Current concepts of involvement of glutamate in ischemic damage of the brain tissue

Glutamate neurotoxicity cannot be considered the only reason for neuronal damage. Other neurotransmitters and molecular messengers like nitric oxide, may be involved in the toxic effect of glutamate. Different conditions in focal and global ischemia, stage of the ischemic damage evolution, the degree of ischemia, and activation of glutamate receptors, should also be taken into consideration when assessing a neurological outcome.     

New trends in CLL treatment

We review here results obtained from the various treatment modalities that have been used in CLL patients: chemotherapy; radiotherapy; splenectomy; leukapheresis; monoclonal antibodies and other immunomodulating agents. We conclude that it is still unclear whether patients in stage A (good prognosis) should be treated; intermediate forms of the disease (stage B) should, in most cases, be treated, but a better treatment than chlorambucil has not emerged; results from the Cooperative Group on CLL of Société Fran?aise d'Hématologie indicate that significant progress in the therapy of the advanced stage (stage C) has been achieved with the introduction of the CHOP regimen, using low doses of adriamycin; radiotherapy, splenectomy and immunomodulators such as levamizol, interleukins or interferons, and possibly monoclonal antibodies, are now being actively tested; the results are not yet conclusive.     

Interleukin-2 in cancer treatment: Disappointing or (still) promising? A review

The central question to discuss in this review is whether the results of interleukin-2 (IL-2) treatment are still disappointing or again promising. Although in the (recent) past application of high doses of systemically applied rIL-2 has led to some success, the overall results are not as one had hoped. Considering these poor results it seems clear that the application of high systemic doses rIL-2 was not a good choice. IL-2 has been used more or less as a chemotherapeutic compound in the highest tolerable dose. This has led to a great number of unwanted toxic side-effects. In addition, these doses mainly stimulated nonspecific lymphokine-activated killer activity through low-affinity IL-2 receptors, which does not lead to systemic immunity. On the other hand, several groups have shown that application of intratumoral low doses of IL-2 can be highly effective against cancer and without toxic side-effects. Significant tumor loads constituting up to 6% of the total body weight of a mouse were eradicated after treatment with low-dose rIL-2 given locally. Furthermore local treatment can lead to eradication of a tumor at a distant site. This type of therapy is effective in many systems namely against different tumor types in mice, hepatocellular carcinoma in guinea-pigs and vulval papilloma and carcinoma and ocular carcinoma in cattle. Low-dose IL-2 is very effective in experimental animals if it is given relatively late after inoculation of the tumor cells. In other words, it seems necessary that some sort of immune reaction has started or is developing before low doses of rIL-2 effectively stimulate it. In fact there is strong evidence that T lymphocytes, both CD4⁺ and CD8⁺ cells, are directly involved in the process leading to induction of specific immunity. In our opinion rIL-2 therapy should therefore aim at the stimulation of such (originally weak) specific immune reaction. Under these conditions also systemic immunity can be induced. In conclusion, application of rIL-2 as a modality for cancer treatment is still promising. High priority should be given to a further delineation of the mechanisms involved after local application. The method of giving IL-2 systemically in the highest tolerable dose should be abandoned. Specific stimulation of the immune system by low-dose rIL-2 is a much more promising option.     

Toxic effects of tin compounds on microorganisms

Summary Organotins are used for industrial and agricultural purposes and in antibiologic agents. They are significantly more toxic than inorganic tins, and eventually reach the environment where they can be toxic to a wide variety of organisms. Particular attention has been given to tributyltins which are highly toxic components of antifouling paints. Realization that the molecular species of organotin influences fate and effects of organotins led to development of sensitive methods for quantifying individual molecular species. Even though such methods are now available, little information has been obtained on the ability of microorganisms to bioaccumulate tin compounds. Trisubstituted alkyl and aryltins (R₃Sn's) are more toxic than disubstituted compounds (R₂Sn's) while monosubstituted organotins (RSn's) are still less toxic. R₄Sn's are toxic only if they are metabolized to R₃Sn's. Among trisubstituted compounds propyl-, butyl-, pentyl-, phenyl-, and cyclohexyl Sn's are generally the most toxic to microorganisms. Toxicity in the R₃Sn series is related to total molecular surface area of the tin compound and to the octanol:water partition coefficient,K _ow, which is a measure of hydrophobicity; a highK _ow indicates greater hydrophobicity and predicts greater toxicity. Care must be taken when testing the toxicity of tin compounds, for a number of biological, physical and chemical factors can influence the apparent toxicity. Although little is known of the effects of tin compounds on microbial processes, a number of bacterial processes can be inhibited by organotins and all relate to membrane functions. They include effects on energy transduction, solute transport and retention and oxidation of substrates. Very little is known of how organotins exert their toxic effects on algae and fungi; Information on effects on chloroplasts and mitochondria stems principally from animal systems and from higher plants. Triorganotins act against chloroplasts and mitochondria by causing swelling, by acting as ionophores and by acting against ATPase, while diorganotins appear to act by binding to dithiol groups on enzymes and cofactors. Nucleic acids do not seem to be affected at environmentally relevant concentrations. Virtually nothing is known of the action of tin compounds on microbial enzymes, but resistant mutants are easy to obtain and should facilitate work to understand modes of microbial interaction with tin compounds and mechanisms of resistance.     

Cerebral complications in juvenile rheumatoid arthritis

A study of 170 patients with juvenile rheumatoid arthritis and a review of the literature indicate that this disease can significantly affect the central nervous system. Signs of CNS dysfunction were observed in 13 children. During the acute toxic stages the EEG is abnormal in many cases. Other manifestations of toxic encephalopathy such as irritability, drowsiness, stupor, convulsions and marked meningismus may be evident in severe cases. Meningitis is often suspected but ruled out by the finding of normal CSF. Steroids can rapidly improve the condition of these children. If `unexplained'' seizures occur during the chronic stage, the diagnosis of cerebral vasculitis should be entertained.     

Snat: a SNP annotation tool for bovine by integrating various sources of genomic information

Background

Genome-wide association (GWA) study has recently become a powerful approach for detecting genetic variants for common diseases without prior knowledge of the variant's location or function. Generally, in GWA studies, the most significant single-nucleotide polymorphisms (SNPs) associated with top-ranked p values are selected in stage one, with follow-up in stage two. The value of selecting SNPs based on statistically significant p values is obvious. However, when minor allele frequencies (MAFs) are relatively low, less-significant p values can still correspond to higher odds ratios (ORs), which might be more useful for prediction of disease status. Therefore, if SNPs are selected using an approach based only on significant p values, some important genetic variants might be missed. We proposed a hybrid approach for selecting candidate SNPs from the discovery stage of GWA study, based on both p values and ORs, and conducted a simulation study to demonstrate the performance of our approach.

Results

The simulation results showed that our hybrid ranking approach was more powerful than the existing ranked p value approach for identifying relatively less-common SNPs. Meanwhile, the type I error probabilities of the hybrid approach is well-controlled at the end of the second stage of the two-stage GWA study.

Conclusions

In GWA studies, SNPs should be considered for inclusion based not only on ranked p values but also on ranked ORs.     

Parasitic infection and oxidative status are associated and vary with breeding activity in the Seychelles warbler

Parasites can have detrimental effects on host fitness, and infection typically results in the stimulation of the immune system. While defending against infection, the immune system generates toxic oxidants; if these are not sufficiently counteracted by the antioxidant system, a state of oxidative stress can occur. Here, we investigated the relationship between parasitic infection-using malarial infection as a model-and oxidative status in a natural population of the Seychelles warbler, while taking into account potentially interacting environmental covariates. We found that malaria is associated with increased susceptibility to oxidative stress, but this depends on the breeding stage: only during the energetically demanding provisioning stage did infected birds have higher oxidative stress susceptibility than non-infected birds. The imbalance in oxidative status was caused by a marked increase in oxidant levels observed only in infected birds during provisioning and by an overall reduction in antioxidant capacity observed in all birds across the breeding cycle. This finding implies that higher workload while dealing with an infection could aggravate oxidative repercussions. Malarial infection was not associated with body condition loss, suggesting that even when conditional effects are not directly visible, detrimental effects may still manifest themselves over the longer term through the oxidative consequences.     

A technique for measuring the susceptibility of wheat bulb fly larvae to insecticides in the laboratory

A simple assay is described for measuring the toxicity of insecticides to larvae of wheat bulb fly (Delia coarctata) in the laboratory. The method should be suitable for other small soil insect larvae that cannot be obtained in large numbers and are difficult to treat and confine. A limitation of the technique is that it works only with insecticides that are soluble enough to be toxic in aqueous solution.     

Toxic Dilatation of the Colon in the Course of Ulcerative Colitis

Toxic dilatation of the colon has been observed in a patient suffering from ulcerative colitis during an acute relapse of the disease. This uncommon and serious complication was suspected because there was a gradual worsening of the patient''s condition, accompanied by toxic phenomena. The diagnosis was confirmed by a flat plate of the abdomen which disclosed considerable dilatation of the colon. The etiology of toxic dilatation is not known but the use of opiates and anticholinergic agents has been suggested as a possible factor. These therapeutic agents should be avoided in the acute stage. Barium enema examination during acute relapses of ulcerative colitis may also precipitate the onset of this complication. It is recommended that, during the acute stage of the disease, the barium enema be replaced as often as possible by flat films of the abdomen which also enable diagnosis of this complication.     

Management of three toxic Delphinium species based on alkaloid concentrations

A systematic approach to the taxonomic classification of the tall larkspur complex (Delphinium spp.) has been developed and implemented using molecular genetics, plant morphology, and alkaloid profiles, as shown in other papers in this series. This approach supports the classification of three distinct species (D. glaucum, D. barbeyi and D. occidentale), as the species differ in genetics and toxicity. Toxic alkaloid concentrations over the growing season were integrated with data on diet selection to make management recommendations on a species-specific basis to reduce the risk of poisoning cattle. Alkaloid concentrations in tall larkspurs in excess of 3 mg/g impart moderate or high risk to grazing cattle if sufficient quantities are consumed. D. glaucum is most toxic, with toxic alkaloid concentrations that exceed 3 mg/g throughout the grazing season until late maturity. Cattle should be denied access to dense patches of this species throughout the grazing season until after seed shatter. Concentration of toxic alkaloids in D. barbeyi is highest in vegetative plants, but D. barbeyi is unpalatable to cattle until flowering racemes begin to elongate. We recommend grazing D. barbeyi ranges early in the season when it is not palatable, then removing cattle from early flowering stage through mid-pod stage when cattle are most likely to be poisoned. Cattle can again safely graze D. barbeyi late in the season when the toxic alkaloid concentration typically declines below 3 mg/g. Some populations of D. occidentale and the D. barbeyi×D. occidentale hybrids do not contain toxic alkaloids, and pose little risk of poisoning throughout the year. Toxicity of northern populations of D. occidentale varies from year-to-year for unknown reasons. Cattle losses from D. occidentale are usually less severe than from D. barbeyi, but generally the same recommendations apply as for D. barbeyi. Toxicity sampling is an essential management tool. Tall larkspur populations can be tested for toxicity throughout the growing season. Whenever toxic alkaloid concentrations exceed 3 mg/g in leaves, flowers, or pods, cattle should be removed from the area and not returned until pods begin to shatter and risk of poisoning is lower. In general, tall larkspurs are safe to graze when alkaloid concentrations fall below 3 mg/g because it is difficult for cattle to eat sufficient larkspur to become fatally poisoned.     

Latex constituents from Calotropis procera (R. Br.) display toxicity upon egg hatching and larvae of Aedes aegypti (Linn.)

Calotropis procera R. Br. (Asclepiadaceae) is a well-known medicinal plant with leaves, roots, and bark being exploited by popular medicine to fight many human and animal diseases. This work deals with the fractionation of the crude latex produced by the green parts of the plant and aims to evaluate its toxic effects upon egg hatching and larval development of Aedes aegypti. The whole latex was shown to cause 100% mortality of 3rd instars within 5 min. It was fractionated into water-soluble dialyzable (DF) and non-dialyzable (NDF) rubber-free materials. Both fractions were partially effective to prevent egg hatching and most of individuals growing under experimental conditions died before reaching 2nd instars or stayed in 1st instars. Besides, the fractions were very toxic to 3rd instars causing 100% mortality within 24 h. When both fractions were submitted to heat-treatment the toxic effects were diminished considerably suggesting low thermostability of the toxic compounds. Polyacrylamide gel electrophoresis of both fractions and their newly fractionated peaks obtained through ion exchange chromatography or desalting attested the presence of proteins in both materials. When submitted to protease digestion prior to larvicidal assays NDF lost most of its toxicity but DF was still strongly active. It may be possible that the highly toxic effects of the whole latex from C. procera upon egg hatching and larvae development should be at least in part due to its protein content found in NDE However the toxicity seems also to involve non protein molecules present in DF.     

Interaction of chromatid lesions induced by N-nitroso-N-methylurea and N-nitroso-N-ethylurea inVicia faba

After treatment of primary roots ofVicia faba with N-nitroso-N-methylurea (NMU) and afterwards with N-nitroso-N-ethylurea (NEU) only an additive effect has been found. When NEU was used for the first treatment and NMU was applied afterwards an interaction of induced lesions was observed in the production of interchanges. These results might be interpreted as follows: NMU induces primary chromatid lesions in a later stage of interphase than NEU, so that these lesions cannot be induced in the same cell, if NMU is applied first. Because of the complexity of events leading to aberrations, a lot of which are unknown, our interpretation should be accepted with due reserve and cannot be more than a working hypothesis for further experimental tests.     

1H NMR-based metabonomic profiling of rat serum and urine to characterize the subacute effects of carbamate insecticide propoxur

Carbamate insecticide propoxur is widely used in agriculture and public health programs. To prevent adverse health effects arising from exposure to this insecticide, sensitive methods for detection of early stage organismal changes are necessary. We present here an integrative metabonomic approach to investigate toxic effects of pesticide in experimental animals. Results showed that propoxur even at low dose levels can induce oxidative stress, impair liver function, enhance ketogenesis and fatty acid β-oxidation, and increase glycolysis, which contribute to the hepatotoxocity. These findings highlight the applicability of ¹H NMR spectroscopy and multivariate statistics in elucidating the toxic effects of propoxur.     

High herbivore pressure favors constitutive over induced defense

Theoretical and empirical studies show that, when past or current herbivory is a reliable cue of future attack and defenses are costly, defenses can be induced only when needed and thereby permit investment in other functions such as growth or reproduction. Theory also states that, in environments where herbivory is constantly high, constitutive defenses should be favored. Here, we present data to support the second aspect of the induced resistance hypothesis. We examined herbivore‐induced responses for four species of Inga (Fabaceae), a common canopy tree in Neotropical forests. We quantified chemical defenses of expanding leaves, including phenolic, saponin and toxic amino acids, in experimental field treatments with and without caterpillars. Because young leaves lack fiber and are higher in protein than mature leaves, they typically lose >25% of their leaf area during the few weeks of expansion. We predicted that the high rates of attack would select for investment in constitutive defenses over induction. Our data show that chemical defenses were quite unresponsive to herbivory. We demonstrated that expanding leaves showed no or only small increases in investment in secondary metabolites, and no qualitative changes in the phenolic compound profile in response to herbivory. The proteinogenic amino acid tyrosine, which can be toxic at high concentrations, showed the greatest levels of induction. Synthesis: These results provide some of the first support for theoretical predictions that the evolution of induced vs. constitutive defenses depends on the risk of herbivory. In habitats with constant and high potential losses to herbivores, such as tropical rainforests, high investments in constitutive defenses are favored over induction.     

Specific compositions of amyloid-beta peptides as the determinant of toxic beta-aggregation

Alzheimer's disease (AD) may be caused by toxic aggregates formed from amyloid-beta (Abeta) peptides. By using Thioflavin T, a dye that specifically binds to beta-sheet structures, we found that highly toxic forms of Abeta-aggregates were formed at the initial stage of fibrillogenesis, which is consistent with recent reports on Abeta oligomers. Formation of such aggregates depends on factors that affect both nucleation and elongation. As reported previously, addition of Abeta42 systematically accelerated the nucleation of Abeta40, most likely because of the extra hydrophobic residues at the C terminus of Abeta42. At Abeta42-increased specific ratio (Abeta40: Abeta42 = 10: 1), on the other hand, not only accelerated nucleation but also induced elongation were observed, suggesting pathogenesis of early-onset AD. Because a larger proportion of Abeta40 than Abeta42 was still required for this phenomenon, we assumed that elongation does not depend only on hydrophobic interactions. Without any change in the C-terminal hydrophobic nature, elongation was effectively induced by mixing wild type Abeta40 with Italian variant Abeta40 (E22K) or Dutch variant (E22Q). We suggest that Abeta peptides in specific compositions that balance hydrophilic and hydrophobic interactions promote the formation of toxic beta-aggregates. These results may introduce a new therapeutic approach through the disruption of this balance.     

Pancreatic acinar cell: its role in acute pancreatitis

The pancreatic acinar cell is the functional unit of the exocrine pancreas. It synthesizes, stores, and secretes digestive enzymes. Under normal physiological conditions, digestive enzymes are activated only once they have reached the duodenum. Premature activation of these enzymes within pancreatic acinar cells leads to the onset of acute pancreatitis; it is the major clinical disorder associated with pancreatic acinar cells. Although there have been major advances in our understanding of the pathogenesis of this disease in recent years, available treatment options are still limited to traditional nonspecific and palliative interventions. Novel therapeutic strategies have been suggested based on ongoing research in the physiology and pathophysiology of the disease; these include the administration of systemic antibiotics, antioxidants, cytokine antagonists, and more recently, inhibition of the renin-angiotensin system. Notwithstanding this promising development, most of these potential therapies are still in an experimental stage or clinical trial. Further investigation is needed to prove the efficacy of these novel treatment modalities.     

植物体细胞胚胎发生及其相关应答基因的研究进展

体细胞胚胎发生途径不仅是植物大规模克隆繁殖的重要途径,也是研究从单细胞到整体植株发育全过程的理想试验体系。植物体细胞胚胎发生的研究已经取得了很大的进展,但是也依然存在许多问题。根据近年来的相关研究报道,简述植物体细胞胚胎发生及此过程中相关应答基因的研究概况,探讨植物体细胞胚胎发生的生理生化基础,并对今后应该加强研究的关键问题提出了自己的看法。     

我国水产养殖事业的发展及今后的努力方向

我国水产养殖事业的发展及今后的努力方向曾呈奎（中国科学院海洋研究所青岛２６６０７１）我国水产养殖事业在新中国成立以前,只有个别零星古老的,传统的事业。在养殖海产鱼虾方面北方有几百年来的＂港养对虾和鱼＂,而在南方也有类似的鱼塘。在海藻栽培方面,则有几百年来的福建金门县的礁养海萝及平潭县的礁养紫菜等。这些古老的传统养殖方法虽然产生一些效果,但产量较小。     

DNA-hsp65 Vaccine as Therapeutic Strategy to Treat Experimental Chromoblastomycosis Caused by Fonsecaea Pedrosoi

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. Patients with the disease are still considered a therapeutic challenge, mainly due to its recalcitrant nature. There is no “gold standard” treatment for this neglected mycosis, but rather there are several treatment options. Chemotherapy alternatives include 5-flucytosine, itraconazole, terbinafine, fluconazole, thiabendazole, ketoconazole and amphotericin B, although the healing of severe cases is still uncommon. However, several studies have reported the DNA vaccine to be promising in the treatment for fungal infections; this vaccine allows the host to restore depressed cellular immunity, minimizing the toxic effects from conventional antifungal therapies. This work was therefore carried out aiming to establish a suitable model for experimental CBM, suggesting also new therapies, including DNA-hsp65 vaccine. By analyzing the morphometrical and histopathological aspects and by quantifying the fungal burden, the results showed the establishment of a chronic, although transitory, experimental CBM model with lesions similar to those presented in humans. A treatment regimen using intralesional itraconazole or amphotericin B was effective in treating experimental CBM, as was a therapy using naked DNA-hsp65 vaccine. It has also been shown that chemotherapy associated with DNA-hsp65 vaccine is promising in the treatment for CBM.     

How bad are invaders in coastal waters? The case of the American slipper limpet Crepidula fornicata in western Europe

Introduced species are assumed to exert a variety of negative ecological effects in their new environments. However, rigid studies on such effects are still rare. Using a case study we exemplify pitfalls and obstacles for research on ecological effects of invaders and highlight the need for a concise framework. The suspension feeding gastropod Crepidula fornicata was accidentally introduced with American oysters to Europe and was soon after defamed as an ‘oyster pest’ although no evidence was provided in justification. Recently, small-scale experiments with C. fornicata and the Pacific oyster Crassostrea gigas failed to prove competition. As an epizootic, however, C. fornicata is impeding native mussels Mytilus edulis but at the same time provides protection against starfish predation. It also may serve as a sink for infectious trematode parasites and hence be beneficial for bivalve basibionts. Another positive effect of C. fornicata, especially at the coast of France where it is superabundant, may be that it causes a shift of phytoplankton blooms from toxic flagellates to diatoms. The multiple interactions with recipient coastal ecosystems result in a complex interplay of negative as well as positive effects of the invader on native biota. Positive effects of invaders might occur with the same frequency as negative ones, and the general prejudice that introduced species exert per se a negative effect may dictate the outcome of research. We argue that considering both, negative as well as positive effects of an introduced species is needed to eventually enable us to evaluate the overall effect of an invasion on recipient ecosystems. Besides pointing to the importance of positive effects, this case study also shows that research on effects of introduced species should (1) be species specific, (2) consider different spatial scales, (3) clarify which stage of an invasive process is under observation and (4) clearly distinguish between ecological effects, human-relevant impacts and the ethical judgment of both. A concise framework for research on ecological effects of introduced species – which still has to be developed – should incorporate these aspects.