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PubMed2006

Human blood late outgrowth endothelial cells for gene therapy of cancer: determinants of efficacy.

Human adult blood late outgrowth endothelial cells (BOECs) are potential yet untested cellular vehicles to target tumor-cytotoxic effectors to tumors. We show that, following intravenous injection into irradiated mice, BOECs home to Lewis lung carcinoma (LLC) lung metastases, but less so to liver or kidney metastases. BOECs targeted most but not all of the lung metastases, to a different degree. While most of the homed BOECs took up an extravascular position, some integrated into tumor vessels. Sequestration into normal tissue was low. Placental growth factor mediated both migration and invasion of BOECs into LLC spheroid masses in vitro, as did VEGF. When armed with a suicide gene, BOECs exerted a bystander effect on LLC cells in vitro and in vivo. Surprisingly, i.v. administration of armed BOECs into mice bearing multi-organ LLC metastases did not prolong survival. In addition to homing efficacy other parameters impacted upon the efficacy of BOECs. These include the ultimate susceptibility of BOECs to suicide gene-induced cell death, their paracrine proliferative effect on LLC cells and their low proliferation rate compared to LLC cells. Addressing these determinants may make BOECs a useful addition to the arsenal of tumor-targeting moieties.

Angiogenesis Inhibitors↗
PubMed1999

A novel domain of the inhibitory glycine receptor determining antagonist efficacies: further evidence for partial agonism resulting from self-inhibition.

Different amino side chains in the N-terminal extracellular region of the inhibitory glycine receptor (GlyR) have been shown to be crucial for ligand recognition. Here we describe a novel domain of the GlyRalpha1 subunit that constitutes an important determinant of antagonist activity. The antagonists strychnine, nipecotic acid, and isobutyric acid displayed reduced potencies at recombinant GlyRs formed from alpha1 subunits, in which lysine 104, phenylalanine 108, or threonine 112 were replaced by alanine. Agonist affinities, in contrast, were slightly increased at these mutant receptors. Taurine and beta-aminoisobutyric acid, which are partial agonists at the wild-type GlyR, behaved as full agonists at the mutant GlyRs and failed to inhibit glycine-induced currents. This is consistent with apolar residues at positions 104, 108, and 112 of the alpha1 subunit reducing the antagonistic, but not the agonistic, binding of beta-amino acids. Our data support a model in which the partial agonism of beta-amino acids results from their self-inhibitory activity.

Amino Acid Substitution↗
PubMed2000

Wound healing trajectories as predictors of effectiveness of therapeutic agents.

BACKGROUND: One goal of wound healing research is to discover agents to accelerate healing. Regulatory agencies have suggested stringent criteria to determine efficacy, that of 100% wound closure. Data analysis at a single point such as 100% closure does not provide detailed information about agent effectiveness over the entire span of healing. HYPOTHESIS: Wound healing trajectories can provide such information and can be used to demonstrate utility as alternative end points for wound healing trials. DESIGN: Data from 160 patients in 11 clinical trials of diabetic foot ulcers conducted at 2 centers were evaluated. Wound healing trajectories were constructed for patients whose wounds healed (100% closure) and those whose did not (<100% closure) over a 20-week period. The percentage of patients achieving total healing vs time of treatment was plotted and divided into patients receiving a test agent or placebo. RESULTS: The healing trajectories were almost identical for patients achieving complete healing at the 2 centers, as were the trajectories for patients with less than 100% closure. However, the trajectories of patients achieving total healing were significantly different from those not achieving 100% closure. Fifty-two percent of all patients achieved 100% healing by 20 weeks; 61% of patients receiving an experimental agent had total healing compared with 39% of placebo-treated patients. Linear regression suggested that all patients would achieve total healing by 37 weeks. CONCLUSIONS: Since wound healing trajectories for diabetic foot ulcers treated at 2 centers so closely mimic one another, trajectories might be useful efficacy end points, and used to compare significant points along a continuum rather than a single static end point. Shifting of the wound healing trajectory from an impaired to a more ideal course may be considered when determining efficacy of new wound treatments.

Debridement↗
PubMed2001

Prevention of venous thromboembolism after knee arthroscopy with low-molecular weight heparin (reviparin): Results of a randomized controlled trial.

PURPOSE: Deep venous thrombosis (DVT) is a common, important complication of major orthopaedic surgery, particularly knee arthroplasty. Knee arthroscopy is increasingly performed on an outpatient basis. Few reports have elucidated the incidence of venous thromboembolism (VTE) in patients undergoing arthroscopic surgery receiving no prophylaxis. The objective of the present trial was to evaluate the risk of VTE in those patients and to determine efficacy and safety of a low-molecular weight heparin (LMWH) in preventing VTE. TYPE OF STUDY: This is the first controlled randomized trial using objective diagnostic methods with blinded outcome assessment to reveal the incidence of VTE in outpatient arthroscopy and determine efficacy and safety of a LMWH (reviparin sodium) in preventing VTE in these patients. METHODS: There were 262 patients undergoing elective knee arthroscopy prospectively randomized to receive either no treatment or reviparin once daily subcutaneously for 7 to 10 days. The blindly assessed primary outcome measure was the incidence of DVT detected by compression color-coded sonography. Both groups were comparable with regard to demographics and baseline characteristics. RESULTS: 239 patients were evaluable (122 no treatment, 117 receiving LMWH). 6 DVT were detected - 5 in the control group (5/117 - 4.1%) and only one in the active treatment group (1/116 - 0.85%). This particular patient had a low level of protein C and a subnormal level of protein S. The odds ratio of 4.95 approximates a relative risk reduction of about 80%. Treatment with reviparin was safe and well tolerated. There was no major bleeding, four patients with minor bleedings. One patient had a transitory fall in platelet count below 100 giga-particles/L without any clinical symptoms. CONCLUSIONS: Patients undergoing knee arthroscopy have a moderate risk of VTE and effective prophylaxis can be achieved with LMWH (reviparin).

Adult↗
PubMed2004

Reduction of tissue hyperplasia with a rhenium-188 mercaptoacetyltriglycine-3-filled balloon: preliminary study in a canine urethral model.

PURPOSE: To evaluate the efficacy of beta-radiation therapy with rhenium-188 mercaptoacetyltriglycine-3 (MAG(3))-filled balloons to reduce tissue hyperplasia secondary to stent placement in 18 canine urethras. MATERIALS AND METHODS: Eight dogs were treated with 188-Re MAG(3)-filled balloon dilation immediately after stent placement and were killed 4 weeks later (group I, n = 4) or 8 weeks later (group II, n = 4). Five dogs were treated with 188-Re MAG(3)-filled balloon dilation 2 weeks after stent placement and were killed 4 weeks after stent placement (group III). The remaining five dogs were treated with conventional balloon dilation immediately after stent placement and were killed 4 weeks later; these animals formed the control group (group IV). Retrograde urethrography (RUG) was performed during follow-up and three histologic parameters were investigated: the number of epithelial layers, papillary projection thickness, and degree of submucosal inflammatory cell infiltration. The areas inside and outside the ends of the stents were evaluated in each case after animal sacrifice. After testing statistical significance of data for RUG and histologic findings in the four study groups, the Mann-Whitney U test was used to compare groups I and II to determine delayed effects of irradiation, groups I and III to determine benefits of delayed irradiation, groups I and IV to determine efficacy of immediate irradiation for reducing tissue hyperplasia, and groups III and IV to determine efficacy of delayed irradiation for reducing tissue hyperplasia. RESULTS: There were no significant differences in the four study groups on RUG before animal sacrifice. Between groups I and II, group II showed significantly lower mean values in five of six histologic comparisons. Between groups I and III, group III showed significantly lower mean values in only papillary projection thickness inside the stent ends. Between groups I and IV, group I showed significantly lower mean values in all three histologic parameters outside the stent ends. Between groups III and IV, group III showed significantly lower mean values in only two histologic parameters (papillary projection thickness in the in-stent area and inflammatory cell infiltration outside the stent edges). CONCLUSION: beta-Irradiation with use of a 188-Re MAG(3)-filled balloon shows the potential to reduce tissue hyperplasia secondary to stent placement in a canine urethral model. Treatment with 188-Re MAG(3)-filled balloons at the time of stent placement shows not only favorable outcomes for reducing tissue hyperplasia but also improved delayed effects until 8 weeks.

Animals↗
PubMed2005

An open study to determine the efficacy of blue light in the treatment of mild to moderate acne.

BACKGROUND: The effective management of acne remains a challenge; achieving an optimal response whilst minimizing adverse events is often difficult. The rise in antibiotic resistance threatens to reduce the future usefulness of the current mainstay of therapy. The need for alternative therapies remains important. Phototherapy has previously been shown to be effective in acne, with renewed interest as both endogenous and exogenous photodynamic therapies are demonstrated for this condition. OBJECTIVES: To determine the effect of narrowband blue light in the reduction of inflammatory and non-inflammatory lesions in patients with mild to moderate acne and to evaluate patient tolerance of the therapy. METHODS: We performed an open study utilizing a blue LED light source in 30 subjects with mild to moderate facial acne. Two weeks after screening, lesions were counted and recorded by lesion type. Over 4 weeks, patients received eight 10- or 20-minute light treatments, peak wavelength 409-419 nm at 40 mW/cm2. Assessments were taken at weeks 5, 8 and 12 and lesion counts were recorded. Repeated measures-ANOVA and Dunnett's tests, respectively, allowed assessment of the different scores over time and permitted comparison of mean counts. RESULTS: An overall effect on inflammatory counts was observed at week 5, and a statistically significant decrease in inflamed counts was detected at the week 8 assessments, which continued to week 12. There was little effect on non-inflamed lesions. The treatment was well tolerated with adverse events experienced generally rated as being mild and usually self-limiting. CONCLUSIONS: Eight 10- or 20-minute treatments over 4 weeks with a narrowband blue light was found to be effective in reducing the number of inflamed lesions in subjects with mild to moderate acne. The treatment had little effect on the number of comedones. The onset of the effect was observable at the first assessment, at week 5, and maximal between weeks 8 and 12. Blue light phototherapy using a narrowband LED light source appears to be a safe and effective additional therapy for mild to moderate acne.

Acne Vulgaris↗
PubMed1996

Can prostate-specific antigen be used as a valid end point to determine the efficacy of chemotherapy for advanced prostate cancer?

It is current practice in many clinical trials evaluating new chemotherapy regimens for the treatment of advanced prostate cancer to use prostate-specific antigen (PSA) decline as a response criteria with the assumption that the level of PSA reflects the efficacy of chemotherapy. Advanced prostate cancer is heterogeneous; therefore, the validity of PSA decline as a measurable end point was studied in advanced human prostate-cancer cell lines: androgen-sensitive LNCaP and androgen-insensitive PC3 cells. Each cell line was grown for 4 days with escalating doses of Adriamycin or vinblastine. Cell counts, intracellular PSA concentrations, and secreted PSA levels were determined daily for 4 days. Untreated LNCaP cells had constant secretion of PSA per cell. In contrast, LNCaP cells treated with Adriamycin or vinblastine had an 80% reduction in cell numbers and a 3-fold increase in secreted PSA per cell by day 4. In contrast, PC3 cells had a different response to Adriamycin and vinblastine. Both drugs reduced cell numbers by 97% of control values and suppressed PSA production in the remaining viable cells by 4 days in culture. Thus, prostate-cancer cell production of PSA is variable with chemotherapy and the PSA level may not accurately reflect the actual tumor response to chemotherapy.

Antibiotics, Antineoplastic↗
PubMed1990

Significance of tissue levels for prediction of antibiotic efficacy and determination of dosage.

Determination of tissue levels is widely thought to provide useful information in the investigation of a new antibiotic, however this assumption is not fully justified. In this paper the following questions are covered. Firstly, the methodological problems encountered in the measurement of antibiotic levels in solid tissues and extravascular fluids are described. Secondly, the difficulties encountered in interpreting tissue concentrations are discussed, given the heterogeneity of distribution of drugs, potential intracellular penetration, binding to tissue proteins and local factors reducing antibacterial activity. Thirdly, the respective importance of animal and human data on tissue levels for prediction of efficacy is analysed. In some animal models it is possible to study the conditions affecting antibacterial activity and to obtain data relevant to the clinical situation. However, the inoculum effect, the metabolism of bacteria, the mechanism of the bactericidal action of drugs and the type of infected tissue are important factors to be taken into account. In humans, data obtained from infected tissue is sparse and contributes little to knowledge. Knowledge of tissue levels may be important for establishing whether data obtained in animals can be applied to humans or not. Fourthly, the importance of tissue levels in determining antibiotic dosages is evaluated. In humans, tissue levels are of limited value in the determination of unitary dose and dosage intervals in relation to the clinical response. Trough serum levels of free drug, half-life at the beta-phase and rate of in vitro killing are the most important parameters to be considered. Their relative importance depends mainly on the mode of action of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[The factors determining the efficacy of the rehabilitative treatment of patients who have had a myocardial infarct].

Factors responsible for the efficacy of rehabilitative treatment of patients with a history of myocardial infarction were defined on the basis of the 2-year follow-up of 235 patients who suffered myocardial infarction, bicycle ergometry data, studies into intracardiac hemodynamics, oxygen supply in exercise tests, and criteria for the significance of the tetrachoric indicator with regard to the confidence limits. In patients who suffered uncomplicated myocardial infarction, prediction of the decreased work fitness in the long-term period is determined by the presence of angina pectoris and arterial hypertension. It has been established that whether will be lowered in future can be judged from the changes seen in the magnitude of the liminal power and the end diastolic volume of the left ventricle during the first 6 months following myocardial infarction.

Adult↗
PubMed2003

Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy.

Based on experiment and computational simulation, we present a structural explanation for the differing efficacies of indole agonists at the human serotonin 5-HT2A receptor (5HT2AR). We find that serotonin [5-hydroxytryptamine (5-HT)] forms hydrogen-bonds with Ser3.36 in helix 3 and Ser5.46 in helix 5. Disruption of these hydrogen bonds by methyl-substitution of the cationic primary amine or of the backbone N1-amine, respectively, leads to a reduction in agonist efficacy. Computational simulation predicts that mutation of Ser3.36 to Ala should allow a similar interaction with helix 3 both for agonists that have unmodified cationic amine side chains and for those with substituted amines. Experimentally, this mutation was found to largely eliminate the differences in efficacy caused by cationic amine substitution for a series of indole congeners. Similarly, substitution of the N1-amine, which interacts with Ser5.46, reduced efficacy more markedly at the wild-type (WT) than at the Ser5.46Ala mutant receptor. Computational modeling of binding pocket interactions of ligands with WT and mutant receptor constructs demonstrate how the Ser3.36 and Ser5.46 interactions serve to modify the agonist's favored position in the binding pocket. A striking correlation was found between differences in the position assumed by the indole ring and differences in agonist activity. These data support the hypothesis that the position of the agonist interacting with the receptor is influenced by specific interactions in helices 3 and 5 and determines the degree of receptor activation by agonist through a mechanism that is likely to be shared by other G-protein coupled receptors in this class.

Alanine↗
PubMed1982

A placebo-controlled study to determine the efficacy of oral disopyramide phosphate for the prophylaxis of ventricular dysrhythmias after acute myocardial infarction.

1 To evaluate oral disopyramide phosphate in the prophylaxis of dysrhythmias occurring in acute myocardial infarction (MI) patients (presenting within 12 h of symptoms, age 21-70 years), a placebo-controlled, randomized double-blind, in hospital trial was conducted. After prognostic stratification (anterior and non-anterior MI at each of 4 regional hospitals) patients were randomly assigned to receive oral disopyramide phosphate (loading dose 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh less than 55, 55-85, or greater than 85 kg, respectively or matching placebo. The primary exclusion criteria were overt heart failure, systolic BP less than 100 mmHg, significant heart block or history of urinary retention. Active drug or placebo was continued for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 premature ventricular contractions (PVCs)/min, R on T PVCs, multifocal PVCs, bigeminal PVCs, ventricular tachycardia or ventricular fibrillation) or (b) onset of exclusion criteria. In addition, plasma drug concentrations were determined and 24 h electrocardiographic tapes were obtained on day 1, and on one of days 4-7 but these results are not presented here. 2 Out of 121 patients entering the trial, 101 had confirmatory ECG and enzyme changes. Of these, 9 of 47 patients receiving disopyramide phosphate required lignocaine compared to 20 of 54 receiving placebo (19% v 37%; P = 0.047). Corresponding numbers for patients discontinuing trial medication for other non-fatal complications of MI were 5 and 3, and for those dying, were 3 (2 infarct extensions and 1 massive infarction), and 0, respectively. Respective numbers discontinuing trial medication for possible drug side effects (viz. urinary retention requiring catheterization) were 6 and 1 (P = 0.031). 3 In circumstances where i.v. therapy is deemed impractical, use of oral disopyramide phosphate given prophylactically in patients with acute MI may reduce the incidence of "warning arrhythmias' by a clinically significant extent.

Adult↗
PubMed2002

Computer simulations to determine the efficacy of different genome resource banking strategies for maintaining genetic diversity.

Genome resource banks (GRBs) and assisted reproductive techniques are increasingly recognized as useful tools for the management and conservation of biodiversity, including endangered species. Cryotechnology permits long-term storage of valuable genetic material. Although, the actual application to endangered species management requires technical knowledge about sperm freezing and thawing, a systematic understanding of the quantitative impacts of various germ plasm storage and use scenarios is also mandatory. In this study, various GRB strategies were analyzed using the historical data from three managed populations of endangered species with varied pedigrees (Eld's deer, Przewalski's horse, and Sumatran tiger). The following types of sperm banks were assessed: (1) a "Wild Bank" consisting of sperm (i.e., genes) from 5 to 10 males unrelated to the managed population and to each other; and (2) a "Best Male" bank containing sperm from only the most genetically valuable males alive in the ex situ population at the time the bank was established. These different bank types were then used to evaluate the effectiveness of different bank usage frequencies. The efficiency of each scenario was assessed by examining the level of inbreeding and gene diversity in the population. Overall, a sperm usage frequency of five times per year was determined to be the most efficient and "wild banks" were highly successful at enhancing genetic diversity. The value of a GRB established from the ex situ population depends on how closely related the banked males are to future generations. A GRB will have significantly less benefit when banked males also produce many successful offspring, or when donors are already genetically over-represented in the population at the time of establishing the GRB.

Animals↗
PubMed2006

The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma.

BACKGROUND: Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma. However, approximately one-third of patients show little or no initial response to this partial beta(2)-agonist. METHODS: We conducted a randomized, double-blind, proof-of-concept study to investigate whether a full beta(2)-agonist, isoproterenol, offers a therapeutic advantage in adults presenting with acute severe asthma (FEV(1)<50%) who fail to respond to an initial treatment of the partial beta(2)-agonist, albuterol. Study subjects were randomized to receive a 2-h continuous nebulization of either albuterol (7.5mg/h) (n=10, mean FEV(1)=37% predicted) or isoproterenol (7.5mg/h) (n=9, mean FEV(1)=33% predicted). Respiratory symptoms, vital signs and pulmonary function measures were collected. RESULTS: Subjects from both treatment groups had similar baseline characteristics. The percent improvements from baseline FEV(1) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol (44 vs. 17% and 63 vs. 24%, respectively, P<0.05). The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol (P<0.01). Both treatments were well tolerated, though the mean increase in pulse rate at 60 and 120min (21 vs. 1 and 23 vs. 6beats/min, respectively, P<0.05) and the mean change in serum potassium at 120min (-0.52 vs. -0.07meq/L, P<0.05) from baseline were significantly greater in the isoproterenol group. CONCLUSIONS: Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol, the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms.

Acute Disease↗
PubMed2005

IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection.

Leishmaniasis affects 12 million people, but there are no vaccines. Immunological correlates of vaccine efficacy are unclear. Polarized Th1 vs Th2 responses in Leishmania major-infected mice suggested that a shift in balance from IL-4 to IFN-gamma was the key to vaccine success. Recently, a role for IL-10 and regulatory T cells in parasite persistence was demonstrated, prompting re-evaluation of vaccine-induced immunity. We compared DNA/modified vaccinia virus Ankara heterologous prime-boost with Leishmania homolog of the receptor for activated C kinase (LACK) or tryparedoxin peroxidase (TRYP). Both induced low IL-4 and high IFN-gamma prechallenge. Strikingly, high prechallenge CD4 T cell-derived IL-10 predicted vaccine failure using LACK, whereas low IL-10 predicted protection with TRYP. The ratio of IFN-gamma:IL-10 was thus a clear prechallenge indicator of vaccine success. Challenge infection caused further polarization to high IL-10/low IFN-gamma with LACK and low IL-10/high IFN-gamma with TRYP. Ex vivo quantitative RT-PCR and in vitro depletion and suppression experiments demonstrated that Ag-driven CD4+ CD25+ T regulatory 1-like cells were the primary source of IL-10 in LACK-vaccinated mice. Anti-IL-10R treatment in vivo demonstrated that IL-10 was functional in determining vaccine failure, rendering LACK protective in the presence of high IFN-gamma/low IL-5 responses.

Animals↗
PubMed1998

Factors determining the efficacy of distal excitatory synapses in rat hippocampal CA1 pyramidal neurones.

1. A new preparation of the in vitro rat hippocampal slice has been developed in which the synaptic input to the distal apical dendrites of CA1 pyramidal neurones is isolated. This has been used to investigate the properties of distally evoked synaptic potentials. 2. Distal paired-pulse stimulation (0.1 Hz) evoked a dendritic response consisting of a pair of EPSPs, which showed facilitation. The first EPSP had a rise time (10-90%) of 2.2 +/- 0.05 ms and a half-width of 9.1 +/- 0.13 ms. The EPSPs were greatly reduced by CNQX (10 microM) and the remaining component could be enhanced in Mg(2+)-free Ringer solution and blocked by AP5 (50 microM). In 70% of the dendrites, the EPSPs were followed by a prolonged after-hyperpolarization (AHP) which could be blocked by a selective and potent GABAB antagonist, CGP55845A (2 microM). These results indicate that the EPSPs are primarily mediated by non-NMDA receptors with a small contribution from NMDA receptors, whereas the AHP is a GABAB receptor-mediated slow IPSP. 3. With intrasomatic recordings, the rise time of proximally generated EPSPs (3.4 +/- 0.1 ms) was half that of distally generated EPSPs (6.7 +/- 0.5 ms), whereas the half-widths were similar (19.6 +/- 0.8 ms and 23.8 +/- 1 ms, respectively). These results indicate that propagation through the proximal apical dendrites slows the time-to-peak of distally generated EPSPs. 4. Distal stimulation evoked spikes in 60% of pyramidal neurones. At threshold, the distally evoked spike always appeared on the decaying phase of the dendritic EPSP, indicating that the spike is initiated at some distance proximal to the dendritic recording site. Furthermore, distally and proximally generated threshold spikes had a similar voltage dependency. These results therefore suggest that distally generated threshold spikes are primarily initiated at the initial segment. 5. At threshold, spikes generated by stimulation of distal synapses arose from the decaying phase of the dendritic EPSPs with a latency determined by the time course of the EPSP at the spike initiation zone. With maximal stimulation, however, the spikes arose directly from the peak of the EPSPs with a time-to-spike similar to the time-to-peak of subthreshold dendritic EPSPs. Functionally, this means that the effect of dendritic propagation can be overcome by recruiting more synapses, thereby ensuring a faster response time to distal synaptic inputs. 6. In 42% of the neurones in which distal EPSPs evoked spikes, the relationship between EPSP amplitude and spike latency could be accounted for by a constant dendritic modulation of the EPSP. In the remaining 58%, the change in latency was greater than can be accounted for by a constant dendritic influence. This additional change in latency is best explained by a sudden shift in the spike initiation zone to the proximal dendrites. This would explain the delay observed between the action of somatic application of TTX (10 microM) on antidromically evoked spikes and distally evoked suprathreshold spikes. 7. The present results indicate that full compensation for the electrotonic properties of the main proximal dendrites is not achieved despite the presence of Na+ and Ca2+ currents. Nevertheless, distal excitatory synapses are capable of initiating spiking in most pyramidal neurones, and changes in EPSP amplitude can modulate the spike latency. Furthermore, even though the primary spike initiation zone is in the initial segment, the results suggest that it can move into the proximal apical dendrites under physiological conditions, which has the effect of further shortening the response time to distal excitatory synaptic inputs.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

A randomised, double blind, placebo-controlled study to determine the efficacy of immune modulation therapy in the treatment of patients suffering from peripheral arterial occlusive disease with intermittent claudication.

OBJECTIVES: this study examined the effect of immune modulation therapy (IMT) on claudication distances. MATERIALS AND METHODS: a double-blind placebo controlled trial was performed on patients with disabling intermittent claudication with randomisation stratified for short and long distance IC. For IMT, following exposure to UV light, oxidisation and 42.5 degrees C, 10 ml of citrated autologous blood was administered by intra-muscular injection. One course consisted of 6 injections in 3-weeks followed by 3-weeks rest. Patients received 2, 3 or 4 courses depending on response. The primary end-point was the number of responders (>50% increase in initial claudication distance (ICD)) in each group. Secondary end-points included percentage changes in ICD and change in quality of life. RESULTS: at week 24, there were more responders in the IMT group (20/31, 65%) compared to placebo (16/39, 41%) (p=0.06). In the subgroup of short distance claudicants this difference reached significance (IMT 17/26, 65%) (Placebo 12/33, 36%) (p=0.04). The median increase in ICD was significantly greater in the IMT group (81%) compared to placebo (44%, p=0.04). These results were supported by quality of life measurements. CONCLUSIONS; IMT is a safe and apparently effective treatment for patients with short distance claudication.

Aged↗
PubMed1992

Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma.

This study was aimed at defining the therapeutic value of percutaneous ethanol injection in patients with solitary hepatocellular carcinoma less than 4 cm. Ultrasound-guided ethanol injection was performed in 24 cirrhotic patients (9 Child A, 10 Child B and 5 Child C), with hepatocellular carcinoma not suitable for surgical treatment. Its efficacy was assessed by repeated ultrasound, computed tomography and tumor biopsy during a follow-up ranging between 4 and 41 mo. Ethanol injection did not achieve a complete tumor necrosis in five cases after a minimum of 12 injections. Seven of the remaining 19 cases, with initial success, have shown recurrence during follow-up, thus resulting in 50% success rate, which was significantly related to baseline tumor size. The six patients with nodules less than 2 cm achieved a complete response, whereas this was recorded in 2 of the 7 with tumor size between 2 and 3 cm, and in only 1 of the 11 cases between 3 and 4 cm. The 1- and 2-yr survival of Child's A and B patients was 87% and 70%, respectively. These results indicate that percutaneous ethanol injection is a useful treatment for hepatocellular carcinoma, especially in tumors less than 3 cm. The high survival rate among patients with nonadvanced liver disease suggests that this therapeutic approach can be considered an alternative approach to surgical resection for tumors smaller than 3 cm.

Aged↗