bluuebunny/crossref_metadata_2025 huggingface dataset:
Common gene expression signatures in t(8;21)‐ and inv(16)‐acute myeloid leukaemia
Authors: Ichikawa Hitoshi , Tanabe Kenji , Mizushima Hiroshi , Hayashi Yasuhide , Mizutani Shuki , Ishii Eiichi , Hongo Teruaki , Kikuchi Akira , Satake Masanobu
Published: September 2006

Human acute myeloid leukaemia (AML) involving a core‐binding factor (CBF) transcription factor is called CBF leukaemia. In these leukaemias, AML1 (RUNX1, PEBP2αB, CBFα2)‐MTG8 (ETO) and CBFβ (PEBP2β)‐MYH11 chimaeric proteins are generated by t(8;21) and inv(16) respectively. We analysed gene expression profiles of leukaemic cells by microarray, and selected genes whose expression appeared to be modulated in association with t(8;21) and inv(16). In a pair‐wise comparison, 15% of t(8;21)‐associated transcripts exhibited high or low expression in inv(16)‐AML, and 26% of inv(16)‐associated transcripts did so equivalently in t(8;21)‐AML. These common elements in gene expression profiles between t(8;21)‐ and inv(16)‐AML probably reflect the situation that AML1‐MTG8 and CBFβ‐MYH11 chimaeric proteins affect a common set of target genes in CBF leukaemic cells. On the other hand, 38% of t(8;21)‐associated and 24% of inv(16)‐associated transcripts were regulated in t(8;21)‐ and inv(16)‐specific manners. These distinct features of t(8;21)‐ and inv(16)‐associated genes correlate with the bimodular structures of the chimaeric proteins (CBF‐related AML1 and CBFβ portions, and CBF‐unrelated MTG8 and MYH11 portions).
Regulation of DNA synthesis in bacteria: analysis of the Bates/Kleckner licensing/initiation‐mass model for cell cycle control
Authors: Cooper Stephen
Published: September 2006

Bates and Kleckner have recently proposed that bacterial cell division is a licensing agent for a subsequent initiation of DNA replication. They also propose that initiation mass for DNA replication is not constant. These two proposals do not take into account older data showing that initiation of DNA replication can occur prior to the division event. This critical analysis is derived from measurements of DNA replication during the division cycle in cells growing at different, and more rapid, growth rates. Furthermore, mutants impaired in division can initiate DNA synthesis. The data presented by Bates and Kleckner do not support the proposal that initiation mass is variable, and the proposed pattern of DNA replication during the division cycle of the K12 cells analysed is not consistent with prior data on the pattern of DNA replication during the division cycle.
Thiosulphate oxidation in the phototrophic sulphur bacterium Allochromatium vinosum
Authors: Hensen Daniela , Sperling Detlef , Trüper Hans G. , Brune Daniel C. , Dahl Christiane
Published: September 2006

Two different pathways for thiosulphate oxidation are present in the purple sulphur bacterium Allochromatium vinosum: oxidation to tetrathionate and complete oxidation to sulphate with obligatory formation of sulphur globules as intermediates. The tetrathionate:sulphate ratio is strongly pH‐dependent with tetrathionate formation being preferred under acidic conditions. Thiosulphate dehydrogenase, a constitutively expressed monomeric 30 kDa c‐type cytochrome with a pH optimum at pH 4.2 catalyses tetrathionate formation. A periplasmic thiosulphate‐oxidizing multienzyme complex (Sox) has been described to be responsible for formation of sulphate from thiosulphate in chemotrophic and phototrophic sulphur oxidizers that do not form sulphur deposits. In the sulphur‐storing A. vinosum we identified five sox genes in two independent loci (soxBXA and soxYZ). For SoxA a thiosulphate‐dependent induction of expression, above a low constitutive level, was observed. Three sox‐encoded proteins were purified: the heterodimeric c‐type cytochrome SoxXA, the monomeric SoxB and the heterodimeric SoxYZ. Gene inactivation and complementation experiments proved these proteins to be indispensable for thiosulphate oxidation to sulphate. The intermediary formation of sulphur globules in A. vinosum appears to be related to the lack of soxCD genes, the products of which are proposed to oxidize SoxY‐bound sulphane sulphur. In their absence the latter is instead transferred to growing sulphur globules.
Colombia and Cuba, contrasting models in Latin America's health sector reform
Authors: Vos Pol De , Ceukelaire Wim De , Stuyft Patrick Van der
Published: September 2006

Latin American national health systems were drastically overhauled by the health sector reforms the 1990s. Governments were urged by donors and by the international financial institutions to make major institutional changes, including the separation of purchaser and provider functions and privatization. This article first analyses a striking paradox of the far‐reaching reform measures: contrary to what is imposed on public health services, after privatization purchaser and provider functions are reunited. Then we compare two contrasting examples: Colombia, which is internationally promoted as a successful – and radical – example of ‘market‐oriented’ health care reform, and Cuba, which followed a highly ‘conservative’ path to adapt its public system to the new conditions since the 1990s, going against the model of the international institutions. The Colombian reform has not been able to materialize its promises of universality, improved equity, efficiency and better quality, while Cuban health care remains free, accessible for everybody and of good quality. Finally, we argue that the basic premises of the ongoing health sector reforms in Latin America are not based on the people's needs, but are strongly influenced by the needs of foreign – especially North American – corporations. However, an alternative model of health sector reform, such as the Cuban one, can probably not be pursued without fundamental changes in the economic and political foundations of Latin American societies.

Keywords Latin America , Cuba , Colombia , health sector reform , privatization , national health system
Point‐of‐use water treatment and diarrhoea reduction in the emergency context: an effectiveness trial in Liberia
Authors: Doocy Shannon , Burnham Gilbert
Published: September 2006

Communicable diseases are of particular concern in conflict and disaster‐affected populations that reside in camp settings. In the acute emergency phase, diarrhoeal diseases have accounted for more than 40% of deaths among camp residents. Clear limitations exist in current water treatment technologies, and few products are capable of treating turbid water. We describe the findings of a 12‐week effectiveness study of point‐of‐use water treatment with a flocculant–disinfectant among 400 households in camps for displaced populations in Monrovia, Liberia. In intervention households, point‐of‐use water treatment with the flocculant–disinfectant plus improved storage reduced diarrhoea incidence by 90% and prevalence by 83%, when compared with control households with improved water storage alone. Among the intervention group, residual chlorine levels met or exceeded Sphere standards in 85% (95% CI: 83.1–86.8) of observations with a 95% compliance rate.
Comprehensive findings on clinical, bacteriological, histopathological and therapeutic aspects of cutaneous tuberculosis
Authors: Umapathy K. C. , Begum R. , Ravichandran G. , Rahman F. , Paramasivan C. N. , Ramanathan V. D.
Published: September 2006

Objective  To define the bacteriological and histological correlates of the three predominant clinical forms of cutaneous tuberculosis and to evaluate the efficacy of a 9‐month daily regimen containing rifampicin and isoniazid.

Methods  In the dermatological clinics of two major teaching hospitals in Chennai, 213 patients with suspected clinical manifestations of cutaneous tuberculosis underwent examination and a skin biopsy for bacteriological and histological tests. They were treated with a daily regimen of rifampicin and isoniazid for 9 months and follow‐up for 3 years.

Results  Bacteriological and/or histological confirmation of tuberculosis was obtained in 88% of the cases. Lupus vulgaris lesions were seen mainly in the extremities and verrucosa cutis occurred predominantly on the sole and foot, while the cervical and axillary regions were the commonest sites for scrofuloderma. Ninety‐two per cent of the patients showed resolution of the lesions within the first 6 months of chemotherapy; 1% failed to respond to this regimen. There was no relapse in any of the cases during the follow‐up period of 3 years.

Conclusions  Clinical findings were adequate to identify major forms of cutaneous tuberculosis as evidenced by bacteriological and histopathological examination. A daily regimen of rifampicin and isoniazid for 9 months was effective in treating cutaneous tuberculosis.
Domestic violence during pregnancy and risk of low birthweight and maternal complications: a prospective cohort study at Mulago Hospital, Uganda
Authors: Kaye Dan K. , Mirembe Florence M. , Bantebya Grace , Johansson Annika , Ekstrom Anna Mia
Published: September 2006

Objectives  To investigate whether domestic violence during pregnancy is a risk factor for antepartum hospitalization or low birthweight (LBW) delivery.

Methods  A prospective cohort study was conducted in Mulago hospital, Kampala, Uganda, among 612 women recruited in the second pregnancy trimester and followed up to delivery, from May 2004 through July 2005. The exposure (physical, sexual or psychological violence during pregnancy) was assessed using the Abuse Assessment Screen. The relative and attributable risks of LBW and antepartum hospitalization were estimated using multivariate logistic regression analysis.

Results  The 169 women [27.7% 95% CI (24.3–31.5%)] who reported domestic violence during pregnancy did not differ significantly from the unexposed regarding sociodemographic characteristics, but differed significantly (P < 0.05) regarding domicile variables (had less household decision‐making power, more resided in extended families and more had unplanned pregnancy). They delivered babies with a mean birthweight 2647.5 ± 604 g, on average 186 g [(95% CI 76–296); P = 0.001] lower than those unexposed. After adjusting for age, parity, number of living children, pregnancy planning, domicile and number of years in marriage, the relative risk (RR) of LBW delivery among women exposed to domestic violence was 3.78 (95% CI 2.86–5.00). Such women had a 37% higher risk of obstetric complications (such as hypertension, premature rupture of membranes and anaemia) that necessitated antepartum hospitalization [RR 1.37 (95% CI 1.01–1.84)].

Conclusion  In this pregnancy cohort, domestic violence during pregnancy was a risk factor for LBW delivery and antepartum hospitalization.
Local terminology for medicines to treat fever in Bougouni District, Mali: implications for the introduction and evaluation of malaria treatment policies
Authors: Patterson Amy E. , Winch Peter J. , Gilroy Kate E. , Doumbia Seydou
Published: September 2006

Objective  To explore Bambara language terminology and classification for locally available antimicrobial medicines in order to better target promotional messages and improve evaluation measures in Bougouni District, Mali.

Methods  Mothers (n = 20) and drug vendors (n = 15) were asked to freelist medicines used to treat childhood illnesses, and to identify all medicines that corresponded to each of the listed terms from an array of medicines displayed with their packaging.

Results  Each Bambara language medicine term can refer to numerous modern medicines, and each modern medicine has several Bambara names. The term nivakini (Nivaquine), often translated as ‘chloroquine’, refers to a wide range of medicines commonly used to treat malaria, many with no antimalarial effect. Antibiotics were also identified as common treatments for malaria. Mothers and vendors used slightly different terminology when discussing treatments for malaria, and sometimes employed the same term to refer to different medicines. Neither mothers nor vendors clearly differentiated between antimalarial medicines. Colour, shape and packaging play a large role in their recognition, classification and use.

Conclusions  Current household survey methods are likely to provide inaccurate estimates of appropriate treatment of febrile illness, and thus alternative approaches are recommended. In introducing new malaria treatments, malaria control programmes should differentiate recommended treatments from other medications through distinctive packaging, drug appearance and appropriate Bambara language terms.

Keywords malaria

treatment

home management

private sector

terminology

cognitive anthropology
Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high‐penetrance genes
Authors: Naseem H , Boylan J , Speake D , Leask K , Shenton A , Lalloo F , Hill J , Trump D , Evans DGR
Published: September 2006

We assessed the association between breast cancer (BC) and colorectal cancer (CRC) from referral pattern to the Regional Genetics Service including molecular analysis. Hospital computer records and/or department referral books were used to identify cases referred to the Regional Genetic Service during a 16‐year period (1990–2005 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details and results from mutation testing. Families were assessed for hereditary breast and colorectal cancer (HBCC) criteria, and all families with eligible individuals were tested for the 1100delC mutation in CHEK2. A total of 8612 families were identified. One hundred and sixteen of 1631 (7.5%) families with a primary referral for CRC fulfilled the criteria for HBCC, whereas only 68/6981 (1%) BC referrals fulfilled these criteria. Blood samples were obtained from 113 individuals from 83/184 families. Only 1/113 (1%) has screened positive for the CHEK2 mutation, whereas 14 (17%) families segregate BRCA1/2 mutations and at least 7 (8.5%) carry MLH1/MSH2 mutations. HBCC syndrome, if it exists as a separate entity, is not likely to be due to CHEK2 mutations. Many families are explicable by existing high‐penetrance genes, and further work is necessary to elucidate whether the remainder is due to chance or as yet undiscovered genes.
Prehatching maternal investment and offspring immunity in the pied flycatcher (Ficedula hypoleuca)
Authors: KILPIMAA J. , ALATALO R. V. , SIITARI H.
Published: September 2006

Maternal investment in offspring immunity via egg quality may be an adaptive evolutionary strategy shaped by natural selection. We investigated how maternal investment in eggs can influence offspring immunity by conducting two experiments. First, we manipulated foraging performance of the mothers before egg laying by attaching a small weight to their back feathers. During the nestling period, we investigated offspring total antibody production at the age of 7 days and after antibody challenge, and conducted a partial cross‐fostering design to separate the effects of the experiment and rearing‐related variation on offspring immunity. In a separate experiment, partial cross‐fostering with antibody challenging without female pied flycatcher manipulation was conducted for another set of nests. Total antibody levels at the age of 7 days were reduced in nestlings of the experimental female pied flycatchers when compared with the set of unmanipulated nests. Maternal investment in the eggs may affect some aspects of offspring immunity during the early nestling period and this investment is costly. However, antibody response to a set of novel antigens (sheep red blood cells) at the end of the nestling period was not affected by the female pied flycatchers treatment. Instead our results suggest that general antibody responsiveness is mainly determined by the rearing environment and total antibody levels before the injection.
Effect of Organic and Inorganic Nutrients for Soil Quality Conservation and Yield of Rainfed Low Land Rice in Sub‐tropical Plateau Region
Authors: Banik P. , Ghosal P. K. , Sasmal T. K. , Bhattacharya S. , Sarkar B. K. , Bagchi D. K.
Published: September 2006

The effect of organic sources of nutrients and inorganic fertilizers, was studied on grain yield of lowland rice and some aspect of soil quality parameters in a field experiment at Agricultural Experimental Farm of Indian Statistical Institute, Giridih, situated at eastern plateau region of India, during consecutive years 1997–2002. Chemical fertilizers and various organic matters were applied to two rice cultivars, Sabita and Subarna. The highest mean grain yield was 3.53 t ha−1 and maximum agronomic efficiency was 60.3 % with the application of inorganic fertilizer followed by cow dung, where 3.47 t ha−1 grain yield was recorded with an agronomic efficiency of 57.5 %. Grain yield of rice recorded under organic sources of nutrients was not significantly different from that of inorganic fertilization though there was improvement in soil quality parameters under organic sources. Soil organic carbon (0.72 %), microbial biomass‐C (279.23 μg g−1 dry soil), urease activity with buffer (33.54 μg urea hydrolyzed g−1 oven‐dry soil) and non‐buffer (21.97 μg urea hydrolyzed g−1 of oven‐dry soil) methods and acid phosphatase activity (2.24 μg para‐nitrophenol released g−1 of oven‐dry soil) analysed following the harvest of the crop were highest under cow dung manure treatment; the most efficient organic source under the experiment. Mean grain yield of rice was significantly higher in Sabita cultivar over Subarna. The regression analyses among the variables have shown that there was linear relationship among soil parameters and grain yield of rice.
Modelling Biomass Accumulation and Partitioning in Chickpea (Cicer arietinum L.)
Authors: Soltani A. , Robertson M. J. , Rahemi‐Karizaki A. , Poorreza J. , Zarei H.
Published: September 2006

Quantitative information regarding biomass accumulation and partitioning in chickpea (Cicer arietinum L.) is limited or inconclusive. The objective of this study was to obtain baseline values for extinction coefficient (KS), radiation use efficiency (RUE, g MJ−1) and biomass partitioning coefficients of chickpea crops grown under well‐watered conditions. The stability of these parameters during the crop life cycle and under different environmental and growth conditions, caused by season and sowing date and density, were also evaluated. Two field experiments, each with three sowing dates and four plant densities, were conducted during 2002–2004. Crop leaf area index, light interception and crop biomass were measured between emergence and maturity. A KS value of 0.5 was obtained. An average RUE of 1 g MJ−1 was obtained. Plant density had no effect on RUE, but some effects of temperature were detected. There was no effect of solar radiation or vapour pressure deficit on RUE when RUE values were corrected for the effect of temperature. RUE was constant during the whole crop cycle. A biphasic pattern was found for biomass partitioning between leaves and stems before first‐seed stage. At lower levels of total dry matter, 54 % of biomass produced was allocated to leaves, but at higher levels of total dry matter, i.e. under favourable and prolonged conditions for vegetative growth, this portion decreased to 28 %. During the period from first‐pod to first‐seed, 60 % of biomass produced went to stems, 27 % to pods and 13 % to leaves. During the period from first‐seed to maturity, 83 % of biomass was partitioned to pods. It was concluded that using fixed partitioning coefficients after first‐seed are not as effective as they are before this stage. Environmental conditions (temperature and solar radiation) and plant density did not affect partitioning of biomass.
Accumulation of Secondary Metabolites Formed by Field Fungi in Autumn‐Saved Herbage
Authors: Golinski P. , Opitz von Boberfeld W. , Kostecki M. , Kaczmarek Z. , Golinski P. K.
Published: September 2006

Taking into consideration the fact that in recent years weather conditions were sufficient to feed cattle on pasture until late autumn or early winter, an experiment was carried out during the years 2000 and 2003 on a low input pasture to show the effect of the pre‐utilization date (June, July, August) and the harvest date in the autumn/winter period (November, December, January) on the accumulation of the following secondary metabolites formed by fungi: ergosterol (ERG), ochratoxin A (OA) and zearalenone (ZEA) in the autumn‐saved herbage. The highest levels of concentration of these metabolites were 470.3, 1.63 and 34.9 ng g−1 respectively. Lower ERG levels were influenced by later pre‐utilization, which is a logical consequence of the shorter period of time for field toxigenic fungi development. Pre‐utilization in August is strongly recommended as the concentration of ochratoxin A (OA) in the autumn‐saved herbage in January was the lowest (not much changed in comparison with earlier harvest). Later harvest was also affected by higher ZEA concentrations in the analysed samples, which indicates that, under conditions of prolonged pasture utilization, field toxigenic fungi (producing ZEA) increased their population and had proper weather conditions stimulating the biosynthesis of the toxin. The later suggests that the final harvest of autumn‐saved herbage should be made rather in December than in January. Higher levels of humidity influenced higher concentrations of ERG and ZEA in the autumn‐saved herbage.
Trend and Stability Analysis to Interpret Results of Long‐Term Effects of Application of Fertilizers and Manure to Cotton Grown on Rainfed Vertisols
Authors: Blaise D. , Ravindran C. D. , Singh J. V.
Published: September 2006

A field experiment was conducted from 1985–1986 to 2002–2003 on Vertisols under rainfed conditions to evaluate the effect of cropping systems and application of fertilizers and manure on seed cotton yield. To determine the long‐term effects, trends and stability analyses were performed. Soil samples (0–0.15 and 0.15–0.30 m) were collected at the end of year 18 and analysed for available P and AB‐DTPA extractable Zn. Among cropping systems, Asiatic diploid cotton (Gossypium arboreum) yielded 233 kg ha−1more seed cotton than the upland tetraploid cotton (Gossypium hirsutum). Yield trend was positive forG. arboreumcompared withG. hirsutum. However, the slope was not significant. Stability analyses indicated overall higher yield stability forG. arboreumthanG. hirsutum. Compared with monocroppingG. hirsutum,G. hirsutum–sorghum (Sorghum bicolorL.) (H‐S) rotation was significantly more stable. Soil samples (0–0.30 m) of the manure‐amended plots had significantly greater P and Zn content (above the critical limit) compared to those receiving inorganic fertilizers alone. With regard to nutrient management practices, seed cotton yield was the highest for the integrated nutrient management (INM) treatment receiving a combination of organic and inorganic fertilizers. Among primary nutrients, the effect of P was significant while that of K was not. Balanced fertilizer application was significantly better than treatments receiving N and NK. Yield trends were, in general, not significant. However, a positive trend was noticed for treatments receiving manure compared to fertilizer alone. Stability analysis, on the other hand, indicated that the slopes were, in general, significant. Among the nutrients, mean yield response with and without P was 1007 and 672 kg ha−1respectively. Combined application of manure and fertilizer (INM) resulted in the highest mean yield response (1218 kg ha−1) and the slope was highly significant (P < 0.004). In the manure‐amended plots, a better nutrient status probably imparted a greater degree of yield stability. The present study suggests that compared to trend analysis, stability analysis being sensitive as it recognizes the treatment × environment interaction, is a better option to interpret results from long‐term agronomic experiments.
The Tripartite Symbiosis Formed by Indigenous Arbuscular Mycorrhizal Fungi,Bradyrhizobium japonicumand Soya Bean Under Field Conditions
Authors: Antunes P. M. , De Varennes A. , Zhang T. , Goss M. J.
Published: September 2006

The tripartite symbiosis formed by indigenous arbuscular mycorrhizal fungi (AMF),Bradyrhizobium japonicum(Kirchner) Jordan and soya bean (Glycine maxL. Merr. cv. Evans) was investigated under field conditions to test the hypotheses that: (i) the tripartite symbiosis enhances nodulation and nodule activity; and (ii) its establishment does not rely on improved phosphorus (P) uptake through the fungal partner. Soil tillage was used to produce treatments with contrasting AMF colonization potentials while the amount ofB. japonicuminoculum was kept constant. Nodulation, AMF colonization and the P and nitrogen (N) nutrition of plants were evaluated at 10 and 51 (full‐bloom) days after emergence. N2fixation was estimated by the difference method and by the isotopic dilution method. At the early stage of plant growth, AMF hyphal colonization and nodulation were, respectively, 16 % and 33 % greater in plants from untilled than from rototilled soil. The establishment of the tripartite symbiosis was observed under field conditions, and factors other than P nutrition were critical to its formation. However, the tripartite symbiosis did not promote N2fixation under the high soil P conditions of this study.
Application of Stress Indices for Heat Tolerance Screening of Common Bean
Authors: Porch T. G.
Published: September 2006

Common bean is adapted to relatively cool climatic conditions and temperatures of >30 °C during the day or >20 °C at night result in yield reduction. The long‐term goal of breeding for heat tolerance is the development of germplasm with improved field level tolerance under variable temperature conditions. Using previously developed stress indices, this study presents results from high temperature screening of 14 genotypes in both the greenhouse and field in Puerto Rico. A total of three sets of paired trials were conducted in the field and in the greenhouse under high temperature (stress) and lower temperature (low‐stress) conditions. The geometric mean (GM), stress tolerance index (STI) and stress susceptibility index (SSI) were used to evaluate the genotypic performance under stress and low‐stress conditions. The results indicate that it was possible to identify superior genotypes for heat tolerance based on their stress indices. In this evaluation of heat tolerance indices, STI and GM, although correlated, were found to be effective stress indices for the selection of genotypes with good yield potential under stress and low‐stress conditions.
Fertility Results of Artificial Inseminations Performed with Liquid Boar Semen Stored in X‐CellTM vs BTS Extender
Authors: Haugan T , Gaustad AH , Reksen O , Gröhn YT , Hofmo PO
Published: September 2006

Contents

The objective of the present field study was to compare the fertility results for boar semen diluted in X‐cellTM stored up to 4–5 days before artificial insemination (AI) with semen diluted in Beltsville thawing solution (BTS) used for AI following 2–3 days of storage (where the first day being the collection day). A total number of 2601 double inseminations in Norwegian herds were included in this two‐trial study. All the boars used in the study were mature cross‐bred Norwegian Landrace × Duroc (LD), which were routinely used for AI in Norway. The inseminated gilts and sows were Norwegian Landrace × Yorkshire (LY). The AI doses contained 2.5 billion spermatozoa, and consisted of a mixture of semen from three, occasionally four, boars (i.e. heterospermic semen). Fertility was measured in terms of the likelihood of farrowing and subsequent litter size. The fertility of the semen in both of the extenders was satisfactory and no significant differences were found either in semen stored 4–5 days in X‐cellTM compared with 2–3 days in BTS or in semen stored 2–3 days in X‐cellTM compared with 2–3 days in BTS. The storage capability findings for the long‐term extender X‐cellTM could significantly simplify the practical issues of semen production and the distribution of AI doses containing 2.5 billion spermatozoa. However, in pig production systems where all semen is used within 2–3 days, the short‐term extender BTS is as good as the more expensive extender X‐cellTM.
Ryanodine receptor–transmitter release site coupling increases quantal size in a synapse‐specific manner
Authors: Dunn Tyler W. , Syed Naweed I.
Published: September 2006

The mechanisms by which presynaptic neurones differentially regulate synaptic transmission with multiple postsynaptic targets in the brain are not fully understood. Using intracellular sharp electrode and whole‐cell voltage‐clamp recordings of soma–soma synapses between identifiedLymnaeaneurones, we provide direct evidence that quantal size is regulated presynaptically through the coupling of multiple release sites. This coupling effectively multiplies quantal size, thereby providing significant influence over parameters of synaptic transmission that are influenced by quantal size, such as the variance in transmitter release at stationary release probabilities. Variation in the degree of coupling is dependent on the identity of the postsynaptic cell, even though the variation in quantal size is of presynaptic origin. We have therefore demonstrated the presence of a novel mechanism by which presynaptic neurones may differentially regulate quantal size at select synaptic connections, in turn providing them with a means of regulating synaptic transmission with multiple postsynaptic cells.
The axotomy‐induced neuropeptides galanin and pituitary adenylate cyclase‐activating peptide promote axonal sprouting of primary afferent and cranial motor neurones
Authors: Suarez Victor , Guntinas‐Lichius Orlando , Streppel Michael , Ingorokva Shota , Grosheva Maria , Neiss Wolfram F. , Angelov Doychin N. , Klimaschewski Lars
Published: September 2006

The neuropeptides galanin and pituitary adenylate cyclase‐activating peptide (PACAP) are markedly up‐regulated in response to peripheral nerve lesion. Both peptides are involved in neuronal differentiation and neurite outgrowth during development. In this study, we investigated the effects of galanin and PACAP on axonal elongation and sprouting by adult rat sensory neurones in vitro and facial motor neurones in vivo. Dissociated rat dorsal root ganglion neurones were plated on laminin substrate and analysed morphometrically. Both the mean axonal length and the number of branch points significantly increased in the presence of galanin or PACAP (2–5 µm). Effects on axonal collateralization were investigated in the rat facial nerve lesion model by direct application of the peptides to collagen‐filled conduits entubulating the transected facial nerve stumps. Triple retrograde labelling of brainstem neurones confirmed that the peptides potently induce axonal sprouting of cranial motor neurones. The number of neurones regenerating into identified rami of the facial nerve increased up to fivefold. Biometrical analysis of whisking behaviour revealed that galanin and PACAP impaired the functional outcome when compared with vehicle‐treated animals 8 weeks after surgery. In conclusion, although galanin and PACAP have been established as neurotrophic molecules with respect to axonal development and regeneration, their potential as treatments for peripheral nerve lesions appears limited because of the extensive stimulation of collateral axon branching. These branches are misrouted towards incorrect muscles and cause impairment in their coordinated activity.
Brain‐derived neurotrophic factor facilitates in vivo internalization of tetanus neurotoxin C‐terminal fragment fusion proteins in mature mouse motor nerve terminals
Authors: Roux Sylvie , Saint Cloment Cécile , Curie Thomas , Girard Emmanuelle , Mena Francisco‐Javier Miana , Barbier Julien , Osta Rosario , Molgó Jordi , Brûlet Philippe
Published: September 2006

In a previous study it was reported that fusion proteins composed of the atoxic C‐terminal fragment of tetanus toxin (TTC) and green fluorescent protein or β‐galactosidase (GFP‐TTC and β‐gal‐TTC, respectively) rapidly cluster at motor nerve terminals of the mouse neuromuscular junction (NMJ). Because this traffic involves presynaptic activity, probably via the secretion of active molecules, we examined whether it is affected by brain‐derived neurotrophic factor (BDNF). Quantitative confocal microscopy and a fluorimetric assay for β‐gal activity revealed that co‐injecting BDNF and the fusion proteins significantly increased the kinetics and amount of the proteins' localization at the NMJ and their internalization by motor nerve terminals. The observed increases were independent of synaptic vesicle recycling because BDNF did not affect spontaneous quantal acetylcholine release. In addition, injecting anti‐BDNF antibody shortly before injecting GFP‐TTC, and before co‐injecting GFP‐TTC and BDNF, significantly reduced the fusion protein's localization at the NMJ. Co‐injecting GFP‐TTC with neurotrophin‐4 (NT‐4) or glial‐derived neurotrophic factor (GDNF), but not with nerve growth factor, neurotrophin‐3 or ciliary neurotrophic factor, also significantly increased the fusion protein's localization at the NMJ. Thus, TTC probes may use for their neuronal internalization endocytic pathways normally stimulated by BDNF, NT‐4 and GDNF binding. Different tyrosine kinase receptors with similar signalling pathways are activated by BDNF/NT‐4 and GDNF binding. Thus, activated components of these signalling pathways may be involved in the TTC probes' internalization, perhaps by facilitating localization of receptors of TTC in specific membrane microdomains or by recruiting various factors needed for internalization of TTC.
Marked alterations in the gait timing and rhythmicity of patients withde novoParkinson's disease
Authors: Baltadjieva Rossitza , Giladi Nir , Gruendlinger Leor , Peretz Chava , Hausdorff Jeffrey M.
Published: September 2006

Little is known about the gait characteristics of subjects withde novoParkinson's disease (PD). We hypothesized that alterations in the spatio‐temporal characteristics of gait will already be quantifiable in these patients. The gait of 35 patients with idiopathic PD (mean age 60 years) who were in the early stages of the disease (Hoehn and Yahr stage 1.8 ± 0.5, median 2.0, range 1.0–2.5) and were not yet treated with any anti‐parkinsonian medications were compared with the gait of age‐ and sex‐matched healthy controls (n = 22). The patients walked more slowly and with reduced swing times while also exhibiting increased left/right swing asymmetry and marked inconsistencies in the timing of gait. By contrast, significant group differences in the peak forces at heel‐strike and in the stride‐to‐stride variability of the ground reaction forces (a reflection of muscle output consistency) were not observed. These findings indicate that inde novoPD, an altered gait pattern is observed, even though dramatic changes in the gait pattern may not yet be apparent visually (e.g. fairly intact gait speed). Furthermore, the results demonstrate that the observed alterations are not just side‐effects of treatments or complications of the disease. Instead, there is evidence for motor programming deficits in gait, as revealed by increased gait variability and asymmetry in timing. PD apparently impinges on the regulation of a consistent gait rhythm, even early in the course of the disease when observed alterations are not the result of any pharmacologic treatment.
Insulin‐like growth factor binding proteins: regulation in chronic active plaques in multiple sclerosis and functional analysis of glial cells
Authors: Chesik Daniel , De Keyser Jacques , Glazenburg Lisa , Wilczak Nadine
Published: September 2006

Studies in experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS), suggest that astrocyte‐secreted insulin‐like growth factor binding protein‐2 (IGFBP‐2) helps target IGF‐1 to IGF‐1 receptor‐expressing oligodendrocytes and promote remyelination. We examined the presence of IGFBPs 1–6 in astrocytes in normal post‐mortem human brain tissue and lesions of MS by means of immunohistochemistry. Under normal conditions all six IGFBPs were detected. Compared to controls, hypertrophic astrocytes at the borders of chronic active MS lesions displayed increased immunoreactivity for IGFBP‐2 and IGFBP‐4. In vitro studies were performed to analyse the effects of IGFBPs on cellular proliferation of neonatal rat glial cells. Treatment of astrocytes with IGF‐1 and ‐2 enhanced proliferation whereas IGFBP‐2 and ‐4 inhibited cellular growth. Interestingly, combined treatment with IGFBP‐2 and IGF‐1 potentiated effects on cellular proliferation whereas combined treatment with IGFBP‐2 and IGF‐2 inhibited growth. Unlike IGFBP‐2, IGFBP‐4 inhibited proliferation in combined treatment with IGF‐1. In contrast, combined treatment with IGFBP‐2 and IGF‐1 resulted in decreased cell survival of oligodendrocyte precursor cells. Our results suggest that the up‐regulation of IGFBP‐2 in reactive astrocytes in MS lesions may primarily serve to enhance the IGF‐1‐mediated mitogenic stimulus for astrocytes rather than supporting oligodendrocyte survival.
The importance of the rat hippocampus for learning the structure of visual arrays
Authors: Sanderson David J. , Pearce John M. , Kyd Rachel J. , Aggleton John P.
Published: September 2006

It has been assumed that the integrity of the rodent hippocampus is required for learning the spatial distribution of visual elements in an array. Formally assessing this assumption is, however, far from straightforward as standard tests are amenable to alternative strategies. In order to provide a stringent test of this ability rats were trained on three concurrent visual discriminations in a water tank in which the stimuli in each pair of discriminations contained exactly the same elements but they differed in their spatial arrangement e.g. A|B vs. its mirror image B|A. Such ‘structural’ discriminations are a specific subtype of ‘configural’ or ‘nonlinear’ tasks. Following acquisition half of the rats received hippocampal lesions and all rats were retrained on the structural discriminations. Hippocampal lesions impaired the ability to relearn these ‘structural’ discriminations. In contrast, two other groups of rats with similar hippocampal lesions showed no impairment on relearning two non‐structural, configural discriminations: transverse patterning and biconditional learning. All three tasks used the same apparatus, the same stimulus elements, and similar training regimes. Superior performance by the rats with hippocampal lesions during a generalization decrement probe showed that hippocampal lesions had diminished sensitivity to ‘structural’ features on the biconditional task. While the rat hippocampus need not be required for all configural learning, it is important for the special case when the spatial arrangements of the elements are critical. This ability may be a prerequisite for the creation of mental snapshots, which underlie episodic memory.
Animal models of migraine: looking at the component parts of a complex disorder
Authors: Bergerot A. , Holland P. R. , Akerman S. , Bartsch T. , Ahn A. H. , MaassenVanDenBrink A. , Reuter U. , Tassorelli C. , Schoenen J. , Mitsikostas D. D. , Van Den Maagdenberg A. M. J. M. , Goadsby P. J.
Published: September 2006

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain‐producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease‐producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraine's component parts to allow a better understanding of the problem and the development of new treatment strategies.
Targeted transgene expression in neuronal precursors: watching young neurons in the old brain
Authors: Couillard‐Despres Sebastien , Winner Beate , Karl Claudia , Lindemann Gudrun , Schmid Peter , Aigner Robert , Laemke Joern , Bogdahn Ulrich , Winkler Juergen , Bischofberger Josef , Aigner Ludwig
Published: September 2006

Progress in the field of neurogenesis is limited by the lack of animal models allowing direct detection and analysis of living cells participating in neurogenesis. We engineered a transgenic mouse model that expresses the fluorescent reporter proteins enhanced green fluorescent protein or Discoma sp. reef coral red fluorescent protein under the control of the doublecortin (DCX) promoter, a gene specifically and transiently active in neuronal precursors and young neurons. The expression of the reporter proteins correlated with expression of the endogenous DCX protein, and with developmental and adult neurogenesis. Neurogenesis was unaffected by the presence of the fluorescent proteins. The transgenic mice allowed direct identification of the very few newly generated neurons present in the aged brain. We performed electrophysiological analysis and established that newly generated hippocampal granule cells in aged and young mice shared identical physiological properties. Hence, although the rate of neurogenesis tapers with ageing, a population of highly excitable young neurons indistinguishable to those found in younger animals is continuously generated. Therefore, maintenance of the fundamental properties of neuronal precursors even at advanced age suggests that stimulation of neurogenesis may constitute a valid strategy to counteract age‐related neuronal loss and cognitive declines.
Modulation of p75NTR‐dependent motor neuron death by a small non‐peptidyl mimetic of the neurotrophin loop 1 domain
Authors: Pehar Mariana , Cassina Patricia , Vargas Marcelo R. , Xie Youmei , Beckman Joseph S. , Massa Stephen M. , Longo Frank M. , Barbeito Luis
Published: September 2006

The p75 neurotrophin receptor (p75NTR) is expressed by degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS). The mature and pro‐form of nerve growth factor (NGF) activate p75NTR to trigger motor neuron apoptosis. However, attempts to modulate p75NTR‐mediated neuronal death in ALS models by downregulating or antagonizing p75NTR with synthetic peptides have led to only modest results. Recently, a novel ligand of p75NTR, compound LM11A‐24, has been identified. It is a non‐peptidyl mimetic of the neurotrophin loop 1 domain that promotes hippocampal neuron survival through p75NTR and exerts protection against p75NTR‐mediated apoptosis of oligodendrocytes induced by proNGF. Thus, LM11A‐24 appears to activate p75NTR‐linked survival but not death mechanisms, and may interfere with the ability of neurotrophins to induce apoptosis. Given these findings, we hypothesized that LM11A‐24 might be a particularly potent inhibitor of motor neuron degeneration. We examined the effects of LM11A‐24 on apoptosis of cultured rat embryonic motor neurons. Interestingly, in contrast to the effects observed in hippocampal cultures, LM11A‐24 was unable to prevent motor neuron apoptosis induced by trophic factor deprivation. However, picomolar concentrations of LM11A‐24 prevented p75NTR‐dependent motor neuron death induced by either exogenous addition of NGF or spinal cord extracts from symptomatic superoxide dismutase‐1G93A mice, in the presence of low steady‐state concentrations of nitric oxide. LM11A‐24 also inhibited motor neuron death induced by NGF‐producing reactive astrocytes in co‐culture conditions. These studies suggest that modulation of p75NTR by small molecule ligands targeting this receptor might constitute a novel strategy for preventing motor neuron degeneration.
Neurokinin3receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine‐enhancing action in the nucleus accumbens core
Authors: Jocham Gerhard , Lezoch Katharina , Müller Christian P. , Kart‐Teke Emriye , Huston Joseph P. , De Souza Silva M. Angélica
Published: September 2006

Several lines of evidence indicate a role for neurokinin3receptors (NK3‐Rs) in behavioural activation and mechanisms governing reinforcement processes. In this study we investigated the effect of pretreatment with the NK3‐R antagonist, SR142801, (0.2 and 2.0 mg/kg) on the cocaine‐induced (10.0 mg/kg i.p.) increase in extracellular dopaminergic activity in the nucleus accumbens (NAc).In vivomicrodialysis in the NAc of freely moving rats showed that cocaine increased concentrations of dopamine (DA) to ∼350% in the core and ∼450% in the shell. Pre‐treatment with SR142801 significantly potentiated this effect in the core (to ∼550%), whereas this effect was not found in the shell. We also investigated the effects of NK3‐Rs antagonism on cocaine‐induced hyperactivity and conditioned place preference. SR142801 blocked the hyperactivity, but neither the conditioned place preference nor the conditioned locomotor activity induced by cocaine, although there was a slight tendency towards a reduced place preference. When given alone, SR142801 had no effects on behaviour or extracellular dopamine concentrations in any of the structures investigated. These data provide evidence for a contribution of NK3‐Rs in the acute behavioural and neurochemical effects of cocaine, involving dopaminergic activity in the core of the nucleus accumbens.
Changes in extracellular hypothalamic glucose in relation to feeding
Authors: Mayer C. H. , Fink H. , Rex A. , Voigt J. ‐P.
Published: September 2006

The aim of the present in vivo microdialysis study was to investigate the relation between feeding and changes in glucose concentrations in the rat ventromedial hypothalamus (VMH). Absolute ambient glucose concentrations in VMH were 1.43 mm in non‐deprived rats as compared to 0.94 mm after 24‐h food deprivation. To examine whether feeding influences hypothalamic glucose, changes of glucose concentration over time were determined relative to a baseline. Experiments were conducted in relation to both, nutritional state (food‐deprived rats vs. non‐deprived rats) and feeding conditions throughout the experiment (freely feeding rats vs. rats without access to food). The results of this microdialysis study show clearly that glucose concentration in the VMH of rats increases significantly in relation to food intake. The data demonstrate that a 24‐h food deprivation before the experiment further augments this increase (up to 350% from baseline) as compared to non‐deprived conditions (up to 60% from baseline). However, the magnitude of food related increase in VMH glucose does not correlate with the individual amount of food eaten. In conclusion, the present study shows for the first time that VMH glucose concentrations increase with food intake in the early dark phase, indicating that such changes do not only occur after pharmacological treatment, but also under physiological feeding conditions. The results further indicate that the feeding related increase in VMH glucose depends on the nutritional state of the organism.