Search

It has been suggested that colorectal neoplasms with or without microsatellite instability (MSI) can stimulate angiogenesis in different ways. The vascular endothelial growth factor (VEGF) system is essential for the angiogenetic process and the growth of malignant tumours. The aim of this study was to analyse the relationship between serum VEGF-A and the MSI status of patients with colorectal cancer (CRC).In the study, 249 patients with CRC were divided into a test cohort of 83 patients and a validation cohort of 166. MSI was determined using immunohistochemistry. Tumours lacking protein expression of any of the four mismatch repair genes (MLH1, PMS2, MSH2 or MSH6) were labelled as high MSI. The rest were considered to be microsatellite stable (MSS). The serum VEGF-A analyses were performed by ELISA.The tumours of 15 patients in the test cohort and 27 in the validation cohort were classified as MSI. In the test cohort, patients with an MSI tumour had a significantly higher median serum VEGF-A concentration [617 pg/ml (95% CI 445-863)], compared with patients with an MSS tumour, [317 pg/ml (95% CI 224-386)], P = 0.01. A similar relationship was confirmed in the validation cohort, P = 0.04.This study provides some evidence to suggest that patients with an MSI tumour have higher serum VEGF-A levels than patients with an MSS tumour. If further validated, these findings could be of importance when considering the effects of anti-VEGF-A treatment.

Udgivelsesdato: 2010-Mar AIM: The purpose of this study was to analyse the results of preoperative short course radiotherapy in a consecutive, national cohort of patients with rectal cancer. METHODS: Through a validated, prospective national database we identified 520 Danish patients who presented with high-risk mobile tumours in the lower two thirds of the rectum and were referred for preoperative radiotherapy with 5 x 5 Gy. The inclusion period was 56 months. Radiotherapy data was retrospectively collected. RESULTS: Of the 520 patients, 514 completed radiotherapy and 506 had surgery. Surgery was considered curative in 439 patients. The 3-year local recurrence rate was 4.0% (95% CI 2.5-6.5%) and the distant recurrence rate at 3 years was 18.7% (95% CI 15.4-22.5%). The 5-year disease free survival rate was 40.2% (95% CI 27.0-53.1%) and overall survival 50.4% (95% CI 36.1-63.1%). Most tumours (61%) were classified as T3 or T4 and 41% of the local recurrences occurred in patients with a fixed tumour at surgery. CONCLUSION: This study confirms data from randomised studies that the short course 5 x 5 Gy regime is a feasible treatment for locally advanced rectal cancer even when applied in a population outside clinical trials.

Aims To compare pharmacokinetic characteristics of two biphasic insulin aspart (BIAsp) formulations: BIAsp30 and BIAsp70 (30% and 70%, respectively, of fast-acting insulin aspart) during 15 days of multiple dosing (thrice daily). Methods A total of 22 patients with Type 1 diabetes (nine women, 13 men) aged 41.4 ± 9.9 years (mean ± sd) with a diabetes duration of 18.9 (2.3–40.3) years (median and range) completed the randomized, double-blinded, two-period crossover study. On day 1 and day 15 of each treatment period, 24-h serum insulin and glucose profiles were evaluated. Total area under the insulin aspart concentration–time curve (AUC(0−24 h)), AUC after dinner administration stratified into early (AUCdinner(0−6 h)) and intermediate-phase (AUCdinner(6−14 h)), maximum insulin concentration (Cmax), time to maximum insulin concentration (Tmax) after each meal were recorded. Results On day 15 BIAsp70 was associated with a shorter Tmax, and more than 40% elevated Cmax. Comparing with BIAsp30, AUC(0−24 h) and AUCdinner(0−6 h) were increased by 25% and 28%, respectively, but AUCdinner (6−14 h) was markedly lower for BIAsp70 [BIAsp30/BIAsp70: 1.9; 95% CI (1.42, 2.55)]. Similar findings were also observed on day 1. The fasting or pre-meal serum insulin levels on day 15 tended to be higher with BIAsp30, but the differences were not statistically significant. Conclusions The pharmacokinetic properties of BIAsp30 and 70 remain constant during 2 weeks of daily administration in patients with Type 1 diabetes. In comparison with BIAsp30, the administration of BIAsp70 results in a shorter time to and larger maximum insulin aspart concentration. Furthermore, total and early post-dinner insulin AUC were greater, whereas late-phase insulin exposure was lower with BIAsp70.

Today plant transformation is a core research tool in plant biology and a practical tool for cultivar improvement. There are verified methods for stable introduction of novel genes into the nuclear genomes of over 120 diverse plant species (Birch 1997). More than 3000 field trials of transformed plants are in progress or have been completed in at least 30 countries. These trials involve over 40 plant species modified for various economic traits (Dale 1995).

NS521 (1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine) belongs to a group of novel benzimidazolones, which exhibit neurotrophic-like activities. In vitro, NS521 rescued neuronal PC12 cells from death induced by serum and nerve growth factor deprivation. The survival effect of NS521 appeared to reflect a delay of the apoptotic process, because the extent of DNA fragmentation was attenuated transiently by NS521. NS521 did not preserve the neurites of the rescued cells, which, otherwise, appeared to be healthy and were able to regenerate when serum and nerve growth factor were added back to the culture. In vivo, NS521 provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. A neuroprotective effect of NS521 in the peripheral nervous system also was observed in rats after transection of the sciatic nerve, where daily treatment with NS521 was found to inhibit retrograde degeneration of the transected nerve. The neuroprotective effect of NS521 is unlikely to be mediated through neurotrophin receptors, such as TrkA, because NS521 did not induce phosphorylation of the 44- and 42-kDa isoforms of mitogen-activated protein kinases (ERK1/2) in PC12 cells.

Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian Central Nervous System (CNS). GABA participates in the regulation of neuronal excitability through interaction with specific membrane proteins (the GABAA receptors). The binding of GABA to these postsynaptic receptors, results in an opening of a chloride channel integrated in the receptor which allows the entry of Cl- and consequently leads to hyperpolarization of the recipient cell. The action of GABA is allosterically modulated by a wide variety of chemical entities which interact with distinct binding sites at the GABAA receptor complex. One of the most thoroughly investigated modulatory site is the benzodiazepine binding site. The benzodiazepines constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects. Their usefulness, however, is limited by a broad range of side effects comprising sedation, ataxia, amnesia, alcohol and barbiturate potentiation, tolerance development and abuse potential. Consequently, there has been an intensive search for modulatory agents with an improved profile, and a diversity of chemical entities distinct from the benzodiazepines, but with GABA modulatory effects have been identified. The existence of endogenous ligands for the GABAA receptor complex beside GABA has often been described, but their role in the regulation of GABA action is still a matter of controversy. The progress of molecular biology during the last decade has contributed enormously to the understanding of benzodiazepine receptor pharmacology. A total of 14 GABAA receptor subunits have been cloned from mammalian brain and have been expressed/co-expressed in stable cell lines. These transfected cells constitute an important tool in the characterization of subtype selective ligands. In spite of the rapidly expanding knowledge of the molecular and pharmacological mechanisms involved in GABA/benzodiazepine related CNS disorders, the identification of clinically selective acting drugs is still to come.

Fourteen male Göttingen minipigs were used in this study. Nine were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dosage of 1 mg/kg/day, SC, for 6 days, the last five pigs received saline injections for 6 days. All MPTP-treated animals developed Parkinson symptoms, i.e., muscle rigidity, hypokinesia, and impaired coordination within 5 days. The brain levels of dopamine (DA), and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in caudatum and putamen 2, 14, and 93 days (n = 3/time point) after the last drug administration. In eight of the MPTP-treated animals, striatal DA, DOPAC, and HVA concentrations were reduced from 50 to 95% compared to control animals at all time intervals. Animals with the lowest striatal DA concentrations showed the most severe signs of Parkinsonism. The number of cells in substantia nigra (SN) showed a decline only 3 months after MPTP treatment. The minipigs represent a nonprimate model of MPTP-induced parkinsonism syndromes lasting at least months.

The epidemiological and clinical features of all adult tuberculosis (tbc) cases in a Danish county over a 12 year period (82 cases) are presented. Most patients with pulmonary disease have thorax X-ray pictures showing pathological changes. Of the patients who only have extrapulmonary disease, 88% have normal X-ray examinations of the lungs. The patients can be divided into two groups: Danes and foreigners. The Danish patients are older, 81% are over the age of forty. They mostly have pulmonary disease (85%). They often have one or several concomitant diseases. The foreigners are younger, 90% are below the age of forty. They frequently have extrapulmonary disease (35%). They seldom have concomitant diseases.

Male Wistar rats were tested in the Morris water maze task 1 week after 6, 9, or 12 min of transient global ischemia. The 9-min and 12-min ischemia groups were significantly impaired in the acquisition and the reversal experiment. A systematic counting of CA1 neurons in the whole hippocampal formation revealed a unilateral number of CA1 neurons of 286,000 in the sham group, of which 2/3 were located in the dorsal hippocampus. The ischemia groups showed a significant decline in the number of dorsal CA1 neurons, whereas only the 12-min ischemia group showed a significant but minor decline (10%-15%) in the number of ventral CA1 neurons. A correlation analysis showed that the escape distance declined with increasing number of viable CA1 neurons, but poor correlation coefficients were obtained. Thus, some of the ischemic rats with even very few viable CA1 neurons in the dorsal hippocampus were capable of performing this spatial learning task at sham-group level.

Addition of compost to oil polluted soil increases oil degradation rate. It appears that compost is also able to degrade low degradable oil components, as for instance phytane.

Protein crystals grown from aqueous media invariably contain substantial amounts of the crystallizing solution, and the structure of the protein molecules and surrounding solvent can be determined from X-ray diffraction data. Electron density maps of crystalline proteins based on such data show networks of water peaks in the solvent space within approximately 6A of the protein surface. In general, the peaks are highest for water molecules within hydrogen bonding distance of acceptor or donor atoms on the protein. With increasing distance from the protein, the water peaks decrease in height, and beyond approximately 6A they merge into the structureless solvent continuum, typical of most crystalline proteins. A few water sites are often found within the protein molecule. These water molecules appear to be trapped within the protein and presumably are more tightly bound than water external to the protein.

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboxylate) is a metabolically stable beta-carboline derivative with potent anxiolytic and few sedative and ataxic effects in rodents. The anticonvulsant and muscle relaxant actions of abecarnil have been evaluated in mice, rats, gerbils and baboons. Abecarnil raised the threshold for tonic electroconvulsions in mice after corneal but not after auricular application, had no effect on maximal electroshock-induced tonic convulsions triggered by either method, protected mice against the tonic hindlimb extension in PTZ-, picrotoxin- and 3-mercaptopropionate-induced seizures and blocked clonus after PTZ, DMCM (methyl-4-ethyl-6,7-dimethoxy-9H-pyrido-(3,4-b)-indol-3-carboxylate) and 3-mercaptopropionate. Abecarnil had no effect on convulsions induced by bicuculline and strychnine. Furthermore, abecarnil blocked kindled seizures after chronic administration of PTZ and FG 7142 (beta-carboline-3-carboxylic acid methylamide) and protected mice and rats against limbic convulsions induced by pilocarpine. Severity and afterdischarge duration of amygdala-kindled seizures were reduced in rats treated with abecarnil. Abecarnil also antagonized selectively convulsions induced by i.c.v. administration of kainate, but not those triggered by N-methyl-D-aspartate or quisqualate. In genetic models of reflex epilepsy, abecarnil was effective against sound-induced convulsions in DBA/2 mice, against air blast-induced generalized seizures in gerbils and against myoclonus in baboons Papio papio. The anticonvulsant effect of abecornil in a PTZ seizure model in mice was potentiated by ethosuximide, whereas no significant potentiation was found with diazepam, clonazepam, diphenylhydantoin, carbamazepine and phenobarbital. Electromyographic monitoring in a etorphine model of muscle rigidity in rats showed no or little muscle relaxant effect of abecarnil.(ABSTRACT TRUNCATED AT 250 WORDS)

Abecarnil (isopropyl 6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a novel ligand for central benzodiazepine (BZ) receptors, possessing anxiolytic and anticonvulsant properties, but with considerably reduced muscle relaxant effects in comparison to diazepam (DZP). In vitro, abecarnil inhibited the binding of the BZ [3H]lormetazepam to rat cerebral cortex membranes with an IC50 value of 0.82 nM in comparison to 56 nM for DZP. The ability of abecarnil to displace [3H]lormetazepam was enhanced 1.24-fold in the presence of 30 microM gamma-aminobutyric acid; the corresponding value for DZP was 2.8-fold. DZP and abecarnil were equally effective in enhancing the binding of t-[35S]butylbicyclophosphorothionate to rat cortical membranes. In vivo, abecarnil exhibited a 3- to 6-fold higher affinity to forebrain BZ receptors than DZP. Abecarnil was from 2 to 10 times more potent than DZP in most rodent tests of anxiolytic activity, and in reducing locomotor activity in mice and rats thoroughly habituated to the test chamber. However, in rats newly exposed to a novel cage, abecarnil was less potent than DZP in reducing locomotor activity. In tests of motor coordination, abecarnil, in contrast to DZP, showed no or only weak activity, and in potentiating the effects of ethanol and hexobarbital on motor performance abecarnil was 4 to 25 times less potent than DZP. Abecarnil antagonized the effects of BZs in the chimney and loss of righting reflex tests, but not in the rotarod test.(ABSTRACT TRUNCATED AT 250 WORDS)

Application of the Rayleigh criterion for the limit of resolution of a simple lens with axial illumination leads to the value 0.61λ. In two-dimensional electron density maps based on X-ray data, the limit of resolution has been considered to be 0.61 dmin, the counterpart of the optical case, and in three-dimensional maps 0.715 dmin. It is shown here that point atoms separated by these distances are not resolved in two- and three-dimensional electron density maps. Such maps are amplitude functions rather than intensity functions as in the optical case. Application of the Rayleigh criterion to the three-dimensional amplitude function for point atoms leads to a value of 0.917 dmin, for the limit of resolution in three-dimensional electron density maps. This result is confirmed by superposing both analytic and numeric functions for point atoms and numeric functions for real atoms with B = 0 and 10 A2. Finally, some implications of diffraction effects in X-ray structure analysis are considered.

The phases for the x-ray data for crystals of azurin from P. aeruginosa have been refined and extended from 3 A to 2.7 A resolution by a method based on the direct space averaging of the electron density of the four molecules in the asymmetric unit. The electron density in the present map is much improved over the earlier one, and most of the side-chains are now evident. In the detailed fitting of a model to the present map, an alternative interpretation, conforming to the plastocyanin model and reversing the chain directions in strands one and two of the original azurin model, was found to better represent certain features of the present map. The surface of the molecule closest to the copper consists of an extended region of invariant or semiconserved hydrophobic residues. There is not a region of conserved charge that is not paired with a compensating charge.

The crystal structure of 9‐methyladenine has been determined with limited x‐ray diffraction data. The final R factor is 0.091 with atomic standard deviations of about 0.006 A. The x‐ray determination confirms the proposed structure based on polarized absorption measurements. We conclude that the first ultraviolet transition for 9‐methyladenine is short axis (C4–C5) polarized.

The reaction of thioureus or N-Substituted Thioureas with dimethyl acetylene dicarboxylate is an extremely simple reaction which proceeds rapidly and quantitatively. The resultant heterocyclic products have been the subject of numerous publication, 2–8 the variety of which demonstrates the truly international interest in the field. Various structures have ben proposed and received support: the 5-membered ring systems 1, 3-thiazolidines (3)2–4 and 2-thiohydantoius (e.g.12)5 and the 6-membered 1,3-thiazines (5)6–8. The most convincing chemical and spectroscopic evidence has been reported by loan and ifa 6 in support of the 1,3-thiazine system. This work has since been challenged by ourselves 9 and others4. Indeed the recent work by Cameron et al 4, who have carried out an X-Ray structure analysis on Product (1)(Derived from the reaction of N-thiocarbomaoyl-piperidine and dimethyl actylane dicarboxylate), fully justifies our reservation.

The Chernobyl accident caused a variety of radionuclides to be released. The most abundant of the longer-lived nuclides were the two caesium isotopes 137Cs and 134Cs, with half lives of 30 yr and 2.06 yr respectively1. For many years2–5 these radionuclides have been used as oceanographic tracers in the north-east Atlantic Ocean. Their sources are the fuel reprocessing plants in Western Europe. The radiocaesium released from Chernobyl, however, was deposited very inhomogeneously6, thus seriously perturbing its use as a tracer. So, there is a need to identify another tracer with the same sources but unperturbed by input from Chernobyl. Technetium-99 is not sedimented to any great degree and thus as a conservative tracer7 can be considered as a candidate. In a recent study2 we found the same dilution factor for technetium as for radiocaesium when comparing concentrations in the North Sea with those in coastal waters around Greenland, supporting the idea of technetium as a substitute tracer for radiocaesium. Here we report a study of the possible contributions to 99Tc in order to determine the Chernobyl input. We chose the Baltic Sea for our study because it probably shows higher concentrations of Chernobyl debris than any other sea. We show that the Chernobyl contribution is such that 99Tc can be used as a tracer.

The effects of the beta-carboline ZK 93426, a putative benzodiazepine receptor antagonist, were investigated in the social interaction test of anxiety and in the holeboard. Like the receptor antagonist Ro 15-1788, ZK 93426 (2.5-10 mg/kg) caused a specific reduction in social interaction (interpreted as an anxiogenic effect) and caused a significant elevation in exploratory head-dipping (5 mg/kg). When low (ineffective) doses of both compounds (1 mg/kg ZK 93426; 4 mg/kg Ro 15-1788) were administered together they significantly reduced social interaction. No further reductions in social interaction were observed when effective doses of both compounds (5 mg/kg ZK 93426; 10 mg/kg Ro 15-1788) were tested in combination; it is likely that this is due to almost total benzodiazepine receptor occupancy at effective doses of either compound. When doses of each compound (5 mg/kg ZK 93426; 10 mg/kg Ro 15-1788) that resulted in stimulation of head-dipping were examined in combination, the elevation in exploration was no longer observed. Since at higher doses of both compounds there is an attenuation of the elevation in head-dipping, it is again likely that the effects of the two compounds are additive.