[Systematic review of the side effects of benzodiazepines]. / Aandacht voor bijwerkingen van benzodiazepinen is belangrijk: een systematisch overzicht.

- Benzodiazepines are used frequently, despite the risk of severe side effects.- The Generic module 'Side effects; prevention, monitoring and treatment of side effects of drugs for psychiatric disorders' will be published soon. This contains recommendations for reduction in the risk for falls and fractures, cognitive problems and dependency related to the use of benzodiazepines or Z-drugs (zopiclone, zolpidem).- Prescribing physicians and pharmacists are compulsorily required to provide extensive information to patients on the anticipated effects and side effects of benzodiazepines, and on the limited prescription period.- A lot of information has become available from systematic literature reviews by the Benzodiazepines working group. Different benzodiazepines present similar risks of falls and fractures; higher doses present a higher risk, and Z-drugs are no safer.- In comparison with placebo, benzodiazepines and Z-drugs soon cause cognitive problems, even at low doses and in drugs with a short half-life. There is almost no development of tolerance for these cognitive problems.- Tailored patient education letters for ceasing benzodiazepine use are more effective than the standard letters. Different dose-tapering schemes have comparable success rates (on average 50%). Augmentation with cognitive behavioural therapy is effective for dose reduction.- It is therefore important to carefully consider the use of benzodiazepines before using them.

[Tricyclic antidepressant plasma levels in depression: a practical guide]. / Tricyclische antidepressiva en plasmaspiegels bij depressie: een praktische leidraad.

BACKGROUND: Plasma levels can be used to monitor the clinical efficacy of tricyclic antidepressants (TCAs). In practice, the interpretation of plasma levels can be problematical, for several reasons: varying time-intervals between ingestion and blood sampling, the number of times per day a particular antidepressant is administered, the presence of active metabolites and the use of slow-release substances. AIM: To present realistic recommendations regarding the interpretation of plasma levels of TCA in clinical practice. METHOD: We studied the relevant literature. CONCLUSION: On the basis of the literature we make the following recommendations:

Initial screening of little known predatory mites in Brazil as potential pest control agents.

The objective of this study was to evaluate the oviposition rate and the survivorship of some of the most common predators on plants of the natural vegetation of southeastern Brazil, when confined with different food sources. Forty-four laboratory tests were carried out, each corresponding to a different combination of predator species and food source. The predators tested were: Phytoseiidae--Amblyseius acalyphus, Euseius citrifolius, Iphiseiodes zuluagai, Metaseiulus (Metaseiulus) camelliae, Typhlodromips cananeiensis; Stigmaeidae--Agistemus floridanus, Zetzellia malvinae; Tydeidae--Pronematus sp. For most predators, the highest oviposition rate and survivorship were obtained when the prey was one of the tenuipalpid mites, Brevipalpus phoenicis or Tenuipalpus heveae. With the exception of A. floridanus, the predators had low oviposition rate and survivorship on Calacarus heveae relative to their respective rate on other food sources. Predators had also generally low oviposition rate and survivorship when feeding on Tetranychus urticae, Oligonychus gossypii or Frankliniella sp.

Critical use of methyl bromide for soil disinfestation in Belgium during 2005.

During 2005, Belgium enforced a strict procedure for the assignment of critical-use permits for methyl bromide (MeBr) as a soil disinfestant. This procedure involved an inspection of the site before disinfestation by a representative of a registered institute, and a mandatory demonstration of the presence of a pest or disease for which a critical use permit could be granted according to the Critical Use Nominations (CUNs). The procedure was subject to random inspections by an independent institute. The results of these inspections demonstrated proper and timely evaluation of the permit requests. A total of 113 requests for a MeBr disinfestation permit were submitted in 2005. Out of these, 105 referred to applications in 2005. The remaining 8 requests referred to applications in 2006 and were denied a permit based on the lack of MeBr quotum granted to Belgium for 2006. Of the 105 requests for applications in 2005, 93 received a MeBr application permit for soil disinfestation. These 93 permits represented 15911 kg or 37.3% of the total quotum assigned to Belgium in 2005 (42676 kg). Most of the quotum was used for butterhead lettuce (11456 kg or 72% of the applied MeBr). For most commodities, a surplus in quotum was available. However, for chrysanthemum, the amount requested for critical use exceeded the available quotum. The most important pests and diseases for which a permit was assigned were Meloidogyne, Sclerotinia, Rhizoctonia, Olpidium, Pythium, Pyrenochaeta, Verticillium, and a combination of these fungi and nematodes. The 12 requests for which no permit was granted represented 2010 kg or 11.3% of the total amount requested. In addition, institutes carrying out the assignment procedure reported at least 62 extra cases where they had been contacted by a grower but where no official permit request was filed based on the first inspection. When including those cases, the total reduction of the potentially used amount of MeBr is about 44 %. When adding an estimated 10 to 15% reduction due to the use of alternatives by growers who did not start the permit assignment procedure, the total reduction is approximately 50-55%.

Trace element determinations using a 15-keV synchrotron X-ray microprobe.

At the Synchrotron Radiation Source (SRS), Daresbury, U.K., a synchrotron microprobe was constructed, in order to create an instrument capable of analyzing at the ppm or in favorite cases sub-ppm level with a lateral resolution of 10 x 15 microns2. In order to span a wide range of elements to be analyzed, a beam energy of 15 keV was chosen. Focusing and monochromation of the white beam was done in one single step with a high-precision ellipsoidally concave curved Si(111) crystal. Sufficient flux of X-rays in a narrow energy band is available in the spot to measure trace elements at the femtogram level. Measurements on standard materials, reference standard materials, and biological samples showed the lower relative minimum detection limits and higher sensitivity for the higher Z-elements obtainable with micro-SXRF (synchrotron X-ray fluorescence) as compared with microtechniques using ion accelerators. Moreover, the much lower energy deposited in the specimen represents a major argument to prefer X-rays to ions for the analysis of radiation-sensitive samples.

Influence of size and polarity of residue 31 in porcine pancreatic phospholipase A2 on catalytic properties.

Residue 31 of porcine pancreatic phospholipase A2 (PLA2) is located at the entrance to the active site. To study the role of residue 31 in PLA2, six mutant enzymes were produced by site-directed mutagenesis, replacing Leu by either Trp, Arg, Ala, Thr, Ser or Gly. Direct binding studies indicated a three to six times greater affinity of the Trp31 PLA2 for both monomeric and micellar substrate analogs, relative to the wild-type enzyme. The other five mutants possess an unchanged affinity for monomers of the product analog n-decylphosphocholine and for micelles of the diacyl substrate analog rac-1,2-dioctanoylamino-dideoxy-glycero-3-phosphocholine. The affinities for micelles of the monoacyl product analog n-hexadecylphosphocholine were decreased 9-20 times for these five mutants. Kinetic studies with monomeric substrates showed that the mutants have Vmax values which range between 15 and 70% relative to the wild-type enzyme. The Vmax values for micelles of the zwitterionic substrate 1,2-dioctanoyl-sn-glycero-3-phosphocholine were lowered 3-50 times. The Km values for the monomeric substrate and the Km values for the micellar substrate were hardly affected in the case of five of the six mutants, but were considerably decreased when Trp was present at position 31. The results of these investigations point to a versatile role for the residue at position 31: involvement in the binding and orientating of monomeric substrate (analogs), involvement in the binding of the enzyme to micellar substrate analogs and possibly involvement in shielding the active site from excess water.

Biomedical applications of proton induced X-ray emission.

Apart from studies on aerosols, the majority of applications of proton induced X-ray emission (PIXE) with a normal beam or a microprobe (micro-PIXE) is found in biology and medicine. Two aspects of broad beam PIXE are often decisive for the choice of this analytical technique. Compared to other techniques capable of analysis down beyond the ppm level, PIXE can be carried out with a very small amount of material and minute fractions of the composite samples, even in the scale of micrometers and quite often with minimal sample preparation, which are important requirements for biomedical investigations. Secondly, the speed of the total analysis opens the possibility to analyze large numbers of samples in a reasonable time, which is often necessary in biomedical studies in order to obtain sufficiently significant correlations between trace element concentrations and biomedical phenomena. Few, if any, techniques can compete with micro-PIXE; quantitative trace element analysis on a micrometer scale still represent a challenging problem. The electron microprobe normally lacks the sensitivity while the laser induced techniques suffer as yet from quantification problems. This paper describes recent developments especially in micro-PIXE in biomedical research.

The effect of dietary zinc deficiency on the mossy fiber zinc content of the rat hippocampus. A microbeam PIXE study. Particle Induced X-Ray Emission.

The effect of dietary zinc deficiency on the mossy fiber zinc content of the rat hippocampus was investigated using PIXE (Particle Induced X-Ray Emission) spectroscopy. Using the proton microbeam (60 X 60 microns), 2 mm line-scans were made on hippocampal sections and the data were expressed as absolute zinc concentrations. Values of 55 and 136 ppm (dry weight) were found for the mean background zinc level and the maximum mossy fiber zinc level, respectively, in animals fed a control diet containing 50 ppm zinc. Treatment of these animals with dithizone caused about 50% reduction in the maximum mossy fiber zinc level. Feeding a zinc-deficient diet for 28 days did not cause a decrease in the mossy fiber zinc level, however, feeding the zinc-deficient diet for 90 days reduced the maximum mossy fiber zinc level by about 30%. The results are discussed in relation to the behavioral abnormalities that have been observed in zinc-deficient animals.

Incorporation routes of elements into human hair; implications for hair analysis used for monitoring.

A study has been made on the incorporation of some trace elements and minerals into human hair by measuring their distributions across hair diameters. For this study the Particle Induced X-ray Emission (PIXE) technique using the proton microbeam of the Vrije Universiteit of Amsterdam has been applied. Results of measurements on single hair strands at different positions in the root and outside the skin provide evidence that the elements not only can enter the cortex via the matrix but also via the hair root sheaths. Moreover, there are indications that the distribution of an endogenous element is not always homogeneously spread over a cross section of the hair. Endogenous Fe and Pb seem to be peaked on the periphery of the hair by natural means, while the elements S,Zn and Cu of the samples measured are found to be distributed homogeneously across the hair diameter. The consequences for hair analysis in use for monitoring the trace elements status of an individual are discussed.

Copper and zinc metabolism in aspartylglycosaminuria and Salla disease.

Changes in the metabolism of copper and zinc are described in aspartylglycosaminuria (AGU) patients. AGU patients had significantly reduced serum zinc concentrations. However, hair zinc levels were normal, and hyperzincuria could not be demonstrated. The copper content in the hair of AGU patients was highly elevated. Serum copper and ceruloplasmin concentrations were within normal range. In AGU, small-molecular-weight glycoasparagine storage products accumulate in tissues and are excreted in urine in large amounts. They may interfere with the transport mechanisms of trace elements, and thus alter their distribution and availability for tissues. The changes in copper and zinc levels may contribute to the pathogenesis of some of the clinical signs of AGU and Salla disease.

Disturbed metabolism of copper and zinc in aspartylglycosaminuria: possible involvement with connective tissue changes.

In aspartylglycosaminuria (AGU), a lysosomal storage disorder of glycoprotein degradation, there are some abnormalities in collagen and proteoglycan metabolism. Because of earlier observations suggesting a disturbance of copper balance, the metabolism of copper and zinc was studied in more detail to find out if possible trace metal disturbances could be correlated with connective tissue disorder. Highly elevated copper concentrations in the hair and significantly reduced zinc levels in serum and urine were detected in AGU patients indicating a disturbance of trace element balance. However, the patients had normal serum copper levels, and the concentrations of zinc and copper in cultured fibroblasts did not differ from those of control cells. Normal lysyl oxidase activities in cell culture indicate that collagen cross-link formation is not affected. The changes in copper and zinc balance are probably secondary to the basic enzyme deficiency, and may contribute to the development of the clinical signs and symptoms of AGU although the mechanisms involved are not yet understood.

Discrepancies between histological and physical methods for trace element mapping in the rat brain.

This paper contains a comparison between four experimental methods for the detection of trace metals in biological tissues, e.g. autoradiography, dithizone-, Timm-staining and microPIXE (Particle Induced X-ray Emission). As research object the hippocampus of the rat was chosen and mainly the Zn-distribution in the fascia dentata has been examined. The comparison was judged on four criteria: spatial resolution, specificity, quantification and influence of the protein binding of the metal on the outcome of each method. Some additional Timm and microPIXE experiments have been performed to compare the metal concentrations for both normal and Zn-deficient rats. The Zn/Cu ratio for both kinds of rats were calculated and some striking differences in the concentrations were obtained. The Zn/Cu ratio for a normal rat was found to be about 40% higher than for a deficient one.

Mechanism of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum.

Evidence was found that the inhibitory action of Cu(DMP)2NO3, the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline (DMP), on Mycoplasma gallisepticum is a consequence of the ultimate toxicity of copper, and not that of the ligand, DMP. From uptake studies with radiolabeled 67Cu and [14C]DMP, we concluded that significantly more copper than DMP is bound to the mycoplasmal cell. It appeared that dissociation of Cu(DMP)2+ occurred shortly after interaction with the cell membrane. Copper was transported across the cytoplasmic membrane. A strong dependence of copper uptake on the incubation medium was observed in the absence of DMP. The main function of the ligand DMP appeared to be as a vehicle for the transport of copper from nontoxic copper-medium complexes to membrane-buried cellular ligands.

Mode of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum.

Various physiological important activities of Mycoplasma gallisepticum were inhibited by the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline [Cu(DMP)2NO3]. The energy-yielding metabolism was inhibited because the conversion of pyruvate into lactate was found to be blocked by Cu(DMP)2NO3, indicating a selective inhibition of lactate dehydrogenase. Also, the production rate of acetate and the rate of oxygen uptake by whole cells of M. gallisepticum appeared to be strongly decreased. Experiments with crude cell extracts showed an inhibition of reduced nicotinamide adenine dinucleotide (NADH) oxidase by Cu(DMP)2NO3 and an even stronger inhibition of NADH oxidase and lactate dehydrogenase by CuSO4. No preferential inhibition of adenosine 5'-triphosphatase and pyruvate kinase was found. Investigations on the influence of Cu(DMP)2NO3 on deoxyribonucleic acid, ribonucleic acid, and protein synthesis with growing cells of M. gallisepticum showed a selective inhibition of the incorporation of [14C]thymidine into deoxyribonucleic acid. Cu(DMP)2NO3 induced a decrease in the total amount of accessible sulfhydryl groups of whole cells of M. gallisepticum, indicating that the observed diverse toxicity of Cu(DMP)2NO3 may be associated with the interaction of copper ions with protein sulfhydryl groups.

Mode of action of copper complexes of some 2,2'-bipyridyl analogs on Paracoccus denitrificans.

Copper complexes of 2,2'-bipyridyl and related compounds and CuSO4 inhibited the growth of paracoccus denitrificans. The copper(I) complex of 2,9-dimethyl-1,10-phenanthroline [Cu(DMP)2NO3] showed the highest activity, whereas the copper(II) complex of 1,10-phenanthroline and CuSO4 inhibited the growth to a lesser extent. The uncomplexed ligands (1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthroline) showed little activity, but in the presence of noninhibitory amounts of CuSO4 this activity increased markedly. Copper ions therefore proved to be essential for the growth-inhibitor effect. The extent of inhibition appeared to be strongly dependent on the initial cell density and on the growth medium. No selective inhibition of deoxyribonucleic acid, ribonucleic acid, or protein synthesis was observed with Cu(DMP)2NO3. Respiratory electron transport of P. denitrificans appeared to be strongly inhibited by Cu(DMP)2NO3 and to a somewhat lesser extent by CuSO4. Both aerobic and anaerobic respirations were inhibited to the same extent, and from the cytochrome redox kinetics it is concluded that the site of this inhibition in the respiratory electron transport chain must be located before cytochrome b. Cu(DMP)2NO3 did not significantly influence the H+/O ratio with whole cells of P. denitrificans, suggesting that the efficiency of oxidative phosphorylation is not affected by CU(DMP)2NO3. Growing cultures of P. denitrificans showed a decrease in intracellular potassium ion content in the presence of increasing amounts of Cu(DMP)2NO3. It is concluded that interference with the cytoplasmic membrane, resulting in inhibition of respiratory electron transport, probably constitutes the main mode of action of copper complexes of 2,2'-bipyridyl analogs on P. denitrificans.