Times Higher Dose Research Articles

Cholesterol-lowering effect of NK-104, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in guinea pig model of hyperlipidemia.

Although benefits of statins have been demonstrated even in normolipidemic patients at high risk, the main target of statin therapy is the hypercholesterolemic patient. The aim of this study was to examine the hypocholesterolemic effect of NK-104 ((+)-monocalcium bis((3R,5S,6S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]- 3,5-dihydroxy-6-heptenoate), CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and its mechanism of action in hypercholesterolemic animals. In guinea pigs fed a diet containing 15% (w/w) fat rich in laurate for 6 weeks, the liver cholesterol content was markedly increased and plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and LDL-apoB were elevated 4.8, 5.2 and 1.7 times, respectively, compared with normal diet fed animals. These changes were maintained by reduced LDL clearance in the presence of markedly cholesterol-enriched LDL in the plasma. In this model, the LDL-C reduction rates by 0.1, 0.3 and 1 mg/kg of NK-104 orally administered for 2 weeks (from week 4 to week 6), were 11, 27 and 32%, respectively, from controls, being similar in normal guinea pigs previously examined. Those for 3 and 10 mg/kg of atorvastatin (CAS 134523-00-5) were 25 and 39%, respectively. Thus about 10 times higher doses of atorvastatin were required than of NK-104 to cause a similar cholesterol-lowering effect. This reduction of plasma cholesterol was accompanied by an improvement of LDL clearance (24 and 47% increase in fractional catabolic rate by 1 mg/kg of NK-104 and 10 mg/kg of atorvastatin, respectively) and LDL composition. In conclusion, in guinea pig hypercholesterolemia caused by high-laurate diet, NK-104 and atorvastatin lowered plasma cholesterol levels with an improvement of LDL composition and with an increase in LDL clearance, presumably through reduction of the liver cholesterol content, although hepatic cholesterol synthesis might have been markedly suppressed in this model.

First and Second High Dose Treatment Supported by Autologous Hematopoetic Cell Transplantation Rescue in Multiple Myeloma

Abstract 4528 Purpose:We aimed to evaluate the outcome of multiple myeloma patients underwent double autologus hematopoietic cell transplantation in our center. Patient&Method:We retrospectively analyzed 31 multiple myeloma patients (22F;9M) receiving two times high dose therapy supported by auto-HCT in Adult BMT Unit of Ankara University between 2005–2010. Median age was 52 years (34–66ys) prior to first auto-HCT. We evaluated the response rates of progression free survival (PFS) of both transplantation, respectively and also overall survival (OS) from the diagnosis. Results:The median time from diagnosis to the first transplantation was 11 months (5–68ms). The response rates were 87% before the first auto-HSCT [2 Complete response (CR),4 near-CR, 7 very good partial remission (VGPR), 14 PR) but four patients (11%) had refractory disease. The response of first auto-HCT was complete remission or partial response in 50% of the pts and 36% for stable disease. Only 4 pts was progressed at early period of 1st auto-HCT. The median time from the 1st to 2nd auto-HSCT was 16 months (3–64 ms). Seventy-seven percent patients sue to progressive disease responded completely or partially to one or two step treatment regimens before the second auto-HSCT. When evaluated the responses after the second auto-HCT, 14 (46%) patients were in CR or near-CR, 12 (38%) for stabile disease and 5 for refractory. PFS was estimated similar after both first and second auto-HCT (median 9 months vs 10 months, p=0.3) (Graphic 1). Five- year OS from the diagnosis was 75±10%. [Display omitted] Conclusion:PFS of the myeloma pts was estimated similar median time after 1st&2nd auto-HSCT. Collection of adequate hematopoietic stem cells enough for more than one auto-HCT in myeloma patients can be appropriate. Although the majority of responses after the first AHSCT were partial responses, complete or near complete responses were dominant after the second AHSCT.Improvement in responses and the similarity of progression free survival can be explained by the contribution of the new antimyelom treatment options Disclosures:No relevant conflicts of interest to declare.

High-energy ionising radiation initiated decomposition of acetovanillone

Hydroxyl radical, hydrated electron and hydrogen atom intermediates of water radiolysis react with acetovanillone with rate coefficients of (1.05±0.1)×1010, (3.5±0.5)×109 and (1.7±0.2)×1010mol−1dm3s−1. Hydroxyl radical and hydrogen atom attach to the ring forming cyclohexadienyl type radicals. The hydroxyl–cyclohexadienyl radical formed in hydroxyl radical reaction in dissolved oxygen free solution partly transforms to phenoxyl radical. In the presence of O2 phenoxyl radical formation and ring destruction are observed. Hydrated electron in O2 free solution attaches to the carbonyl oxygen and undergoes protonation yielding benzyl type radical. In air saturated 0.5mmoldm−3 solution using 15kGy dose most part of acetovanillone is degraded, for complete mineralisation five times higher dose is required. The experiments clearly show that acetovanillone can be efficiently removed from water by applying irradiation technology.

The effect of vitamin D supplementation on peripheral regulatory T cells and β cell function in healthy humans: a randomized controlled trial

Increasing evidence supports the role of vitamin D (vitD) in modifying the risk to develop type 1 diabetes (T1D) and other autoimmune diseases. VitD3 might stimulate regulatory T cells (Tregs), a central player in the maintenance of self-tolerance. In addition, direct effects of vitD on β-cell function are postulated. The aim of our study was to evaluate the effect of a high dose vitD supplementation on Tregs frequency (%Tregs) and β-cell function assessed by a mixed meal tolerance test (MMTT) in healthy humans. A double-blind, placebo controlled trial was performed in 59 healthy adult subjects (49% females). Subjects received oral vitD3 (140,000 IU monthly) or placebo for 3 months. %Tregs within 20,000 CD4+ T cells of peripheral blood was determined by multi-parametric FACS-analysis. A liquid MMTT was carried out before and after treatment. %Tregs increased significantly in the vitD group, but remained unchanged in the placebo group. Fasting C-peptide concentrations did not change significantly in either group. Similarly, the mean AUC for C-peptide after 3 months and the change in mean values from baseline to the end of the treatment were comparable in both groups. A short time high dose vitD3 supplementation significantly increased the frequency of Tregs, but did not further improve β-cell function in apparently healthy subjects. The immunomodulatory potential of vitD might be an important mechanistic link for the association of vitD and T1D.

SU‐D‐301‐02: Increase of Generalized 2D NEQ for the Microangiographic Fluoroscope (MAF) System Using the Medium Rather than the Small Focal Spot

Purpose: To increase the generalized NEQ (GNEQ) for the new high‐ resolution Microangiographic Fluoroscope (MAF) by using the increased tube‐loading capacity of the medium focal spot compared to the small focal spot. Methods: Generalized MTF (GMTF), generalized NNPS (GNNPS) and GNEQ were calculated for the MAF at a fixed object magnification of 1.11 for the medium and small focal spots on the central axis and the medium focal spot on the anode side. Due to increased tube‐loading capacity of the Toshiba Infinix system for the 0.5‐mm medium focal spot compared to the 0.3‐mm small focal spot, the 2D NNPS was calculated at 3.125 times higher dose on the central axis and 2.85 times higher dose on the anode side (considering a 9% reduction in intensity due to the Heel effect) for the medium spot. Results: The GNEQ ratio of medium‐to‐small focal‐spot at the central axis is much greater than 1.0 at low frequencies, with a rapid drop at higher frequencies in the tube axis direction, becoming less than 1.0 above 7 cycles/mm. The GNEQ of medium focal spot at the anode side is higher at nearly all frequencies below the Nyquist due to the reduced effective focal spot size, becoming less than 1.0 above 9 cycles/mm. Conclusions: Improvements in GNEQ can be obtained for the MAF using the medium focal spot as compared to the small focal spot at the central axis position at low frequencies, whereas the GNEQ is improved for almost all frequencies for the medium focal spot at the anode side. There is a clear benefit to utilizing the increased tube output for the medium focal spot, while decreasing the effective anode angle to reduce focal spot size but maintain sufficient FOV for the MAF. Support: NIH Grants R01‐EB008425, R01‐EB002873

Lung dosimetry for inhaled long-lived radionuclides and radon progeny

The current version of the stochastic lung dosimetry model IDEAL-DOSE considers deposition in the whole tracheobronchial (TB) and alveolar airway system, while clearance is restricted to TB airways. For the investigation of doses produced by inhaled long-lived radionuclides (LLR) together with short-lived radon progeny, alveolar clearance has to be considered. Thus, present dose calculations are based on the average transport rates proposed for the revision of the ICRP human respiratory tract model. The results obtained indicate that LLR cleared from the alveolar region can deliver up to two to six times higher doses to the TB region when compared with the doses from directly deposited particles. Comparison of LLR doses with those of short-lived radon progeny indicates that LLR in uranium mines can deliver up to 5 % of the doses predicted for the short-lived radon daughters.

The c.-1639G>A polymorphism of the VKORC1 gene in Serbian population: retrospective study of the variability in response to oral anticoagulant therapy

A single nucleotide polymorphism c.-1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral vitamin K antagonist (VKA). Our aim was to study the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in a group of patients under stable anticoagulation, and to estimate the variability in response to VKA. We conducted a retrospective cohort analysis of 200 stable anticoagulation patients followed from the initiation of VKA. Out of 43 low-dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high VKA dose; among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. Patients with GG genotype required 2.6 times higher dose than patients carriers of AA genotype (P < 0.0001). Carriers of AA genotype were more likely to be overanticoagulated during follow-up after initiation of VKA when compared with carriers of the GA and GG genotypes (P < 0.0001). Patients with GG genotype spent more time below therapeutic range compared with patients carriers of AA (P = 0.0328) and GA genotype (P < 0.0001). VKORC1 c.-1639G>A polymorphism significantly influenced VKA dose and represented a good predictor of individuals predisposed to unstable anticoagulation. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients, carriers of AA genotype, before the initiation of anticoagulation.

High Dose Intensive Chemotherapy, as Is Standard in Childhood Leukemia, Is Feasible and Efficacious in Adult Patients with Acute Lymphoblastic Leukemia (ALL) up to the Age of 40: Results From the Dutch-Belgian HOVON-70 Study.

Abstract 323Event-free survival (EFS) at 5 years in pediatric ALL is > 80% with dose intensive multi-agent chemotherapy. In contrast, adult ALL still has an unsatisfactory outcome, which may partly be due to less cumulative dosing of chemotherapeutic agents and less strict adherence to timing of successive cycles of chemotherapy. Given the earlier reported feasibility of pediatric schedules in adolescent patients, the HOVON group performed a prospective multicenter phase II trial to evaluate the feasibility and efficacy of an intensified treatment regimen in adult patients with newly diagnosed ALL aged 18–40 years. The treatment regimen was based on the French FRALLE-2000 protocol, including dose intensification for steroids, vincristine, L-asparaginase, and high dose methotrexate (MTX).Fifty-four patients, median age 26 years (range 17–39) were enrolled in 15 centres in the Netherlands and Belgium between December 2005 and August 2007. After a prednisolon prephase and a multidrug remission-induction (prednisolon, daunorubicin, vincristine, cyclophosphamide and L-asparaginase), patients received consolidation containing 5000 mg/m2 MTX twice, two intensifications with intensified L-asparaginase, interspersed by an interphase with again two times high dose MTX, and maintenance chemotherapy (oral MTX and 6-mercaptopurine (6-MP) with reinduction with vincristine and prednisolon) for two years. CNS prophylaxis with MTX was delivered intrathecally 18 times. Standard risk patients with an HLA-identical sibling stem cell donor proceeded to allogeneic stem cell transplantation (alloSCT) after the first intensification, high risk patients received alloSCT from either sibling or unrelated donors. Adherence to the treatment schedule was urged by defining a strict timetable. Feasibility was defined by completion of chemotherapeutic and alloSCT protocol treatment within this a pre-defined timeframe.Thirty-five patients (65%) had B-cell phenotype ALL, 17 (31%) had T-cell phenotype and 2 (4%) had biphenotypic leukemia. Moreover, 23 patients (43%) had high risk disease, of whom 9 patients with BCR-ABL positive ALL. In total 33 patients fully completed treatment as scheduled, including 18 alloSCT recipients. Complete remission (CR) was achieved in 91% (95% CI: 80–97). After a median follow-up of 26 months (range 15–36 months), 2-year event-free-survival (EFS) is 68% (95% CI: 53–78), 2-year disease free survival (DFS) 74% (95% CI: 59–84) and the 2-year overall survival (OS) 70% (95% CI: 55–81). Fifteen patients (28%) died, including 8 due to relapsed/refractory ALL, 3 due to infection, 3 due to toxicity and 1 due to graft versus host disease. CTC grade 4-5 toxicities (mainly liver/kidney function abnormalities and peripheral neuropathy) were observed in 15% during induction and 13% during consolidation. Severe infections (CTC grade 3-4) primarily occurred during induction (41%) and consolidation (39%). Failures were due to not reaching CR in 5 patients, early relapse in 2, severe extramedullary drug toxicity in 3, excessive delay in 7 and other reasons not otherwise specified (but most likely due to toxicity) in 4 patients.In conclusion, these data show that a dose-intensified chemotherapeutic regimen based on a pediatric schedule is safe and feasible in most adult ALL patients up to the age of 40, although a delay of subsequent cycles was frequently observed. Early efficacy data suggest a high CR rate and favourable DFS and OS. Based on this experience, a randomised phase III trial has recently been initiated.This trial was supported by the Dutch Cancer Foundation (CKTO 2005-08), EudraCT number 2005-000919-96 Disclosures:No relevant conflicts of interest to declare.

The c.-1639g&gt;A polymorphism of the VKORC1 gene and his influence on the therapeutic response during oral anticoagulants use

A single nucleotide polymorphism c.-1639G > A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G > A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. Out of 43 low dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001). VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients--carriers of AA genotype, before anticoagulation therapy initiation.

Electron irradiation of AlGaN∕GaN and AlN∕GaN heterojunctions

The effects of 10MeV electron irradiation on AlGaN∕GaN and AlN∕GaN heterojunctions grown by molecular beam epitaxy are reported. The irradiation increases the resistivity of the GaN buffer due to compensation by radiation defects with levels near Ec−1eV and decreases the mobility of the two-dimensional electron gas (2DEG) near the AlGaN∕GaN (or AlN∕GaN) interface. The bulk carrier removal rate in the GaN buffer is the same for both types of structures and similar to carrier removal rates for undoped n-GaN films. In structures with a density of residual donors of ∼1015cm−3, irradiation with electron doses of ∼5×1015cm−2 renders the buffer semi-insulating. The 50% degradation of the 2DEG conductivity happens at several times higher doses (close to 3×1016cm−2 versus 6.5×1015cm−2) for AlN∕GaN than for AlGaN∕GaN structures, most likely because of the lower thickness of the AlN barrier.

Acute Ethanol Exposure Attenuates Pattern Recognition Receptor Activated Macrophage Functions

Both clinical and experimental data have linked acute ethanol exposure to increased susceptibility to infection as well as increased morbidity and mortality after injury. Macrophages play an integral role in the innate immune system and are important in priming the adaptive immune system. In this study, we investigated the effect of a single in vivo exposure of macrophages to physiologically relevant levels of ethanol (1.2 and 2.9 g/kg) followed by ex vivo stimulation with lipopolysaccharide (LPS) or bacteria. Our study confirms the work of others showing that a single administration of ethanol suppresses the production of tumor necrosis factor-alpha(TNF-alpha), interleukin-6 (IL-6), and IL-12 in response to LPS. There was no effect of ethanol on LPS induction of cytokine production at 30 min after treatment. In contrast, at 3 h, both doses of ethanol exposure decreased ex vivo TNF-alpha production by splenic and alveolar macrophages. Interestingly, the higher dose of ethanol resulted in sustained suppression of LPS-induced TNF-alpha production at 3 and 6 h after ethanol administration, as well as decreased IL-6 and IL-12 production after 6 h, as compared to control (saline-treated groups). Alveolar macrophages behaved similarly at 3 h after ethanol treatment. LPS-stimulated production of TNF-alpha and IL-6 was reduced at 3 h after ethanol administration, when compared with the saline-treated animals. Alveolar macrophages stimulated for 3 h with bacteria also showed decreased TNF-alpha and IL-6 production after harvested from mice given 2.9 g/kg ethanol for 3 h. This time point and high dose of ethanol also resulted in decreased Pseudomonas aeruginosa phagocytosis by alveolar macrophages. Taken together, we conclude that the effects of physiological levels of ethanol are dose dependent, have effects that last after ethanol is cleared from the circulation, and can affect multiple macrophage functions.

The influence of polymorphisms in cytokine genes on pain and response to analgesia in lung cancer patients receiving palliative treatment

9503 Background: We reported cytokine gene polymorphisms as a significant factor for severe pain at time of registration in 446 White patients newly diagnosed with non-small cell lung cancer. This follow-up study explores the extent to which cytokine gene variants could explain variability in self-reported pain and analgesic response among those patients (n=140) subsequently referred to palliative care specialists for pain treatment and control. Methods: Pain severity (0=no pain; 10-worst pain) was assessed at initial consultation and at first follow- up visit. Total dose of opioids at the time of first-follow up visit was converted to an equivalent dose of parenteral morphine. We genotyped single nucleotide polymorphisms in tumor necrosis factor-alpha (TNF α-308 G/A), interleukin (IL) -6 - 174G/C, and IL-8 -251T/A genes. Results: Forty-one percent (57/140) of the patients reported severe pain (score >7/10) at initial consultation (mean=5.5; median=6; mode=7), which significantly decreased to 25% (mean= 4; median=4; mode=2) at first follow-up visit (McNemar=P<0.01). Mean Morphine Equivalent Daily Dose (MEDD) obtained during the first follow-up visit was 89mg/24h (SD=119) and median was 50 mg/24h. Polymorphisms in TNF and IL6 were significantly associated with pain severity (TNF α-308 G/G=4.12; G/A=5.38; A/A=5.50; p=0.04) and with MEDD (IL-6 -174G/G=69.61; G/C=93.6; C/C=181.67; p=0.004), respectively. Adjusting for demographic and clinical variables, the TNF-308 G/A variant (b=1.309; p=0.036) remained significantly associated with pain severity. In terms of opioid requirements for pain relief, patients carrying the IL6–174C/C genotypes required 4.7 times higher dose [Odds Ratio=4.7; 95%CI=1.2; 15.0] relative to G/G and G/C genotypes. Conclusions: This analysis provides preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Exelixis, Merck, Novartis

Cyclooxygenase-2 Inhibition by Etoricoxib Modulates Plasma Membrane Fluidity in Rat Colon

The present study was designed to investigate the effects of a selective cycloogenase-2 (COX-2) inhibitor, etoricoxib, on the membrane-specific enzymes, lipid composition, and changes in fluidity parameters of rat colonic plasma membrane. Two doses of the drug were used, one within its therapeutic anti-inflammatory range as based on the ED50 value in rats (Eto-1), while the other at 10 times higher dose relating to the toxicity studies (Eto-2), which have not been reported so far. The activity of the membrane alkaline phosphatase was found to be increased after treatment with both the doses of etoricoxib as compared to the control. The total lipid and the cholesterol content showed a decrease while an increase in ganglioside sialic acid content was noted. Phospholipid content and the cholesterol-phospholipid molar ratio showed no change in either of the treatment groups. Fluorescence polarization studies with diphenylhexatriene showed that membrane fluidity was least altered in the isolated brush border membrane from colon or in the liposomes prepared from the membrane lipid extracts. Also, the translational diffusion studied with pyrene showed that the fluidity parameter was decreased as measured by the excimer formation. It is concluded that etoricoxib, a new generation COX-2 inhibitor (called the coxibs), appeared to be a safe nonsteroidal anti-inflammatory drug (NSAID) in the colonic membranes.

Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone

The potent antiproliferative effect of progestins has been utilized in clinical regimens for treatment of endometrial proliferative disorders. The progestin infiltrated intrauterine device used as therapy for endometrial carcinoma as well as endometrial hyperplasia yields a hundred-fold increase of local progestin concentration in the endometrium compared to that of oral treatment. The genetic basis for the complex effects of high dose progestins and the different signalling pathways regulated by these genes have never been accurately surveyed. The aim of the present study was to determine the gene expression pattern in highly differentiated endometrial cancer cells (Ishikawa) after short time exposure to high progesterone doses. In eight independent experiments, cells were treated with progesterone (30 μg/ml) for 4 h and gene expression was compared to that of untreated cells, which served as controls. Microarray analysis revealed 247 differentially expressed genes of which 126 were up-regulated and 121 were down-regulated. Of these, 135 genes are known to be involved in biological processes like cell cycle, cell proliferation and differentiation, developmental processes, immune responses, intracellular protein traffic and transport. Our study shows that microarray analysis can detect relevant gene expression changes in endometrial cells treated with progestin, including those involved in several alternative transcriptional factors and signalling pathways. Many of the differentially expressed genes were not previously known to be affected by progesterone or have unknown biological functions. Characterization of these genes may give new insights into molecular responses to treatment with high progesterone doses. Alternative signalling pathways for progesterone, rather than the classical steroid receptors pathways are also suggested.

Rat survival to anthrax lethal toxin is likely controlled by a single gene

We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all 'sensitive' strains died within 2 h following systemic administration of 240 mug/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.

Systematics of the giant isotope effect in hydrogen ion blistering of materials

The giant isotope effect, observed when D ions were substituted for H ions in low energy blistering of silicon, challenged common assumptions based on ion irradiation theory and H–Si chemistry. We report a systematic investigation of the effect in several materials, in an attempt to identify its origin. Samples of Si, Ge, GaAs, 6H–SiC and SrTiO 3 (STO) were implanted at 5 keV with various H or D doses (1 × 10 16 to 2 × 10 17 cm − 2 ) and rapid thermal annealed. The resulting surface morphology was examined by atomic force microscopy. On Si and GaAs, D-ion blistering requires 2 to 3 times higher doses than H-ion blistering. On SiC, no D-ion blistering whatsoever is observed. On the other hand, on Ge and STO, there is little difference between H and D-induced blistering. For Si, Raman spectroscopy of Si–H/D bonding in conjunction with lattice kinetic Monte-Carlo calculations led to an interpretation of the effect in terms of reactions between the mobile entities, i.e. H (or D) atoms, vacancies and interstitials. The new data will be discussed by reference to this scenario.

Effects of intravitreally and intraperitonally injected atropine on two types of experimental myopia in chicken

Atropine, a non-selective muscarinic receptor antagonist, is currently the most potent agent used to prevent myopia in animal models and children. However, the ocular target tissues are not well defined. To learn more about the effect of atropine on experimental myopia, atropine was applied both intravitreally and systemically (intraperitoneally) to chickens wearing either negative lenses or light diffusers. Furthermore, the effect of ipsilateral intravitreal atropine on myopia development in the saline-treated fellow eye was studied. Monocular intravitreal injections of atropine were performed daily for a period of 4 successive days, starting at day 8 post-hatching. Fellow eyes received saline injections. Chicks were fitted with −7 D lenses, either over the atropine-injected eyes only (unilateral “lens-induced myopia (LIM)”), or over both eyes (bilateral LIM). Other groups of chicks were fitted with translucent diffusers over the atropine-injected eyes (unilateral “form deprivation myopia (FDM)”). Finally, atropine was intraperitoneally injected for 4 days in chicks that wore monocularly −7 D lenses. Refractive errors (RE) were measured with infrared photoretinoscopy and axial length (AL) with A-scan ultrasonography. Atropine prevented development of myopia in both unilateral LIM and FDM in a dose-dependent fashion. Fifty percent inhibition of myopia was observed at a dose of 25 μg (unilateral LIM) or 90 μg atropine (bilateral LIM) and complete inhibition at 750 μg; in unilateral FDM, 50% inhibition occurred at 2.5 μg and almost 100% inhibition at 250 μg. Interestingly, at the highest dose of atropine (2500 μg), the treated eyes became even more hyperopic compared to the saline-injected contralateral eyes with normal visual experience. In the bilateral LIM model, atropine suppressed development of myopia in both the treated and the saline-injected control eye. However, about 8.3 times higher doses were necessary to achieve comparable contralateral suppression. Since this ratio is lower than the vitreous volume to blood volume ratio (about 1:23 in young chicks), it seems unlikely that systemic dilution of the intravitreally injected drug can fully account for the contralateral suppression. Intraperitoneal injection inhibited myopia development only at the highest dose (2500 μg) but, strikingly, this inhibition was still less when the same dose was provided through the vitreous of the fellow eye. Both eyes seem to be coupled by a yet unknown, perhaps neuronal pathway. Estimations of the scleral concentrations of atropine after intravitreal injection are compatible with the assumption that the suppression of myopia by atropine occurs by direct inhibition of scleral chondrocytes.

Effect of Cadmium, Nickel and Zinc on the Antagonistic Activity of Trichoderma Spp. against Pythium irregulare Buisman

The purpose of this study was to survey the growth inhibition with volatile antibiosis and killing of Pythium irregulare by Trichoderma species of various origin under heavy metal stress. Fourteen strains of T. harzianum, 10 strains of T. virens, and 14 strains of T. viride were tested in dual culture with the pathogen on heavy metal poisoned media. Minimum inhibitory concentrations (MIC) for mycelial growth, antibiosis and Pythium-killing were determined. Although the decreasing order of toxicity (Cd≯Ni≯Zn) was the same for the growth of Pythium and the antagonists, the pathogen tolerated 2-4 times higher doses of toxic metals than Trichoderma strains did. The antagonistic activities proved to be more sensitive, they were blocked by 0.16-0.67 mM Cd, 0.16-1.25 Ni or Zn. Pythium-killing was observed at higher doses of Ni than that of Cd or Zn, which were similar toxic to the both investigated activities. The history of long-term heavy metal exposure of some investigated Trichoderma strains did not increase...

Postnatal development and reproductive performance of F 1 progeny exposed in utero to an ayurvedic contraceptive: Pippaliyadi yoga

Pippaliyadi yoga or pippaliyadi vati is an ayurvedic contraceptive used in India since ancient times. It is a combination of powdered fruit berries of Embelia ribes Burm.f. (Myrsinaceae), Piper longum L. (Piperaceae) and borax in equal proportion. Though the contraceptive potential is known since ancient times, no systematic developmental toxicity studies have been carried out. The present study was carried out to evaluate the postnatal developmental toxicity and the reproductive performance of the progeny exposed in utero to pippaliyadi. Pippaliyadi yoga was obtained from National Institute for Pharmaceutical Education and Research (NIPER), India and the developmental toxicity was studied by administering three doses, viz. 140, 300 and 700 mg/(kg day) to gravid females from day 6 to day 16 of gestation. Pippaliyadi did not have any adverse developmental effects with low doses, however, with the five times higher dose, a decrease in body weight of the pups was observed. The reproductive performance of the progeny born to mothers treated with pippaliyadi was not significantly affected. The present study suggests that in utero exposure to pippaliyadi does not have any adverse effect on the postnatal development and reproductive performance of the F 1 progeny.

Open‐Field Behavioural Alterations in Liver‐Impaired and Sham‐Operated Rats after Acute Exposure to the Antidepressant Venlafaxine

Patients with chronic liver impairment often display symptoms of affective psychiatric nature where the choice for antidepressant treatment is rational. Since caution is recommended when these drugs are used in such patients, a dose reduction is usually performed. We have previously reported that a dose reduction to liver-impaired portacaval shunted rats has resulted in similar brain concentrations of venlafaxine as compared to sham-operated control rats that received a two times higher dose. The main aim of the present study was therefore to investigate if this "normalisation" in pharmacokinetics of the portacaval-shunted rats also was true for the pharmacodynamic response in terms of drug effect on spontaneous open-field behaviour. Thus, portacaval-shunted rats received a single reduced dose (5 mg/kg) of venlafaxine or saline, whereas sham-operated rats received either 10 mg/kg or saline. Thereafter, central and peripheral arena locomotor and rearing activities were recorded during 60 min. The venlafaxine-treated portacaval-shunted and sham rats displayed reduced and unchanged overall behavioural activities compared with corresponding controls, respectively. However, the ratios between centrally and peripherally performed behavioural activities were higher in the venlafaxine-treated sham rats, indicating an increase in central arena activity as compared to the sham-saline and portacaval-shunted rats. The present study indicates that, despite a 50% dose reduction, caution still is necessary when antidepressants are used in liver insufficient subjects. This study also shows the importance of detailed open-field behavioural studies in which both central and peripheral activities are recorded for measurement of open-field behavioural drug effects.