bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival
Authors: LAMBERT Elise , BOUDOT Cédric , KADRI Zahra , SOULA-ROTHHUT Mahdhia , SOWA Marie-Line , MAYEUX Patrick , HORNEBECK William , HAYE Bernard , PETITFRERE Emmanuelle
Published: June 2003

Tissue inhibitors of metalloproteinases (TIMP) are specific inhibitors of matrix metalloproteinases (MMPs) and thus participate in maintaining the balance between extracellular matrix deposition and degradation in several physio-pathological processes. Nevertheless, TIMP must be regarded as multifunctional proteins involved in cell growth, angiogenesis and apoptosis. The molecular mechanisms induced by TIMP remain largely unknown. In the present study, we provide evidence that TIMP-1 induces a significant anti-apoptotic effect in the human erythroleukaemic cell line UT-7 and in the murine myeloid cell line 32D. Using specific kinases inhibitors, we show that TIMP-1-mediated cell survival is dependent upon Janus kinase (JAK) 2 and phosphoinositide 3-kinase (PI 3-kinase) activities. By transient transfection of dominant-negative Akt in UT-7 cells, we demonstrate that this kinase is crucial for the TIMP-1 anti-apoptotic effect. Moreover, TIMP-1 enhances specific phosphorylation of both Akt and Bad (Bcl-2/Bcl-XL-antagonist, causing cell death) in a PI 3-kinase-dependent manner and, besides, controls the level of the anti-apoptotic protein Bcl-XL. We conclude that TIMP-1 induces haematopoietic cell survival via the JAK2/PI 3-kinase/Akt/Bad pathway.
Antibacterial properties of the sperm-binding proteins and peptides of human epididymis 2 (HE2) family; salt sensitivity, structural dependence and their interaction with outer and cytoplasmic membranes of Escherichia coli
Authors: YENUGU Suresh , HAMIL Katherine G. , BIRSE Charles E. , RUBEN Steven M. , FRENCH Frank S. , HALL Susan H.
Published: June 2003

During passage through the epididymis, sperm interact with secreted epididymal proteins that promote maturation, including the acquisition of motility and fertilization competence. Viewed previously as distinct from sperm maturation, host defence capabilities are now recognized functions of the human epididymis 2 (HE2) family of sperm-binding proteins. We analysed the potent dose and time-dependent bactericidal activity of recombinant HE2α, HE2β1 and HE2β2 and found that the full-length proteins (10 μg/ml or ~1 μM) caused more than a 50% decrease in Escherichia coli colony forming units within 15 min. By contrast, human β-defensin-1, at a similar concentration, required more than 90 min to exhibit similar antibacterial activity. The epididymis-specific lipocalin, LCN6, failed to kill bacteria. Higher concentrations (25–100 μg/ml) of HE2 proteins and a longer duration of treatment resulted in near total inhibition of bacterial growth. The C-terminal peptides of HE2α, HEβ1 and HEβ2 proteins exhibited antibacterial activity similar to their full-length counterparts, indicating that the antibacterial activity of HE2 proteins resides in these C-terminal regions. Antibacterial activities of HE2 proteins and peptides were slightly inhibited by NaCl concentrations of up to 150 mM, while human β-defensin-1 activity was nearly eliminated. Reduction and alkylation of disulphide bonds in HE2 proteins and their C-terminal peptides abolished their antibacterial activity. Consistent with the ability to kill bacteria, full-length HE2 proteins and C-terminal peptides caused rapid dose-dependent permeabilization of outer and cytoplasmic E. coli membranes. A much longer exposure time was required for human β-defensin-1-mediated permeabilization of membranes, suggesting a possible difference in mode of action compared with the HE2 antibacterial peptides.
Insulin and dexamethasone induce GLUT4 gene expression in foetal brown adipocytes: synergistic effect through CCAAT/enhancer-binding protein alpha
Authors: HERNANDEZ Rosario , TERUEL Teresa , LORENZO Margarita
Published: June 2003

Treatment of foetal brown adipocytes in primary culture with either dexamethasone or insulin, at physiological concentrations, for 24 h up-regulates the expression of the GLUT4 gene, producing a synergistic effect on mRNA accumulation (20-fold increase), in the amount of protein in the total membrane fraction (8-fold increase) and in the transactivation of a full-promoter GLUT4-chloramphenicol acetyltransferase gene (CAT) construct (7-fold increase). However, GLUT1 expression remains essentially unmodified regardless of the presence of the hormones. As a consequence, exposure of brown adipocytes to dexamethasone and insulin results in a dramatic increase of glucose uptake (12-fold). Dexamethasone induces the expression of CCAAT/enhancer-binding protein (C/EBP) α, insulin promotes myocyte enhancer factor-2 DNA-binding activity and both combined produces a significant increase in C/EBPα DNA-binding activity. Moreover, co-transfection with a wild-type C/EBPα construct transactivates a full-promoter GLUT4-CAT fusion gene, whereas a dominant-negative C/EBPα expression vector impairs the hormonal effects. Our results show that the synergism between insulin and glucocorticoids on glucose uptake is a consequence of the activation of the GLUT4 promoter by the transcription factor C/EBPα.
Long‐term observation of reflux oesophagitis developing after Helicobacter pylori eradication therapy
Authors: Sasaki A. , Haruma K. , Manabe N. , Tanaka S. , Yoshihara M. , Chayama K.
Published: June 2003

Background:  Development of reflux oesophagitis after Helicobacter pylori eradication therapy has been reported, but the prognosis is not well known.

Aim:  To evaluate the prognosis of patients with reflux oesophagitis that developed after eradication therapy by long‐term observation.

Methods:  Forty‐five patients who developed reflux oesophagitis after successful H. pylori eradication therapy were followed up prospectively. All 45 patients were followed up by endoscopy more than 3 years after onset of reflux oesophagitis (3‐year follow‐up group) and nine were followed up more than 5 years after onset (5‐year follow‐up group). Endoscopic observations were performed yearly or when upper gastrointestinal symptoms recurred. Reflux oesophagitis was graded according to the Los Angeles Classification System. Presence of gastro‐oesophageal reflux symptoms and medication of proton pump inhibitors, H2‐blockers or prokinetics were investigated at final endoscopy.

Results:  All patients were classified as grade A or B at initial endoscopy. At final observation, the grade of reflux oesophagitis improved in 35/45 (78.8%) patients from the 3‐year follow‐up group and 7/9 (78.8%) patients from the 5‐year follow‐up group. Reflux oesophagitis progressed from grade A to B in only four (8.9%) patients from the 3‐year follow‐up group and in no patients in the 5‐year follow‐up group. No patient progressed to grade C or D. Gastro‐oesophageal reflux symptoms were seen in 12 patients (26.7%) from the 3‐year follow‐up group and four patients (44.4%) from the 5‐year follow‐up group. Among them, medication was needed continuously in only six (13.3%) and two (22.2%) patients, respectively.

Conclusions:  Reflux oesophagitis, which develops after H. pylori eradication therapy, rarely becomes a long‐term clinical problem among patients who complete therapy successfully.
Modelling a minimal residual disease‐based treatment strategy in childhood acute lymphoblastic leukaemia
Authors: Campbell Peter J. , Morley Alexander A.
Published: June 2003

Summary. The measurement of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia offers the promise of individualized, risk‐stratified treatment, but an optimal protocol needs establishing. A model was developed to explore certain unanswered questions. The model assumes that all patients have MRD assessed after induction chemotherapy and children above a certain threshold are offered intensive chemotherapy. Using parameter estimates derived from published studies of MRD, the model predicted event‐free survival (EFS) rates, relapse rates and treatment‐related mortality for a cohort of children in the first presentation who were Philadelphia chromosome negative. Using the level of MRD after induction in order to decide on the use of intensive therapy resulted in an increase in EFS rates of up to 2·9 per 100 children, although if the error of the MRD measurement were too great, the benefit was almost nullified. Taking and analysing more than one marrow sample from the patient for the MRD measurement, in order to reduce sampling and measurement error, improved EFS by a further 1·1 patients per 100 treated, and decreased the number of patients offered intensive therapy by up to 2·6 per 100 treated. The optimal threshold for offering intensive therapy was in the range of 10−3·5− 10−4·5 cells if the intensive treatment‐related mortality was 13–18% (allograft options), but 10−5− 10−6 cells if it was less than 8% (intensified chemotherapy). Using MRD to target patients at a high risk of relapse improved EFS rates, but the accuracy of measurements was of critical importance.
Body sizes of carnivores commensal with humans have increased over the past 50 years
Authors: Yom‐Tov Y.
Published: June 2003

Improved nutrition may cause an increase in body size in animals, while increased ambient temperature may result in a decrease in body size, as expected from Bergmann's rule. In Israel, during the last 50 years both food availability for animals commensal with humans and ambient temperature have increased.

Using museum data, temporal changes in body size of five species of carnivorous mammals commensal with humans were examined.

An increase in body length was found in four species, and appears to be related to improved nutrition owing to a substantial increase in the amount of garbage and agricultural crops available to commensal mammals that has occurred since the establishment of the State of Israel in 1948.

The larger species were more affected than the smaller ones, apparently because of their higher position in the feeding hierarchy or because of having larger home ranges.

The increases are convergent with the increase in human body height observed during the past two centuries.

These changes illustrate the fast rate of animal response to changing environmental conditions.
Functional significance of photoblastic germination in neotropical pioneer trees: a seed's eye view
Authors: Pearson T. R. H. , Burslem D. F. R. P. , Mullins C. E. , Dalling J. W.
Published: June 2003

We investigated the relationship between seed mass and the suitability of microsites for germination for five small‐seeded (< 2·4 mg fresh mass) photoblastic neotropical pioneer trees. We determined the germination response of these species to the ratio of red to far‐red irradiance (r:fr) and compared it to r:fr measured under varying conditions of canopy openness, litter and soil thickness.

At a constant temperature the germination percentage of each of the species increased sharply with increasing r:fr above a species‐specific threshold r:fr. The smallest‐seeded species, Miconia argentea, had the lowest r:fr threshold for germination (0·12) while the larger‐seeded Cecropia species and Solanum hayesii possessed higher values (0·21–0·27). The largest seeded species, Solanum hayesii, also showed a positive germination response to a 10 °C temperature fluctuation, which was independent of the response to r:fr.

The mean r:fr at ground level declined with decreasing gap size but not sufficiently to suppress the germination of these five species. However, a covering of one litter leaf in direct sunlight reduced the r:fr to between 0·18 and 0·83 depending on the species and leaf wetness. The top‐soil at our study site was aggregated and irradiance was transmitted or reflected between soil aggregates with little change in r:fr. Light did not penetrate the aggregates.

We suggest that photoblastic germination in neotropical pioneers has evolved to inhibit germination in response to conditions most likely to alter within the life of an individual seed (i.e. superficial burial by leaf litter or incorporation into the surface soil), rather than to fine scale variation in canopy openness. Among photoblastic species, the pattern of response to r:fr suggests that smaller‐seeded species would germinate in a broader range of microsites than larger‐seeded species. This lower degree of discrimination may be associated with their higher risk of mortality and therefore more limited persistence in the soil seed bank.
Is there an optimal root architecture for nitrate capture in leaching environments?
Authors: DUNBABIN V. , DIGGLE A. , RENGEL Z.
Published: June 2003

Little is known about root architectural attributes that aid the capture of nitrate from coarse‐textured soil profiles of high leaching potential. In this study, a range of root architectures from the herringbone to the dichotomous structure were simulated, and their capacity to take up nitrate leaching through a sandy profile was recorded. All root systems had equal total volume at each point in time, and so were considered cost equivalent. These simulations showed that the root architecture likely to maximize nitrate capture from sandy soils (under the Mediterranean rainfall pattern experienced in Western Australia) is one that quickly produces a high density of roots in the top‐soil early in the season, thereby reducing total nitrate leached with opening season rains, but also has vigorous taproot growth, enabling access to deep‐stored water and leached nitrate later in the season. This is the first published, spatially explicit attempt to assess the ability of different root architectures equivalent in cost, to capture nitrate from a spatially and temporally heterogeneous soil environment.
Up‐regulation of the leaf mitochondrial and peroxisomal antioxidative systems in response to salt‐induced oxidative stress in the wild salt‐tolerant tomato species Lycopersicon pennellii
Authors: MITTOVA V. , TAL M. , VOLOKITA M. , GUY M.
Published: June 2003

The response of the antioxidative systems of leaf cell mitochondria and peroxisomes of the cultivated tomato Lycopersicon esculentum (Lem) and its wild salt‐tolerant related species Lycopersicon pennellii (Lpa) to NaCl 100 mM stress was investigated. Salt‐dependent oxidative stress was evident in Lem mitochondria as indicated by their raised levels of lipid peroxidation and H2O2 content whereas their reduced ascorbate and reduced glutathione contents decreased. Concomitantly, SOD activity decreased whereas APX and GPX activities remained at control level. In contrast, the mitochondria of salt‐treated Lpa did not exhibit salt‐induced oxidative stress. In their case salinity induced an increase in the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and glutathione‐dependent peroxidase (GPX). Lpa peroxisomes exhibited increased SOD, APX, MDHAR and catalase activity and their lipid peroxidation and H2O2 levels were not affected by the salt treatment. The activities of all these enzymes remained at control level in peroxisomes of salt‐treated Lem plants. The salt‐induced increase in the antioxidant enzyme activities in the Lpa plants conferred cross‐tolerance towards enhanced mitochondrial and peroxisomal reactive oxygen species production imposed by salicylhydroxamic acid (SHAM) and 3‐amino‐1,2,4‐triazole (3‐AT), respectively.
Cross‐talk between calcium and reactive oxygen species originated from NADPH oxidase in abscisic acid‐induced antioxidant defence in leaves of maize seedlings
Authors: JIANG M. , ZHANG J.
Published: June 2003

The signal interactions between calcium (Ca2+) and reactive oxygen species (ROS) originated from plasma membrane NADPH oxidase in abscisic acid (ABA)‐induced antioxidant defence were investigated in leaves of maize (Zea mays L.) seedlings. Treatment with ABA led to significant increases in the activity of plasma membrane NADPH oxidase, the production of leaf O2–, and the activities of several antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR). However, such increases were blocked by the pretreatment with Ca2+ chelator EGTA or Ca2+ channel blockers La3+ and verapamil, and NADPH oxidase inhibitors such as diphenylene iodonium (DPI), imidazole and pyridine. Treatment with Ca2+ also significantly induced the increases in NADPH oxidase activity, O2– production and the activities of antioxidant enzymes, and the increases were arrested by pretreatment with the NADPH oxidase inhibitors. Treatment with oxidative stress induced by paraquat, which generates O2–, led to the induction of antioxidant defence enzymes, and the up‐regulation was suppressed by the pretreatment of Ca2+ chelator and Ca2+ channel blockers. Our data suggest that a cross‐talk between Ca2+ and ROS originated from plasma membrane‐bound NADPH oxidase is involved in the ABA signal transduction pathway leading to the induction of antioxidant enzyme activity, and Ca2+ functions upstream as well as downstream of ROS production in the signal transduction event in plants.
Cell‐specific measurement of cytosolic glutathione in poplar leaves*
Authors: HARTMANN T. N. , FRICKER M. D. , RENNENBERG H. , MEYER A. J.
Published: June 2003

The level of glutathione (GSH) in plants is important in defence reactions against biotic and abiotic stresses and can place considerable demand of the sulphur assimilation pathway. Enzymes involved in sulphur assimilation and GSH metabolism are not evenly distributed between different subcellular compartments or between different cell types in leaves or roots; however, there is little information on the effect that such asymmetries have on the actual GSH concentration in each compartment or cell type. In the present study in situ labelling with monochlorobimane (MCB) in combination with confocal laser scanning microscopy was used to quantify GSH in each of the main cell types of poplar leaves from fluorescence of the GSB conjugate formed. Comparison of results from the in situ approach with total GSH levels measured in vitro by high‐performance liquid chromatography suggested that only the cytosolic GSH pool was labelled using this approach. This suggests that an appropriate GST was not present within the chloroplasts to catalyse the conjugation reaction and that chloroplastic GSH does not rapidly exchange with the cytoplasmic pool under the conditions of the assay. Cytosolic GSH levels were between 0.2 and 0.3 mm for both photosynthetic and non‐photosynthetic (epidermal) cell types in wild‐type poplar leaves. Cytosolic levels increased by around two‐fold in transgenic poplars over‐expressing bacterial γ‐glutamylsynthetase (γ‐ECS) in the cytosol of all cell types, but there was no concomitant increase in the chloroplastic GSH pool.
Dry Matter Production and Productivity as Influenced by Staggered Sowing of Mustard Intercropped at Different Row Ratios with Chickpea
Authors: Singh K. K. , Rathi K. S.
Published: June 2003

In a 2‐year experiment on Typic Ustochrept soils of the North Plain Zone of India, the effect of different row ratios (3 : 1, 6 : 2, 4 : 1 and 8 : 2) and staggered sowing of mustard (simultaneous and 15 days later) was studied in intercropping of chickpea (Cicer arietinum) and mustard (Brassica juncea L.). Nodule number, dry weight, grain yield, protein content and yield were higher in monocrop chickpea compared with intercropping. Among row ratios, except for protein content in grain, all the above parameters were significantly higher in the 4 : 1 intercropping of chickpea + mustard. Similarly, delayed sowing of mustard by 15 days also gave higher plant dry weight (1.80–2.36 g plant−1), nodule number (0.41–1.56 and 0.5–3.0 at 55‐ and 70‐day stages, respectively), protein yield (63 kg ha−1), grain yield (290 kg ha−1) and biological yield (1104 kg ha−1) than sowing with chickpea. Widening the row ratio and pairing of the rows of mustard were also found to be beneficial in increasing chickpea growth and yield. Like chickpea, sowing of mustard as a monocrop gave higher growth and yield. Delayed sowing by 15 days reduced the growth and yield of mustard drastically. Productivity, measured in terms of land equivalent ratio, was higher for intercropping of chickpea and mustard in the 4 : 1 row ratio than for sowing of chickpea and mustard in sole stands. Interestingly, the land equivalent ratio was also higher in the simultaneously sown crop than for staggered sowing.
Influence of Sowing and Harvest Time on Fibre Flax (Linum usitatissimum L.) in the Mediterranean Environment
Authors: Rossini F. , Casa R.
Published: June 2003

Triennial field trials were carried out at Viterbo, central Italy, to investigate the influence of the sowing time, nitrogen fertilization and harvest dates of the two fibre flax (Linum usitatissimum L.) varieties Belinka and Ariane. Our results showed that warm and dry weather conditions, prevailing from late spring onwards, caused excessive shortening of the growing cycle of spring crops, with negative consequences for seed and fibre yield and quality. However, autumn sowings gave interesting results. Stem dry weight ranged between 5.6 and 6.7 t ha−1 for autumn sowings and between 1.9 and 4.1 t ha−1 for spring sowings. In autumn sowings, plant height and seed yields were also increased. Seed germinability was good even for early harvest dates. Stem dry weight remained constant at harvest dates following yellow‐green ripening, indicating that biomass was no longer allocated to the stems after that phase.
Bedside swallowing assessments and brain computerized tomography findings in patients with chronic cerebral infarction and their outcomes
Authors: Iwamoto Toshihiko , Koshibu Junko , Kikawada Masayuki , Yoneda Yuichi , Uno Masanobu , Takasaki Masaru , Imamura Toshiharu
Published: June 2003

With the aims of evaluating the predictive value of the Smithard method of bedside swallowing assessment, and of elucidating the brain computed tomography (CT scan) findings characteristic of dysphagia, we studied the outcome and brain CT findings over a 2.2‐year follow‐up period after swallowing assessment in 102 patients with chronic cerebral infarction was performed. The subjects were 61 elderly men, average age 75.1 years, and 41 women, average age 78.1 years. They were divided into a positive group (n = 33), who displayed some difficulty swallowing water, and a negative group (n = 69). Outcomes were compared between the two groups in terms of survival, cause of death, recurrent stroke and onset of pneumonia. Brain CT findings were compared for the type, number and laterality of infarcts, the grade of periventricular lucency (PVL), presence of ventricular dilatation (VD), and degree of cortical atrophy (CA). The time elapsed since stroke till assessment tended to be longer for the positive group (mean 7.1 years) than the negative group (4.4 years), and dementia, impaired consciousness and dependent ADL status were all more common. During the observation period, 18 subjects died, 15 in the positive group as opposed to three in the negative group, resulting in a significantly higher annual death rate (29.9%vs 2.2%, χ2 = 28.3, P < 0.0001). Aspiration pneumonia was thought to be the cause of death in all 15 cases in the positive group, whereas the single case of death from pneumonia in the negative group was thought to have been due to a relapse of Wallenberg's syndrome. The sensitivity and specificity of a positive swallowing assessment as a predictor of pneumonia were estimated as 0.55 and 0.94, respectively. CT findings of multiple infarction, bilateral cerebral hemispheric lesion, high grade PVL, VD and severe CA were more common in the positive group. Multiple regression analysis showed that bilateral infarction, PVL, CA and VD contributed significantly to dysphagia. From the above, aspiration pneumonia was frequently seen in the positive group, and this method showed high sensitivity and specificity in predicting this complication. The Smithard method of bedside swallowing assessment is therefore a useful screening method for identifying patients at high risk of developing pneumonia. The CT findings indicated that dysphagia is more likely with high grade PVL, VD and CA, as well as multiple infarcts. These results suggest that the etiology of dysphagia involves not only the pyramidal tracts, but a combination of factors including extrapyramidal tracts, impaired consciousness, reduced cognitive function and impairment of ADL.
Variation in plant species richness of different life forms along a subtropical elevation gradient in the Himalayas, east Nepal
Authors: Bhattarai Khem Raj , Vetaas Ole R.
Published: June 2003

Aim To explore the variation in species richness along a subtropical elevation gradient, and evaluate how climatic variables explain the richness of the different life forms such as trees, shrubs, climbers, herbs and ferns.

Location The study was made in a subtropical to warm temperate region in the south‐eastern part of Nepal, between 100 and 1500 m above sea level (a.s.l.).

Methods The number of species was counted in six plots (50 × 20 m) in each of the 15 100 m elevation bands covering the main physiognomic structures along an imaginary transect. Each species recorded was assigned to a life form. Potential evapotranspiration (PET, i.e. energy), mean annual rainfall (MAR), and their ratio (MI = moisture index) were evaluated as explanatory variables by means of generalized linear models (GLM). Each variable was tested individually, and in addition MAR and PET were used to test the water‐energy dynamics model for each life form.

Results The richness of herbaceous species, including herbaceous climbers, was unrelated to any of the climate variables. PET was strongly negatively correlated with elevation, and the following relationships were found between increasing PET and richness: (i) shrubs, trees and total species (sum of all life forms) showed unimodal responses (ii) ferns decreased monotonically, and (iii) woody climbers increased monotonically. Richness of all woody groups increased monotonically with MAR and MI. The water‐energy dynamics model explained 63% of the variation in shrubs, 67% for trees and 70% for woody species combined.

Main conclusions For the various herbaceous life forms (forbs, grasses, and herbaceous climbers) we found no significant statistical trends, whereas for woody life forms (trees, shrubs, and woody climbers) significant relationships were found with climate. E.M. O’Brien's macro‐scale model based on water‐energy dynamics was found to explain woody species richness at a finer scale along this elevational‐climatic gradient.
Physiologic Inhibitors of Coagulation in Patients on Chronic Hemodialysis
Authors: Tang Sydney C. W. , Lai Kar Neng
Published: June 2003

Patients on hemodialysis are at increased risk for bleeding and thromboses. The intriguing balance between these risks is more complex than once thought, as endogenous clotting factors and their regulators come into contact with bioincompatible dialyzer membranes, in the setting of an extracorporeal circuit of blood flow, in the face of the uremic state. In this review, we summarize the current data on the interaction between the physiologic inhibitors of coagulation and hemodialysis. Data sources and study selection were obtained from research and review articles related to the endogenous anticoagulation pathway published in English on MEDLINE from 1972 to 2002. While protein C activity and protein S antigen concentrations are increased, there is no change in antithrombin III levels during hemodialysis in relation to predialysis levels. Plasma protein Z, which has only recently been studied in uremic subjects, is increased as well. In addition, hemodialysis leads to elevated tissue factor plasminogen inhibitor, thrombomodulin, tissue plasminogen activator, and plasminogen activator inhibitor‐1 activities. The potential functional significance of these observations is discussed. Finally, as erythropoietin is commonly prescribed to uremic patients and is recognized to be prothrombotic, an appraisal of its interaction with the naturally occurring anticoagulants is presented. It is apparent that we are only beginning to realize the complexity of the interplay between this myriad of serum factors and hemodialysis. Further research is needed to shed light on this underexplored area of hemodialysis.
The Practice of Dialysis in the Developing Countries
Authors: Jha Vivekanand , Chugh Kirpal S.
Published: June 2003

There are few organized data on the practice of dialysis in developing countries, mostly because of a lack of renal registries. The economic, human, and technical resources required for long‐term dialysis make it a major economical and political challenge. Most countries do not have not well‐formed policies for treatment of end‐stage renal disease. The dialysis facilities are grossly inadequate, and there are no reimbursement schemes to fund long‐term dialysis. Hemodialysis units are mostly in the private sector and consist of small numbers of refurbished machines. Water treatment is frequently suboptimal, and this problem has led to a number of complications. Hepatitis B and C infections are widespread in dialysis units. Continuous ambulatory peritoneal dialysis (CAPD) seems to be the ideal dialysis option for patients living in remote areas, but high costs preclude its widespread usage. The Mexican experience suggests that even after it becomes affordable, CAPD needs to be used judiciously. Inadequate dialysis, infections, and malnutrition account for the high mortality among the dialysis population in developing countries. Acute peritoneal dialysis using rigid stylet‐based catheters is the main form of dialysis in remote areas. Pediatric dialysis units are almost nonexistent. A significant lack of resources exists in developing countries, making the provision of highly technical and expensive care like dialysis a challenge.
Interictal Paroxysmal Epileptic Discharges during Sleep in Childhood: Phenotypic Variability in a Family
Authors: Roubertie Agathe , Humbertclaude Véronique , Rivier François , Cheminal Renée , Echenne Bernard
Published: June 2003

Summary:  We report three children of the same parents who exhibited various types of cognitive disorders, ranging from severe mental deficiency with transient autistic‐like regression to specific neuropsychological disabilities, associated with paroxysmal EEG abnormalities with various patterns of severity. This familial association highly suggests a genetic factor responsible for both epileptic discharges on EEG and cognitive dysfunction.
Intrastriatal Methylmalonic Acid Administration Induces Convulsions and TBARS Production, and Alters Na+,K+‐ATPase Activity in the Rat Striatum and Cerebral Cortex
Authors: Malfatti Carlos Ricardo Maneck , Royes Luiz Fernando Freire , Francescato Leandro , Sanabria Emílio Rafael Garrido , Rubin Maribel Antonello , Cavalheiro Esper Abrão , Mello Carlos Fernando
Published: June 2003

Summary:  Purpose: Methylmalonic acid (MMA) inhibits succinate dehydrogenase (SDH) and β‐hydroxybutyrate dehydrogenase activity in vitro. Acute intrastriatal administration of MMA induces convulsions through glutamatergic mechanisms probably involving primary adenosine triphosphate (ATP) depletion and free radical generation. In this study we investigated whether the intrastriatal administration of MMA causes lipoperoxidation and alteration in Na+, K+‐ATPase activity ex vivo and characterized the electrographic changes elicited by the intrastriatal administration of this organic acid.

Methods: MMA‐induced lipoperoxidation, alterations in Na+, K+‐ATPase activity and electrographic changes were measured by measuring total thiobarbituric acid‐reacting substances and inorganic phosphate release by spectrophotometry, and by depth electrode recording, respectively.

Results: We demonstrated that intrastriatal MMA (6 mmol) injection causes convulsive behavior and electrographically recorded convulsions that last ∼2 h. Concomitant with the increase of thiobarbituric acid–reacting substances (TBARS) content, we observed a significant inhibition of Na+,K+‐ATPase activity in the striatum, and activation of Na+,K+‐ATPase activity in the ipsilateral cerebral cortex. Intrastriatal MMA injection increased the content of TBARS in the striatum measured 30 min (32.4 ± 12.0%, compared with the noninjected contralateral striatum) and 3 h (39.7 ± 5.1%, compared with the noninjected contralateral striatum) after MMA injection. TBARS content of the ipsilateral cerebral cortex increased after MMA injection at 30 min (42.1 ± 6.0%) and 3 h (40.4 ± 20.2%), and Na+,K+‐ATPase activity in the ipsilateral cerebral cortex increased during ictal activity (113.8 ± 18%) and returned to basal levels as electrographic convulsions vanished in the cortex. Interestingly, intrastriatal MMA administration induced a persistent decrease in Na+,K+‐ATPase activity only in the injected striatum (44.9 ± 8.1% at 30 min and 68.7 ± 9.4 at 3 h).

Conclusions: These data suggest that MMA induces lipoperoxidation associated with Na+,K+‐ATPase inhibition or activation, depending on the cerebral structure analyzed. It is suggested that Na+,K+‐ATPase inhibition may play a primary role in generating MMA‐induced convulsions.
The Spectrum of Long‐term Epilepsy–associated Tumors: Long‐term Seizure and Tumor Outcome and Neurosurgical Aspects
Authors: Luyken Cordelia , Blümcke Ingmar , Fimmers Rolf , Urbach Horst , Elger Christian E. , Wiestler Otmar D. , Schramm Johannes
Published: June 2003

Summary:  Purpose: To describe the histologic spectrum and clinical characteristics of patients with neuroepithelial tumors and drug‐resistant epilepsy and to analyze clinical data and treatment related to seizure outcome and survival.

Methods: Data were analyzed from 207 consecutive patients with intractable epilepsy (aged 2–54 years), who between 1988 and 1999 had ≥50% resection of supratentorial, neuroepithelial tumors. Extent of resection was assessed on postoperative magnetic resonance imaging (MRI); seizure outcome was classified according to Engel's outcome scale; and follow‐up data were prospectively updated.

Results: Median follow‐up was eight years (range, 2–14 years). Histologic examination revealed 154 classic epilepsy‐associated tumors (ganglioglioma, dysembryoplastic neuroepithelial tumor, pleomorphic xanthoastrocytoma, and pilocytic astrocytomas) and 53 others (astrocytomas and oligodendrogliomas). Four World Health Organization (WHO) grade III tumors were found (astrocytoma, n = 3; ganglioglioma, n = 1). After surgery, 82% of the patients were seizure free (class I). The following factors were associated with improved seizure outcome: Short duration of epilepsy before surgery, single EEG focus, absence of additional hippocampal sclerosis or cortical dysplasia, transsylvian approach, other than astrocytomas, and complete tumor resection. After 5 years, only nine (4%) patients had tumor recurrence, four (2%) with malignant transformation and death. None of the four patients with anaplastic tumors died. Even patients with astrocytomas of WHO grade II or III showed 10‐year recurrence of only 25% and 10‐year survival of 90%.

Conclusions: Tumors associated with long‐term epilepsy should be removed early for two different reasons: high rate of seizure freedom and rare but potential risk of malignant tumor progression. The unexpected long survival of these astrocytomas should be investigated by using immunohistochemistry and molecular biology.
Acute Postoperative Seizures after Frontal Lobe Cortical Resection for Intractable Partial Epilepsy
Authors: Tigaran Simona , Cascino Gregory D. , McClelland Robyn L. , So Elson L. , Richard Marsh W.
Published: June 2003

Summary:  Purpose: To evaluate the incidence and prognostic importance of acute postoperative seizures (APOSs) occurring in the first week after a focal corticectomy in patients with partial epilepsy of frontal lobe origin.

Methods: We retrospectively evaluated 65 patients who underwent a frontal lobe cortical resection for intractable partial epilepsy between April 1987 and December 2000. All patients were followed up for a minimum of 1 year after surgery.

Results: APOSs occurred in 17 (26%) patients. None of the following factors was shown to be significantly associated with the occurrence of APOSs: gender, duration of epilepsy, etiology for seizure disorder, use of subdural or depth electrodes, surgical pathology, or postoperative risk factor for seizures. Patients with APOSs were older at seizure onset and at the time of surgery (p = 0.003 and p = 0.05, respectively). At last follow‐up, patients who had APOSs had a seizure‐free outcome similar to that of individuals without APOSs (47.1% vs. 50.0%; p = 0.77). Patients with APOSs appeared less likely to have a favorable outcome [i.e., fewer than three seizures per year and >95% decrease in seizure activity (58.8 vs. 70.8%; p = 0.35)]. This result may not have reached statistical significance because of the sample size. No evidence suggested that precipitating factors or the timing of APOSs was an important prognostic factor.

Conclusions: The presence of APOSs after frontal lobe surgery for intractable epilepsy does not preclude a significant reduction in seizure tendency. These findings may be useful in counseling patients who undergo surgical treatment for frontal lobe epilepsy.
Pharmacology of Neural Tube Defects
Authors: Pippenger C. E.
Published: June 2003

Summary:  The pharmacology of neural tube defects (NTDs) is a complex issue. Several theories regarding the etiology of NTDs emphasize the importance of interactions between genetic, environmental, and biochemical factors at a key point in time. One such factor is chronic drug therapy, a potential consequence of which is the formation of toxic drug metabolites, including free radicals (FRs), which have been implicated in the etiology of NTDs. Under normal physiological conditions, FRs are quickly destroyed by antioxidant defense systems. However, FR‐mediated cellular damage can occur if these defense systems fail or are overburdened, such as in patients who are genetically deficient in FR scavenging enzyme activity (FRSEA) or who are receiving chronic drug therapy. Congenital defects, including NTDs, resulting from FR‐induced damage have been reported in both experimental animals and humans. For example, the use of antiepileptic drugs (AEDs) during pregnancy that have the propensity to form FRs during their metabolism are associated with an increased risk of the development of congenital malformations, including NTDs. This article reviews the biochemistry of FRs, the factors regulating FR scavenging capacity, and the theories regarding the etiology of NTDs; presents a hypothesis of a unified mechanism for AED‐induced NTDs and other congenital defects; and briefly discusses the roles of folate and selenium in the prevention of NTDs.
Pathobiology and Genetics of Neural Tube Defects
Authors: Finnell Richard H. , Gould Amy , Spiegelstein Ofer
Published: June 2003

Summary:  Purpose: Neural tube defects (NTDs), including spina bifida and anencephaly, are common congenital malformations that occur when the neural tube fails to achieve proper closure during early embryogenesis. Based on epidemiological and clinical data obtained over the last few decades, it is apparent that these multifactorial defects have a significant genetic component to their etiology that interacts with specific environmental risk factors. The purpose of this review article is to synthesize the existing literature on the genetic factors contributing to NTD risk.

Results: To date, there is evidence that closure of the mammalian neural tube initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to an NTD, possibly arising through closure site–specific genetic mechanisms. Candidate genes involved in neural tube closure include genes of the folate metabolic pathway, as well as those involved in folate transport.

Conclusions: Although extensive efforts have focused on elucidating the genetic risk factors contributing to the etiology of NTDs, the population burden for these malformations remains unknown. One group at high risk for having children with NTDs is epileptic women receiving antiepileptic medications during pregnancy. Efforts to better understand the genetic factors that may contribute to their heightened risk, as well as the pathogenesis of neural tube closure defects, are reviewed herein.
McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement
Authors: Jung Hans H. , Hergersberg Martin , Vogt Marco , Pahnke Jens , Treyer Valerie , Röthlisberger Benno , Kollias Spyros S. , Russo David , Frey Beat M.
Published: June 2003

BACKGROUND: The X‐linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement.

STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET).

RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET.

CONCLUSION: Known disease‐causing XK gene mutations comprised deletions, nonsense, or splice‐site mutations predicting absent or truncated XK protein devoid of the Kell‐protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.
Apoptotic markers are increased in platelets stored at 37°C
Authors: Bertino A.M. , Qi X.Q. , Li J. , Xia Y. , Kuter D.J.
Published: June 2003

BACKGROUND: PLTs for transfusion lose viability during storage in blood banking. This loss of viability is accelerated at 37°C, as is the risk of bacterial contamination, and has led to the selection of 22°C as the routine storage temperature. Because PLTs contain an intact apoptotic mechanism, we sought to determine whether PLTs undergo apoptosis during storage and whether storage at 37°C accelerated this process.

STUDY DESIGN AND METHODS: PLT‐rich plasma from PLT concentrates was stored at 37 or 22°C in small aliquots or whole bags, with and without cell‐permeable caspase inhibitors. Number of PLTs, pH, LDH level, and 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium activity were analyzed over time. PLT lysates were prepared and tested for the presence and activation of apoptotic proteins by enzyme assay and Western blotting.

RESULTS: PLT viability was greatly reduced after 1 to 2 days of storage at 37°C; however, signs of apoptosis were evident by 3 hours after temperature shift. In temperature‐stressed PLTs only, a gradual rise in caspase‐3 activity was detected that correlated with the appearance of the 17‐ to 20‐kDa cleavage products of caspase‐3. Gelsolin, a caspase‐3 substrate, underwent cleavage within the same time frame. Bcl‐xL and caspase‐2 also declined significantly; caspase‐9 activity rose. Specific caspase inhibitors could prevent caspase activation but did not improve PLT cellular viability at 37°C.

CONCLUSIONS: PLTs contain apoptotic proteins that are activated during PLT storage at 37°C and may account for the rapid decline in PLT cellular viability. Although ineffective here, inhibition of PLT apoptosis may improve PLT cellular viability.
Reactive oxygen species as essential mediators of cell adhesion
Authors: Chiarugi Paola , Pani Giovambattista , Giannoni Elisa , Taddei Letizia , Colavitti Renata , Raugei Giovanni , Symons Mark , Borrello Silvia , Galeotti Tommaso , Ramponi Giampietro
Published: June 2003

Signal transduction by reactive oxygen species (ROS; “redox signaling”) has recently come into focus in cellular biology studies. The signaling properties of ROS are largely due to the reversible oxidation of redox-sensitive target proteins, and especially of protein tyrosine phosphatases, whose activity is dependent on the redox state of a low pKa active site cysteine. A variety of mitogenic signals, including those released by receptor tyrosine kinase (RTKs) ligands and oncogenic H-Ras, involve as a critical downstream event the intracellular generation of ROS. Signaling by integrins is also essential for the growth of most cell types and is constantly integrated with growth factor signaling. We provide here evidence that intracellular ROS are generated after integrin engagement and that these oxidant intermediates are necessary for integrin signaling during fibroblast adhesion and spreading. Moreover, we propose a synergistic action of integrins and RTKs for redox signaling. Integrin-induced ROS are required to oxidize/inhibit the low molecular weight phosphotyrosine phosphatase, thereby preventing the enzyme from dephosphorylating and inactivating FAK. Accordingly, FAK phosphorylation and other downstream events, including MAPK phosphorylation, Src phosphorylation, focal adhesion formation, and cell spreading, are all significantly attenuated by inhibition of redox signaling. Hence, we have outlined a redox circuitry whereby, upon cell adhesion, oxidative inhibition of a protein tyrosine phosphatase promotes the phosphorylation/activation and the downstream signaling of FAK and, as a final event, cell adhesion and spreading onto fibronectin.
Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes
Authors: Takeda Yoshito , Tachibana Isao , Miyado Kenji , Kobayashi Masatoshi , Miyazaki Toru , Funakoshi Toshiki , Kimura Hiromi , Yamane Hiroyuki , Saito Yoshiyuki , Goto Hiroyuki , Yoneda Tsutomu , Yoshida Mitsuhiro , Kumagai Toru , Osaki Tadashi , Hayashi Seiji , Kawase Ichiro , Mekada Eisuke
Published: June 2003

Tetraspanins CD9 and CD81 facilitate the fusion between gametes, myoblasts, or virus-infected cells. Here, we investigated the role of these tetraspanins in the fusion of mononuclear phagocytes. Expression of CD9 and CD81 and their complex formation with integrins were up-regulated when blood monocytes were cultured under normal conditions. Under fusogenic conditions in the presence of Con A, CD9 and CD81 up-regulation was inhibited, and their complex formation with integrins was down-regulated. Anti-CD9 and -CD81 antibodies, which were previously shown to inhibit the fusion of gametes, myoblasts, and virus-infected cells, unexpectedly promoted the fusion of monocytes and alveolar macrophages. However, these effects were not due to altered cell adhesion, aggregation, or cytokine production. When stimulated in vitro or in vivo, alveolar macrophages and bone marrow cells of CD9- and CD81-null mice formed larger numbers of multinucleated cells than those of wild-type mice. Finally, CD9/CD81 double-null mice spontaneously developed multinucleated giant cells in the lung and showed enhanced osteoclastogenesis in the bone. These results suggest that CD9 and CD81 coordinately prevent the fusion of mononuclear phagocytes.