuated in comparison with the mesenteric artery without addition of GA into whose perfusion fluid (P < 0.05). However, GA did not affect the vasodilation of the ensothelium-neduded mesenteric artery in response to SNP. CONCLUSION: HSP90 is responsible for the hyperdynamic circulation in the portal hypertensive rats.
OBJECTIVE: To study the preventive effect of recombinant human interferon alpha-2b for nasal spray against SARS and other common respiratory viral infections by serum-epidemiological method. METHODS: A randomized, placebo-controlled, double-blind field trial study in populations with 14,391 persons from SARS prevalent cities or provinces in China during May-Jun, 2003 and Dec-Apr, 2004. Interferon alpha-2b was given twice per day, once 9 x 10(5) IU by nasal spray for 5 days. Serum samples were taken at 15 days after last administration. Serological tests included SARS IgG antibody and IgM antibodies against influenza B, parainfluenza virus types 1-3, adenovirus type 3, 7 and respiratory syncytial virus by using commercial ELISA kits. RESULTS: No statistically significant difference in serum SARS IgG antibody positive rate was found between the interferon and control groups among 2,757 serum samples. On the other hand, after using interferon, all four respiratory viruses (parainfluenza virus types 1-3 influenza B, adenovirus types 3, 7 and respiratory syncytial virus) in interferon group had lower IgM antibody positive rates than those in control group. Among them there were statistically significant differences between the interferon and control groups for parainfluenza virus, influenza B and adenovirus. The preventive efficacy of interferon against four respiratory viruses was different, from high to low, the rank was Flu B (66.76%), parainfluenza types 1-3 (66.75%), RSV (39.61%) and adenovirus (32.86%). The average preventive efficacy was 50.27%. CONCLUSION: The recombinant human interferon alpha-2b for nasal spray could decrease the rates of common respiratory viruses infection in the selected population.
Hepatitis C virus (HCV) is a pathogen that is of great medical significance in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Although the HCV proteins have been intensively investigated over the past decade, the biochemical functions of the NS4B protein are still largely unknown. To investigate NS4B as a potential causative agent of liver disease, transgenic mice expressing the NS4B protein in liver tissue were produced. The transgenic animals were phenotypically similar to their normal littermates for up to 18 months of age. Our results suggest that the HCV NS4B protein is not directly cytopathic or oncogenic in our transgenic mice model.
Cell-to-cell communication in bacteria is mediated by quorum-sensing systems (QSS) that produce chemical signal molecules called autoinducers (AI). In particular, LuxS/AI-2-dependent QSS has been proposed to act as a universal lexicon that mediates intra- and interspecific bacterial behavior. Here we report that the model organism Bacillus subtilis operates a luxS-dependent QSS that regulates its morphogenesis and social behavior. We demonstrated that B. subtilis luxS is a growth-phase-regulated gene that produces active AI-2 able to mediate the interspecific activation of light production in Vibrio harveyi. We demonstrated that in B. subtilis, luxS expression was under the control of a novel AI-2-dependent negative regulatory feedback loop that indicated an important role for AI-2 as a signaling molecule. Even though luxS did not affect spore development, AI-2 production was negatively regulated by the master regulatory proteins of pluricellular behavior, SinR and Spo0A. Interestingly, wild B. subtilis cells, from the undomesticated and probiotic B. subtilis natto strain, required the LuxS-dependent QSS to form robust and differentiated biofilms and also to swarm on solid surfaces. Furthermore, LuxS activity was required for the formation of sophisticated aerial colonies that behaved as giant fruiting bodies where AI-2 production and spore morphogenesis were spatially regulated at different sites of the developing colony. We proposed that LuxS/AI-2 constitutes a novel form of quorum-sensing regulation where AI-2 behaves as a morphogen-like molecule that coordinates the social and pluricellular behavior of B. subtilis.
BACKGROUND AND PURPOSE: Intravenous tissue plasminogen activator (tPA) administered within 3 hours of symptom onset is the first available effective therapy for acute ischemic stroke (AIS). Few data exist, however, on its use in very elderly patients. We examined the characteristics, complications, and short-term outcome of AIS patients aged >/=80 years treated with tPA. METHODS: Patients aged >/=80 years (n=30) were compared with counterparts aged <80 years (n=159) included in the tPA Stroke Survey, a US retrospective survey of 189 consecutive AIS patients treated with intravenous tPA at 13 hospitals. RESULTS: Risk of intracerebral hemorrhage (fatal, symptomatic, and total) was 3%, 3%, and 7% in the elderly age group and 2%, 6%, and 9%, respectively, in their younger counterparts (P=NS for all comparisons). Likelihood of favorable outcome, defined as modified Rankin score 0 to 1, National Institutes of Health Stroke Scale score </=5, or marked improvement by hospital discharge, was comparable between groups (37%, 54%, and 43% versus 30%, 54%, and 43%, respectively; P=NS for all comparisons). Elderly patients were more likely to be treated by stroke specialists (87% versus 60%; P=0.005) and less likely to have an identified protocol deviation (13% versus 33%; P=0.03). Elderly patients were discharged more often to nursing care facilities (17% versus 5%; P=0.003). In logistic regression models there were no differences in odds ratio for favorable or poor outcome, other than tendency for higher in-hospital mortality in elderly patients (odds ratio, 2.8; 95% CI, 0.81 to 9.62; P=0.10). CONCLUSIONS: Among AIS patients treated with intravenous tPA, age-related differences in characteristics and disposition were identified. No evidence for withholding tPA treatment for AIS in appropriately selected patients aged >/=80 years was identified.
BACKGROUND: Plasma adiponectin levels increase after the administration of glimepiride. This unique effects would also be expected to improve other adipocytokines and have anti-atherosclerotic action in patients with metabolic syndrome. METHODS: Thirty-four patients with type 2 diabetes mellitus who were administrated glibenclamide were randomly divided into two groups. In 20 patients glibenclamide was changed to glimepiride (GP group), and the administration of glibenclamide (GB group) was continued in 14 patients. Twelve patients receiving insulin therapy (INS group) were enrolled for comparison. The levels of plasma adiponectin, high sensitive-CRP, TNF-alpha, interleukin-6, homeostasis model assessment-insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity (baPWV) and augmentation index (AI) were measured before and 28 weeks after the therapy. RESULTS: HOMA-IR in the GP group was significantly decreased compared to the GB group. Plasma adiponectin levels were significantly increased in the GP group but not in the other groups. TNF-alpha, interleukin-6 and high sensitive-CRP levels were significantly decreased in the GP group, but not in the other groups. The baPWV and AI levels did not change in either the GB or the INS group, but were significantly decreased in the GP group. CONCLUSIONS: Glimepiride appears to improve insulin resistance and atherosclerotic disorders.
OBJECTIVE: To investigate whether apoptosis could be induced by preoperative chemotherapy in breast cancer patients, and determine if it is correlated with clinical response and patients' survival. METHODS: Apoptosis was assayed by in situ DNA end labeling and receptors for estrogen and progesterone were examined immunohistochemically. Comparison of the differences in apoptotic index (AI) and clinical response was made between patients received preoperative chemotherapy and those did not, using the one tailed Student's t-test. The Kaplan-Meier method was utilized to calculate relapse-free and overall survival time. Cox proportional hazards model was used to conduct multivariate analysis of prognostic factors and differences in overall survival and relapse-free survival after adjustment for other variables. RESULTS: Apoptosis was induced by preoperative chemotherapy, especially in lymph node positive patients. Post-chemotherapy AI correlated with better clinical response and increased patient survival, including relapse (disease) free survival and overall survival. CONCLUSION: The extent of apoptosis induced by preoperative chemotherapy of primary breast cancer may possibly predict an individual patient's overall response to treatment.
The emergence of a new agent of cholera, Vibrio cholerae O139, has prompted a reevaluation of the vibriocidal antibody assay. This assay, primarily directed to lipopolysaccharide, is an important correlate of O1 immunity. V. cholerae O139 strains are encapsulated, rendering them relatively resistant to killing by serum. Recent reports suggest that there is strain-to-strain variability in the sensitivity of the vibriocidal assay to fully encapsulated O139 strains. We have assessed a modified vibriocidal assay for fully encapsulated O139 strain AI-1837 and its unencapsulated mutant 2L in sera from 53 volunteers given wild-type AI-1837 or its attenuated derivative CVD 112 and from 48 controls challenged with V. cholerae O1 or strains of the family Enterobacteriaceae. Vibriocidal responses to the AI-1837 and 2L strains were seen in 67 and 89% of volunteers, respectively, following a single exposure to the wild-type strain. However, >50% of all controls had low-level vibriocidal responses to both strains. These nonspecific responses were transient and of the immunoglobulin G isotype. No binding activity against purified O139 lipopolysaccharide (LPS) by immunoblotting was seen in control sera. In contrast, vibriocidal assay and strain 2L LPS responses by immunoblotting were detectable in 91% of tested volunteers following a single exposure to O139. The presence of vibriocidal antibody to AI-1837 or 2L was not associated with protection in rechallenge studies with O139 strain AI-1837. The vibriocidal assay with unencapsulated strain 2L may be used to detect exposure to O139 strain AI-1837 in controlled research trials. However, its lack of specificity does not make it useful for determining exposure to V. cholerae O139 in the field.
PURPOSE: The majority of breast cancers are diagnosed at an early stage, and treatment is focused on cure and prolonging disease-free survival. Local therapy (surgery and/or radiation treatment) is standard, along with systemic adjuvant therapy that may effectively prevent or delay relapse and death in early-stage disease. In premenopausal women, adjuvant therapeutic approaches include combination cytotoxic chemotherapy and endocrine therapy. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was the established chemotherapy regimen; however, newer regimens have more recently been introduced that may offer some benefit over CMF including anthracycline-containing regimens [e.g. cyclophosphamide, epirubicin and 5-fluorouracil (CEF)], and taxane-containing regimens. For women with oestrogen receptor (ER)-positive disease, a second option is endocrine therapy that aims to suppress mitogenic oestrogen signalling. Until recently, 5 years of tamoxifen was regarded as the standard adjuvant endocrine treatment in ER-positive disease. Ovarian ablation is also effective in premenopausal women, and can be achieved by surgery, radiotherapy, or via the use of a luteinising hormone-releasing hormone analogue such as goserelin. Combining tamoxifen and goserelin treatment provides more effective oestrogen blockade than either drug alone. However, as the third-generation aromatase inhibitors (AIs) have demonstrated improved efficacy over tamoxifen in postmenopausal women with early and advanced disease, combination treatment with goserelin plus an AI may provide optimal oestrogen blockade in premenopausal patients. CONCLUSIONS: This review assesses the relative merits of chemotherapeutic and endocrine approaches for the treatment of early breast cancer, and summarises relevant ongoing clinical trials, with an emphasis on the premenopausal setting.
In superfused anterior pituitary reaggregate cell cultures angiotensin II (AII) stimulated both spontaneous and dopamine-inhibited prolactin (PRL) release from subnanomolar concentrations. Angiotensin I (AI) and angiotensin III (AIII) also stimulated PRL release. The magnitude and rate of response to AI was equal to or only slightly lower than that to AII. However, the angiotensin converting enzyme (ACE) inhibitors captopril and teprotide (1 microM) completely abolished the PRL response to 0.1 nM AI and strongly reduced that to 1 nM AI. The intrinsic activity of AIII was lower than that of AII but could be enhanced by adding 2 microM of the aminopeptidase inhibitor amastatin to the superfusion medium. After withdrawal of AIII, PRL secretion rate rapidly returned to baseline levels, whereas after withdrawal of AI or AII, secretion fell to a level remaining significantly higher than basal release. The present findings indicate that stimulation of PRL release by AI is weak unless it is converted into AII by ACE and that aminopeptidase may be important in determining the magnitude and termination of the PRL response. Furthermore, the active peptides induce a different pattern of response.