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PubMed2005

Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones.

Cytoplasmic Ca2+ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca2+ by extracellular application of a low concentration of ryanodine, which activated Ca2+ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overexpression of mutant forms of Cdc42 but not of RhoA in Xenopus spinal cord neurons. Furthermore, Ca2+-induced GTPase activity correlated with activation of protein kinase C and required a basal activity of Ca2+/calmodulin-dependent protein kinase II. Thus, Rho GTPases may mediate axon guidance by linking upstream Ca2+ signals triggered by guidance factors to downstream cytoskeletal rearrangements.

Animals↗
PubMedDate not supplied

Tumor dihydropyrimidine dehydrogenase activity in advanced cervical carcinoma.

Patients with advanced cervical carcinoma were treated with oral fluoropyrimidine (UFT) as neoadjuvant chemotherapy and its antitumor effect was examined. The relationship between thymidylate synthase (TS) or dihydropyrimidine dehydrogenase (DPD) activity in tumor tissue and apoptosis was also investigated. The subjects were 56 patients with advanced cervical carcinoma. The patients received two courses of therapy consisting of UFT at a dose of 600 mg/day for 5 days and 2 days off treatment. The TS and DPD activity in tumor tissue was measured before and after UFT administration by the FdUMP binding assay and a catalytic assay in 38 patients, respectively. Apoptosis was detected by the TUNEL method, and the apoptotic index (AI) was calculated. Tumor tissue activity of TS or DPD was unrelated to clinicopathologic factors or to the activity of the other enzyme. The mean tumor TS and DPD activity before UFT administration was 5.42+/-3.92 pmol/g tissue and 206.54+/-128.58 pmol/mg/min, respectively, and the levels of these enzymes in two patients showing an antitumor effect were below the mean values. The AI increased from 1.10+/-0.57% before UFT to 1.27+/-0.81% afterwards, and the DPD activity before UFT showed an inverse relationship with the AI after UFT (r=-0.6938). In patients with DPD activity below the median value (186.92 pmol/mg/min), UFT administration significantly caused an increase of the AI (p=0.0002). These results indicate that the DPD activity of advanced cervical carcinoma is a determinant of sensitivity to UFT, suggesting an association between UFT therapy and the induction of apoptosis.

Adenocarcinoma↗
PubMed1997

Effect of drug load and plate coating on the particle size distribution of a commercial albuterol metered dose inhaler (MDI) determined using the Andersen and Marple-Miller cascade impactors.

PURPOSE: The purpose of this study is to investigate the effect of drug load, the coating of impactor stages, and the design of cascade impactors on albuterol MDIs particle size distribution measurements. The results of the investigation will be used to explain the "loading effect" recently reported. METHODS: Particle size distribution parameters of a commercial albuterol MDI were measured using both Andersen (AI) and Marple-Miller (MMI) Cascade Impactors, where plates were either left uncoated or coated with silicone or glycerin. A previously validated HPLC-EC method was used for the assay of albuterol collected by the impactor and in single spray content determinations. RESULTS: Coating impactor collection plates had an impact on measured MMAD and GSD values for single puff measurements but very little or no effect for the multi puff measurements. Due to particle bounce, the percent of albuterol fine particles deposited in the filter and impactor finer stages (< 1.10 microns in AI and < 1.25 microns in MMI) in uncoated single puff experiments was much higher in comparison to either coated single puff or multi-puff (coated and uncoated) measurements. CONCLUSIONS: Evaluation of drug load and plate coating are necessary to determine whether observed particle size distributions are representative of the generated aerosol or are the result of particle bounce and reentrainment. In order to minimize particle bounce, especially for single puff determinations, it may be useful to apply a thin layer of a sticky coating agent to the surfaces of impactor plates.

Adrenergic beta-Agonists↗
PubMed1984

Angiotensin III-induced dipsogenic and pressor responses in rodents.

Subcutaneous injections of [des-Asp1]-angiotensin I [( des-Asp1]-AI), angiotensin II (AII), and angiotensin III (AIII) induced drinking in the laboratory rat and the South American rodent Octodon degus, but not in the gerbil. In a second experiment, pretreatment with captopril, an angiotensin converting enzyme inhibitor, prevented the endogenous conversion of subcutaneously injected [des-Asp1]-AI to AIII and prevented drinking in rats and degus. The pharmacological artifact of hypovolemia caused by angiotensin-induced increases in vascular permeability was not observed in members of these species. In a final experiment blood pressure changes resulting from subcutaneous injections of AII and AIII in rats and gerbils were measured. Significant pressor elevations were seen following the administration of both analogues, although AII was more potent. These results demonstrate that AIII is dipsogenic in rats and degus and serves as a pressor agent in rats and gerbils. No ready explanation is available for the gerbil's relative lack of dipsogenicity to the presently tested angiotensins.

Angiotensin I↗
PubMed2006

Antiatherogenic small, dense HDL--guardian angel of the arterial wall?

Our understanding of the relationship between the atheroprotective activities of HDL and heterogeneity of HDL particles has advanced greatly. HDL particles are highly heterogeneous in structure, intravascular metabolism and antiatherogenic activity. In this review, we discuss new findings on the antiatherogenic properties of HDL particles. Small, dense HDL possesses potent antioxidative activity but this is compromised under conditions of atherogenic dyslipidemia. HDL functional deficiency frequently coincides with reductions in HDL-cholesterol concentration and alterations in HDL metabolism and structure. Formation of small, dense HDL particles with attenuated antiatherogenic activity can be mechanistically related to HDL enrichment in triglycerides and in serum amyloid A, depletion of cholesteryl esters, covalent modification of HDL apolipoproteins and attenuated antiatherogenic function of apolipoprotein AI. Low circulating levels of HDL cholesterol might, therefore, be associated with the defective functionality of small HDL particles of abnormal structure and composition. In common metabolic diseases, such as type 2 diabetes and metabolic syndrome, deficiency of HDL particle number and function favor accelerated atherosclerosis. Therapeutic normalization of the quantity, quality and biological activities of HDL particles thus represents a novel approach to attenuating atherosclerosis in dyslipidemic individuals with metabolic disease. Cholesteryl ester transfer protein inhibitors, nicotinic acid, reconstituted HDL and other HDL-raising agents are being investigated. Induction of selective increase in the circulating concentrations of small, dense HDL3 particles with increased antiatherogenic activity seems especially promising, particularly for therapy of atherogenic dyslipidemia.

Biomarkers↗
PubMed2006

Side effects of aromatase inhibitors versus tamoxifen: the patients' perspective.

BACKGROUND: Hormonal therapy is a mainstay in the management of estrogen receptor-positive (ER+) breast cancer. Tamoxifen (TAM) has been the drug widely used until the recent emergence of the aromatase inhibitors (AIs). Although AIs appear to be better tolerated than tamoxifen, they do have a different safety profile and these side effects have not been well characterized in community practice. We surveyed patients with ER+ breast cancers who received adjuvant hormonal therapy to determine how these medications impacted their quality of life and whether side effects or cost influenced decisions to continue therapy. METHODS: A mailed questionnaire and community cancer registry were used. RESULTS: Four hundred fifty-two of 902 surveys were returned for a 50% response rate. Eighty-two percent of respondents were placed on (adjuvant hormonal therapy) some form of estrogen-blocking therapy. Fifty-four percent of these were placed on tamoxifen and 46% on an AI. The most troublesome symptoms for tamoxifen and AI users, respectively, included hot flashes (35%/30%), weight gain (14%/15%), insomnia (17%/17%), and joint aches (12%/23%, P = .002). Thirty-nine percent of TAM users and 46% of AI users were taking medications to control their symptoms. Fifty percent of TAM users and 39% of AI users took vitamin E to help control hot flashes. Forty-two percent of TAM users versus 32% of AI users took Advil (Wyeth, Richmond, VA) for muscle/joint aches; 47.5% of AI users switched medication to improve symptoms as compared with only 37% of tamoxifen users (P = .015). The average cost of medications to control side effects for both tamoxifen and AI users was $67.36 per month. CONCLUSIONS: In our survey, both tamoxifen and AI users reported significant and different side effects. AI users suffered more frequently from musculoskeletal complaints, and more AI users switched therapy. Both AI and tamoxifen users used adjunctive medications for symptom control. In both groups, a large number used vitamin E to help hot flashes despite weak evidence to support its effectiveness in this setting. Cost of therapy and symptom control was not a major barrier to care.

Antineoplastic Agents, Hormonal↗
PubMed2005

Tissue plasminogen activator for acute ischemic stroke: a New York city emergency medicine perspective.

Nationally, only 2-3% of patients with acute ischemic stroke (AIS) currently receive tissue plasminogen activator (TPA). To better understand the reasons, we investigated the practice patterns, level of familiarity and acceptance of TPA for AIS among emergency physicians in New York City (NYC). Fifty-seven 911-receiving hospital emergency department directors were surveyed regarding TPA use. Of those responding, 37% had never used TPA to treat AIS. Lack of neurological support was reported by 33%. Departments with formal protocols were more likely to use TPA for AIS. In conclusion, there is considerable variation in the practice, knowledge, and attitudes regarding the use of TPA for AIS in NYC emergency departments. Improved educational efforts and institutional support may be necessary to ensure the appropriate use of TPA by emergency physicians.

Acute Disease↗
PubMed2005

Relationship between changes in prostate cancer cell proliferation, apoptotic index, and expression of apoptosis-related proteins by neoadjuvant hormonal therapy and duration of such treatment.

OBJECTIVES: To investigate the relationships between changes in the carcinoma cell proliferation index, apoptotic index (AI), and apoptosis-related factors, including bcl-2 and bax, after different durations of neoadjuvant hormonal therapy (NHT) in prostate cancer tissue. METHODS: Pre- and post-NHT specimens were obtained from 42 patients who had undergone NHT and radical prostatectomy. The patients were divided into two groups according to the duration of NHT: group 1 (3 to 7 months, n = 21) and group 2 (8 to 12 months, n = 21; no randomization). Immunohistochemistry was used to determine the expression of bcl-2 and bax and to determine the proliferation index, and the terminal deoxynucleotidyl transferase-mediated nick end-labeling method was used to assess apoptosis and determine the AI. RESULTS: The median proliferation indexes of groups 1 (1.8%) and 2 (1.6%) were significantly lower than the respective values in the pre-NHT specimens (4.9%, P < 0.01). The median AI of group 1 (2.5%) was greater than in the pre-NHT specimens (1.4%). In addition, the post/pre-NHT AI ratio correlated significantly with the duration of NHT in group 1 (r = 0.58, P < 0.01), but not in group 2. Bax expression increased in a manner parallel to that of the AI. CONCLUSIONS: NHT suppresses prostate cancer cell proliferation for 3 to 12 months. Although the AI was increased during 3 to 7 months of NHT, no significant difference was found between the pre-NHT levels and those after 8 to 12 months. Our results support the current belief that the optimal duration of NHT is longer than 3 months.

Adenocarcinoma↗
PubMed2005

A proposed classification for subtypes of arterial ischaemic stroke in children.

The aim of this study was to propose a classification system for childhood arterial ischaemic stroke (AIS). Subtypes from the Trial of Org 10172 in Acute Stroke Therapy (TOAST) classification, previously shown to be applicable to children, were retained in the proposed Paediatric Stroke Classification (PSC). Additional important paediatric AIS aetiologies were identified from a literature review. Preliminary validation was performed by three raters who categorized clinical vignettes from 135 patients (66 male; median age 6.3 y, range 0.1 to 16 y). Eight aetiological subtypes were identified and defined, as follows: (1) sickle cell disease; (2) cardioembolic; (3) moyamoya syndrome; (4) cervical arterial dissection; (5) steno-occlusive cerebral arteriopathy; (6) other determined aetiology; (7) multiple probable/possible aetiologies; and (8) undetermined aetiology. There was very good agreement between the raters about categorization of the vignettes. Causes of disagreement were identified and final categories and definitions were modified accordingly. We conclude that the PSC enables the categorization of children with AIS into aetiological subtypes relevant to this age group. This will be useful in multicentre studies of natural history and treatment but will require further independent validation.

Adolescent↗
PubMedDate not supplied

[Study of tolerance and efficacy of cosmetic preparations with lenitive action in atopic dermatitis in children].

PURPOSE: In AD (atopic dermatitis), the barrier function of skin is impaired, causing dryness and vulnerability: the first-end point to achieve is restoring skin's function to avoid relapses. Our aim was to assess tolerability and effecacy of two cosmetics with moisturizing and lenitive action in subjects affected by AD. PATIENTS AND METHODS: We used a topical preparation (product A) and a new formulation of it (product B) containing glycyrrhetinic acid, alpha-bisabolol, squalene, oryzanol and hohoba-oil. Product B was then compared with a third one (product C), also based on glycyrrhetinic acid and bisabolol. 30 subjects, aged between 4 months and 16 years, were included in the study (13 girls and 17 boys), suffered from mild-moderate AD, not treated with steroids. Patients were treated twice a day for 21 days, as follows: 12 product A (Decortil lipocrema IDI Farmaceutici); 9 product B (Decortil crema, IDI Farmaceutici); 9 product B on the right and product C (Lichtena AI crema UCB Pharma) on the left. We also did: photografic documentation, SCORAD Index, evaluation of objective (erythema, exudation, excoriation, dryness) and subjective (itching and burning) simptomatology (scoring 0-3) and physiopatological cutaneous tests as TEWL (Trans Epidermal Water Loss), corneometry and pHmetry at beginning and at end of treatment. RESULTS: All groups improved both clinically and instrumentally. Corneometry increased, TEWL lowed and pH turned to normality. CONCLUSIONS: Product A is better for restoring cutaneous physiology, B resulted more efficient in rehydration, in acute phase and as emollient agent, whereas C has more lenitive action.

Adolescent↗
PubMed1999

Successful treatment of collagen-induced arthritis in mice with a hydroalcohol extract of seeds of Pterodon pubescens.

The antiarthritic effect of a hydroalcohol extract of Pterodon pubescens (HEPp) seeds was tested using collagen-induced arthritis (CIA) in DBA1/J mice treated with daily oral doses of HEPp in different schedules. The preventive treatment significantly reduced both the arthritic index (AI) and the CIA incidence. Using a therapeutic protocol, only the lower dose of HEPp induced a decrease in both parameters. These results provide a scientific foundation for the popular use of Pp seed infusions in rheumatoid arthritis (RA) treatment.

Animals↗
PubMed1995

Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin.

Alcohol consumption is known to have beneficial effects on cardiac mortality, probably by increasing high density lipoprotein cholesterol (HDL-C). Alcohol also increases triglycerides and, in some studies, total cholesterol and low density lipoprotein cholesterol (LDL-C). Nothing is known, however, of the effects of alcohol on the pharmacokinetics and efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Consequently, 2 studies have been carried out to determine the effects of alcohol consumption on the pharmacokinetics and efficacy of the HMG-CoA reductase inhibitor fluvastatin. Firstly, the effects of acute alcohol consumption on a single, oral 40 mg dose of fluvastatin were examined in a reference-controlled, randomized, crossover study in 10 healthy volunteers. Measurements were made after ingestion of 70 g of ethanol diluted to 20% with lemonade and, following a 7-day period, after ingestion of lemonade alone (reference). The half-life (t1/2) of a single dose of fluvastatin was significantly reduced by acute alcohol consumption compared with reference, whereas the area under the time-concentration curve (AUC), peak concentration (Cmax), and time to peak concentration (tmax) did not differ from the reference group. The lipid profile, measured 8 hr after administration, did not differ significantly from baseline in the reference group, apart from a slight reduction in apolipoprotein (apo)-AI. Triglyceride levels increased with alcohol, probably due to impaired fatty acid oxidation. Surprisingly, total cholesterol and LDL-C fell significantly, possibly due to altered pharmacokinetics, as reflected by the lower t1/2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Anti-irritants I: Dose-response in acute irritation.

The term 'anti-irritant' (AI) was coined in 1965 by Goldemberg to describe a diverse group of topical product ingredients, which were able to reduce the irritation potential of other more irritating ingredients in the same product. 'AIs' are being added to cosmetic formulations in order, allegedly, to benefit tolerability of the products and allow claims such as 'soothing' and 'healing' ingredients. Limited documentation in favour of the efficacy of AIs is published. We studied the dose-related effect of 4 alleged AIs (nifedipine, (-)-alpha-bisabolol, canola oil and glycerol) on experimentally induced acute irritation in healthy volunteers. Each AI was used in 3 concentrations. Acute irritation was induced by occlusive tests with 1% sodium lauryl sulfate and 20% nonanoic acid in N-propanol. The irritant reactions were treated twice daily with AI-containing formulations from the time of removal of the patches. Evaluation of skin irritation and efficacy of treatments were performed daily for 4 days using clinical scoring, evaporimetry (transepidermal water loss), hydration measurement and colourimetry. Only glycerol showed dose-response and effects potentially better than no treatment. There was no significant effect and no difference between the three other AIs.

Acute Disease↗
PubMed1994

Amyloidosis.

Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of abnormal protein fibrils which are derived from different proteins in different forms of the disease. Asymptomatic amyloid deposition in a variety of tissues is a universal accompaniment of ageing, and clinical amyloidosis is not rare. Intracerebral and cerebrovascular beta-protein amyloid deposits are a hallmark of the pathology of both sporadic and familial Alzheimer's disease, beta 2-microglobulin-derived amyloid is a common complication of long term haemodialysis, and islet amyloid polypeptide is the fibril protein in the universal islet amyloidosis of type II diabetes mellitus. New fibril proteins have lately been identified in hereditary amyloidosis, including variants of gelsolin, apolipoprotein AI, lysozyme and fibrinogen. The development of radiolabelled serum amyloid P component (SAP) scintigraphy has allowed amyloid to be diagnosed non-invasively in vivo for the first time, provided unique insight into the distribution and size of amyloid deposits, and yielded novel information on the natural history and the effects of treatment. Amyloid deposits are in a state of dynamic turnover and can regress if new fibril formation is halted. The recent elucidation of the three dimensional structure of human SAP may enable the design of specific therapeutic agents.

Amino Acid Sequence↗
PubMedDate not supplied

[ABO determination in blood stains on stain carriers pretreated with usual household products].

Linen has been treated with 20 different remedies for clothes (impregnating agents, fabric softeners, detergents, finishes, and stainremovers; see tab. 2) in "normal" and "high" concentration. After short, intentionally incomplete washing and after successive drying 5 microliters and 10 microliters blood each of the six major ABH types have been applied. Stains have been ABH typed by the absorption-inhibition test according to Holzer, the absorption-elution test using stain extracts according to Chisum, and another absorptions-elution test performed in tubes. Only 3 of the 20 remedies had no effect on the results (tab.3). The AI-test showed no false results, but partly reduced absorption and haemolysis of the added red blood cells. Both AE-tests gave false-positive and false-negative results. Compared with the tube test the method described by Chisum was more reliable. The rate of false results depended on the concentration of the remedies used for the treatment of the linen. The majority of the incorrect results (but not all!) could have been recognized by processing controls analogously (see tab. 4 and 5; legend in English under tab. 5).

ABO Blood-Group System↗
PubMed2006

Cardiovascular effects of epinephrine under sedation with nitrous oxide, propofol, or midazolam.

OBJECTIVE: During implant surgery, a large amount of local anesthetics containing epinephrine are often required, and the resulting cardiovascular effects of administered epinephrine are not negligible. On the other hand, sedation has wide applications in implant surgery. Nitrous oxide, propofol, or midazolam are commonly used as sedative drugs, and each has also its own cardiovascular effects. The objective of this study was to investigate the cardiovascular effects of epinephrine on patients under sedation with nitrous oxide, propofol, or midazolam. STUDY DESIGN: We studied 9 healthy volunteers. They received epinephrine infusion at a nominal rate of 10, 25, or 50 ng/kg per minute under sedation with 30% nitrous oxide inhalation, 4 mg/kg per hour intravenous propofol or 0.2 mg/kg per hour intravenous midazolam. For each, hemodynamic response and blood pressure and heart rate variability were measured. RESULTS: When epinephrine was infused alone at 50 ng/kg per minute, heart rate (HR) and cardiac index (CI) increased by 19.5% and 40.7%, respectively. Propofol suppressed the epinephrine-induced increase in CI. During midazolam infusion, the highest dose of epinephrine caused a 37.5% increase in HR, which was significantly higher than for epinephrine infusion alone. This response was accompanied by the reduction in high-frequency power of heart rate variability, suggesting decreased parasympathetic activity. Nitrous oxide had no influence on the cardiovascular response to epinephrine. CONCLUSION: Increased cardiovascular activity due to epinephrine can be alleviated by propofol. However, midazolam and nitrous oxide are of no advantage for stabilizing the hemodynamic status of the patient. Intravenous sedation with propofol is useful during oral surgical procedures in which a large amount of epinephrine is required.

Adult↗
PubMed1999

Emergency physician treatment of acute stroke with recombinant tissue plasminogen activator: a retrospective analysis.

UNLABELLED: Stroke teams are advocated for the rapid treatment of patients who have acute ischemic stroke (AIS) with recombinant tissue plasminogen activator (rt-PA). An alternate model uses existing ED resources with specialist consultation as needed. OBJECTIVES: To evaluate the treatment of AIS with rt-PA in this alternate ED model. METHODS: A retrospective observational review was performed of consecutive patients with AIS treated with rt-PA at four hospitals affiliated with an emergency medicine residency. Emergency physicians (EPs) were directly responsible for the treatment of all patients according to predefined guidelines. Records were evaluated from the implementation of the guidelines through December 15, 1997. RESULTS: 37 patients with AIS received rt-PA. Mean age+/-SD was 63+/-16 years (range 22-87), with 25 (68%) male. Patients presented 67+/-29 minutes after stroke onset. After ED arrival, they were seen by the EP in 14+/-13 minutes, had CT in 46+/-22 minutes, and were treated in 97+/-35 minutes. Neurologist consultation occurred in the department for nine patients (24.3%), and by telephone for 14 (37.8%). Symptomatic intracerebral hemorrhage (ICH) occurred in four (10.8%, 95% CI = 0.8% to 20.8%). There were two deaths, neither associated with ICH. Neurologic outcome at discharge compared with presentation in survivors was normal for four patients (11.4%), improved for 16 (45.7%), unchanged for ten (28.6%), and worse for five (14.3%). CONCLUSIONS: In this analysis, EPs, with specialty consultation as required, successfully identified patients with AIS and delivered rt-PA with satisfactory outcomes. Important elements of this model include early patient identification, preestablished protocols, and rapid access to CT scanning and interpretation.

Acute Disease↗
PubMed2003

[Anti-SARS virus activities of different recombinant human interferons in cell culture system].

BACKGROUND: To study the anti-SARS virus activities of different recombinant human interferons on the cell culture system. METHODS: Anti-SARS virus activities of interferons were determined by using CPE inhibition test in human skeletal muscle sarcoma (Rda) cell culture. RESULTS: The average minimum amount of interferon alpha 2b, alpha 1b, beta 1b or omega 1b to inhibit 50% CPE in Rda cell culture was (160.5+/-129.5) IU/ml, (149.0+/-71.7) IU/ml, (69.5+/-61.5) IU/ml, (87.3+/-47.1) IU/ml, respectively or (0.6+/-0.5) ng/ml, (10.6+/-5.1) ng/ml, (3.5+/-3.1) ng/ml, (0.9+/-0.5) ng/ml, respectively. CONCLUSION: All the tested recombinant interferons showed anti-SARS virus activities on the Rda cell culture with different sensitivities.

Antiviral Agents↗