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Human working memory capacity is 7+/-2 in a radial maze with distracting interruption: possible implication for neural mechanisms of declarative and implicit long-term memory.

Human participants were instructed to walk out along each of the arms of a 15-m in diameter, 8-arm radial maze once and only once. In order to approximate the circumstances under which laboratory rats remember visited sites, our human participants were asked to select arms in an unsystematic order. They scored an average of 7.6 to 7.8 correct choices, even if midway during a trial there was a 5-min interruption filled with a verbal-spatial interfering task (a scavenger hunt) or a 15-min interruption filled with a visuospatial task (a maze-running computer simulation). This finding extends our earlier research with humans in 13- or 17-arm radial mazes under nondelay conditions, in which we also found working memory (WM) capacity for about 7 to 9 places, the same as that of laboratory rats. We discuss earlier findings in other laboratories, showing that rats can successfully bridge long radial maze task interruptions of 5 or 8 h, and we compare our results also to those from studies in which human participants were not discouraged from reducing memory load by responding systematically in radial mazes. Because the radial maze task takes minutes to complete even under nondelay conditions its routine consideration as a working memory task in the animal literature alters the assumptions often made about the duration of WM in the human literature. Accumulating empirical findings about place-memory in humans, nonhuman mammals, and birds suggest it might be productive to reevaluate this theoretical issue with respect to present knowledge about the roles of the hippocampus and other brain structures in declarative memory and in procedural or implicit memory, while considering the hypothesis that some forms of information may exploit long-term memory in parallel with working memory.

Adolescent↗

Photosensitivity in lupus erythematosus.

Lupus erythematosus (LE) is an autoimmune disease which can be triggered by environmental factors such as solar irradiation. It has long been observed that especially ultraviolet (UV) exposure can induce and exacerbate skin lesions in patients with this disease. However, despite the frequency of photosensitivity in LE, the mechanisms by which UV irradiation activates autoimmune responses is only now becoming increasingly unfolded by advanced molecular and cellular biological investigations. Phototesting, according to a standardized protocol with UVA and UVB irradiation has proven to be a valid model to study photosensitivity in various subtypes of LE and to evaluate the underlying pathomechanisms of this disease. Detailed analysis of the molecular events that govern lesion formation in experimentally photoprovoced LE showed increased accumulation of apoptotic keratinocytes and impaired expression of the inducible nitric oxide synthase (iNOS). In the near future, gene expression profiling and proteomics will further increase our knowledge on the complexity of the "UV response" in LE. This review summarizes the current understanding of the clinical and molecular mechanisms that initiate photosensitivity in this disease.

Humans↗

Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors.

Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different heterozygous splicing mutations in the LMNA gene, leading to the production and accumulation of truncated Prelamin A. In other patients, a single nucleotide insertion was identified in ZMPSTE24. This variation is located in a homopolymeric repeat of thymines and introduces a premature termination codon. ZMPSTE24 encodes an endoprotease essential for the post-translational cleavage of the Lamin A precursor and the production of mature Lamin A. However, the autosomal recessive inheritance of RD suggested that a further molecular defect was present either in the second ZMPSTE24 allele or in another gene involved in Lamin A processing. Here, we report new findings in RD linked to ZMPSTE24 mutations. Ten RD patients were analyzed including seven from a previous series and three novel patients. All were found to be either homozygous or compound heterozygous for ZMPSTE24 mutations. We report three novel 'null' mutations as well as the recurrent thymine insertion. In all cases, we find a complete absence of both ZMPSTE24 and mature Lamin A associated with Prelamin A accumulation. Thus, RD is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations, most of which lie in a mutation hotspot within exon 9. The accumulation of truncated or normal length Prelamin A is, therefore, a shared pathophysiological feature in recessive and dominant RD. These findings have an important impact on our knowledge of the pathophysiology in Progeria and related disorders and will help direct the development of therapeutic approaches.

Abnormalities, Multiple↗

Distribution of cadmium in leaves of Thlaspi caerulescens.

Knowledge of the intracellular distribution of Cd in leaves is necessary in order to understand the mechanisms of hyperaccumulation in Thlaspi caerulescens. Ganges and Prayon, two ecotypes accumulating Cd to different levels, were grown in nutrient medium containing varying concentrations (0, 5, 10, 50, and 100 microM) of Cd. Several different approaches were combined in this study to (i) validate the results obtained by a specific method and (ii) establish the link between observations and measurements performed at different scales. In both ecotypes, Cd, localized by autoradiography, was found mainly at the edges of the leaves, but also in points of higher concentration spread over the whole limb surface. This localization was clearly correlated with the necrotic spots observed on Prayon leaves. Scanning electron microscopy coupled with energy dispersive X-ray microanalysis (cryo-SEM-EDXMA) and tissue fractionation (apoplasm, cell walls, mesophyll protoplasts, and lower epidermis) showed that Cd had similar patterns of distribution in leaf cells of both ecotypes. Cadmium was found both inside the cells and in the cell walls, mainly in the large epidermal cells but also in small epidermal cells. All the methods used agreed well and the results indicated that metal storage in the plants studied involves more than one compartment and that Cd is stored principally in the less metabolically active parts of leaf cells.

Autoradiography↗

The mitochondrial ADPR link between Ca2+ store release and Ca2+ influx channel opening in immune cells.

The regulation of non-voltage-operated Ca2+ channels in the plasma membrane remains unclear. However, there is often a link between the physiological release of Ca2+ from intracellular stores and opening of Ca2+ influx channels on the plasma membrane. This route has been referred to variously as store-operated Ca2+ entry (SOC), capacitative Ca2+ entry, and Ca2+ release-activated channel opening (CRAC), and often underlies the large changes in cytosolic free Ca2+ that accompany many stimuli in a wide variety of cell types. The linkage between Ca2+ store release and opening of Ca2+ channels on the plasma membrane has remained elusive for a number of years, perhaps in part because different mechanisms exist for this linkage, and are used to differing extents by different cells. We suggest here that one of the mechanisms that may operate in cells of the immune system, but that may be important elsewhere, involves the release of mitochondrial adenosine diphosphate ribose (ADPR) or nicotinamide adenine dinucleotide (NAD+). There is accumulating evidence to support each of the steps necessary for a complete description of this "Ca2+ store release to plasma membrane channel opening" link, but to our knowledge they have not been connected before to make a coherent model.-

Adenosine Diphosphate Ribose↗

Sodium-dependent nitrate transport at the plasma membrane of leaf cells of the marine higher plant Zostera marina L.

NO(3)(-) is present at micromolar concentrations in seawater and must be absorbed by marine plants against a steep electrochemical potential difference across the plasma membrane. We studied NO(3)(-) transport in the marine angiosperm Zostera marina L. to address the question of how NO(3)(-) uptake is energized. Electrophysiological studies demonstrated that micromolar concentrations of NO(3)(-) induced depolarizations of the plasma membrane of leaf cells. Depolarizations showed saturation kinetics (K(m) = 2.31 +/- 0.78 microM NO(3)(-)) and were enhanced in alkaline conditions. The addition of NO(3)(-) did not affect the membrane potential in the absence of Na(+), but depolarizations were restored when Na(+) was resupplied. NO(3)(-)-induced depolarizations at increasing Na(+) concentrations showed saturation kinetics (K(m) = 0.72 +/- 0.18 mM Na(+)). Monensin, an ionophore that dissipates the Na(+) electrochemical potential, inhibited NO(3)(-)-evoked depolarizations by 85%, and NO(3)(-) uptake (measured by depletion from the external medium) was stimulated by Na(+) ions and by light. Our results strongly suggest that NO(3)(-) uptake in Z. marina is mediated by a high-affinity Na(+)-symport system, which is described here (for the first time to our knowledge) in an angiosperm. Coupling the uptake of NO(3)(-) to that of Na(+) enables the steep inwardly-directed electrochemical potential for Na(+) to drive net accumulation of NO(3)(-) within leaf cells.

Cell Membrane↗

Aspergillus oryzae in solid-state and submerged fermentations. Progress report on a multi-disciplinary project.

We report the progress of a multi-disciplinary research project on solid-state fermentation (SSF) of the filamentous fungus Aspergillus oryzae. The molecular and physiological aspects of the fungus in submerged fermentation (SmF) and SSF are compared and we observe a number of differences correlated with the different growth conditions. First, the aerial hyphae which occur only in SSFs are mainly responsible for oxygen uptake. Second, SSF is characterised by gradients in temperature, water activity and nutrient concentration, and inside the hyphae different polyols are accumulating. Third, pelleted growth in SmF and mycelial growth in SSF show different gene expression and protein secretion patterns. With this approach we aim to expand our knowledge of mechanisms of fungal growth on solid substrates and to exploit the biotechnological applications.

Aspergillus oryzae↗

Utilization of acyl-homoserine lactone quorum signals for growth by a soil pseudomonad and Pseudomonas aeruginosa PAO1.

Acyl-homoserine lactones (AHLs) are employed by several Proteobacteria as quorum-sensing signals. Past studies have established that these compounds are subject to biochemical decay and can be used as growth nutrients. Here we describe the isolation of a soil bacterium, Pseudomonas strain PAI-A, that degrades 3-oxododecanoyl-homoserine lactone (3OC12HSL) and other long-acyl, but not short-acyl, AHLs as sole energy sources for growth. The small-subunit rRNA gene from strain PAI-A was 98.4% identical to that of Pseudomonas aeruginosa, but the soil isolate did not produce obvious pigments or AHLs or grow under denitrifying conditions or at 42 degrees C. The quorum-sensing bacterium P. aeruginosa, which produces both 3OC12HSL and C4HSL, was examined for the ability to utilize AHLs for growth. It did so with a specificity similar to that of strain PAI-A, i.e., degrading long-acyl but not short-acyl AHLs. In contrast to the growth observed with strain PAI-A, P. aeruginosa strain PAO1 growth on AHLs commenced only after extremely long lag phases. Liquid-chromatography-atmospheric pressure chemical ionization-mass spectrometry analyses indicate that strain PAO1 degrades long-acyl AHLs via an AHL acylase and a homoserine-generating HSL lactonase. A P. aeruginosa gene, pvdQ (PA2385), has previously been identified as being a homologue of the AHL acylase described as occurring in a Ralstonia species. Escherichia coli expressing pvdQ catalyzed the rapid inactivation of long-acyl AHLs and the release of HSL. P. aeruginosa engineered to constitutively express pvdQ did not accumulate its 3OC12HSL quorum signal when grown in rich media. However, pvdQ knockout mutants of P. aeruginosa were still able to grow by utilizing 3OC12HSL. To our knowledge, this is the first report of the degradation of AHLs by pseudomonads or other gamma-Proteobacteria, of AHL acylase activity in a quorum-sensing bacterium, of HSL lactonase activity in any bacterium, and of AHL degradation with specificity only towards AHLs with long side chains.

4-Butyrolactone↗

Regulation of Triglyceride Metabolism. III. Emerging role of lipid droplet protein ADFP in health and disease.

ADFP is the major lipid droplet protein present in all cells that accumulate lipids either normally or abnormally. Although discovered about 15 years ago, it was only in the last few years that we began to have a working knowledge of its possible role in lipid droplet homeostasis at the whole organism level. In this perspective, we concentrate on the potential function of ADFP in various tissues. Space limitation has precluded a complete cataloging of all publications on the topic. We instead highlight some of the salient developments in the last few years.

Adipose Tissue↗

Human leukocyte antigen genes may outweigh racial background when generating a specific immune response in sarcoidosis.

Presented is a sarcoidosis patient of African origin, who was adopted at an early age and grew up in Sweden. This patient displayed an immune response identical to that previously reported in human leukocyte antigen (HLA)-DR17 positive Caucasian sarcoidosis patients in Scandinavia, with T-cell receptor AV2S3+ T-cells accumulating in the lungs. HLA typing also established that she was DR17 positive, which is a rare HLA type for individuals of African origin. To the authors' knowledge, this specific immune response has not previously been reported in patients of African origin. Moreover, the clinical manifestations of sarcoidosis were similar to those known to be strongly linked to HLA-DR17 in Scandinavians, i.e. with Löfgren's syndrome. The case presented here suggests certain human leukocyte antigen genes to be strongly linked to specific immune responses that are identical irrespective of the racial background. If such an immune response were important for the subsequent clinical manifestations, this case would argue for the importance of human leukocyte antigen genes in the genetic predisposition to sarcoidosis.

Adoption↗

Elevation of carbamazepine-10,11-epoxide by quetiapine.

A 52-year-old woman and a 56-year-old man who were receiving carbamazepine experienced markedly elevated levels of its active metabolite, carbamazepine-10,11-epoxide (CBZ-E), after starting quetiapine therapy. The CBZ-E:carbamazepine ratio increased 3-4-fold in each patient. Levels of CBZ-E returned to baseline after discontinuing this drug combination. The metabolite can accumulate and cause neurotoxicity. The woman experienced ataxia and agitation while receiving quetiapine, which resolved after carbamazepine was switched to oxcarbazepine. The man was asymptomatic. To our knowledge, these are the first two case reports describing this interaction. Quetiapine may inhibit epoxide hydrolase and/or glucuronidation of carbamazepine-10,11-trans-diol in the same way as valproate and possibly lamotrigine do. If carbamazepine and quetiapine are administered concurrently, clinicians should consider monitoring CBZ-E concentrations.

Ataxia↗

Metabolic syndrome X: a review.

Metabolic syndrome X is a multifaceted syndrome, which occurs frequently in the general population. It is more common in men than in women. A large segment of the adult population of industrialized countries develops the metabolic syndrome, produced by genetic, hormonal and lifestyle factors such as obesity, physical inactivity and certain nutrient excesses. This disease is characterized by the clustering of insulin resistance and hyperinsulinemia, and is often associated with dyslipidemia (atherogenic plasma lipid profile), essential hypertension, abdominal (visceral) obesity, glucose intolerance or noninsulin-dependent diabetes mellitus and an increased risk of cardiovascular events. Abnormalities of blood coagulation (higher plasminogen activator inhibitor type 1 and fibrinogen levels), hyperuricemia and microalbuminuria have also been found in metabolic syndrome X. This review summarizes the present knowledge of abnormalities in this syndrome. Each risk factor is reviewed, and potential criteria for diagnosis and therapeutic targets are discussed. Because patients with metabolic syndrome X accumulate cardiac risk factors, they should be given special attention in terms of diagnosis and treatment.

Blood Glucose↗

A study on some phenotypic virulence markers of enteropathogenic Escherichia coli.

BACKGROUND & OBJECTIVES: The problem of enteropathogenic Escherichia coli (EPEC) causing diarrhoea in infants exists in India. But often the enteropathogenic status is not based on adequate characterization. Hence there is a need for evaluating the serotyping being used to identify EPEC for its validity in the light of recent knowledge on phenotypic markers of virulence. This study was done to evaluate the EPEC isolates for two potential virulence factors namely entero-adhesiveness with subsequent actin accumulation and verotoxin production. METHODS: Fifty consecutive EPEC strains identified by serotyping from stool samples of children with diarrhoea during January 1997 to June 1999 were studied for HEp-2 cell adherence, the fluorescent actin staining (FAS) characteristics of Hep-2 cells and vero cytotoxin production. RESULTS: Serotypes O55, O125 and O126 accounted for most of the isolates. In the Hep-2 assay, 72 per cent of the strains showed localised pattern of adherence and 22 per cent showed a mixed pattern of localised and diffuse adherence. In the FAS test 96 per cent strains showed typical staining while none of the strains produced verotoxin. INTERPRETATION & CONCLUSION: 'O' serogrouping appears to be still the simplest and an useful test for presumptive identification of EPEC. The FAS test for confirmation of EPEC was found to be very consistent in indicating EPEC.

Animals↗

A review of atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and accounts for more physician visits and hospital days than any other cardiac rhythm disturbance. Atrial filbrillation is incresing in frequency as the population ages, and therefore, a knowledge of the clinical spectrum and available treatment regimen is essential. Here, we review the pathophysiology, clinical presentation, and current status of management. Experience is being rapidly accumulated in all of the areas discussed in the management of this important clinical entity.

Atrial Fibrillation↗

Functional evaluation of patients with chronic pulmonary hypertension.

The importance of studying the pathophysiological bases and clinical correlates of exercise limitation in patients with pulmonary arterial hypertension (PAH) is well established. Two modes of exercise testing, the 6-min walk test (6MWT) and the cardiopulmonary exercise test (CPET), are currently proposed for diagnostic, therapeutic and prognostic finalities. The 6MWT is inexpensive, feasible and is thought to better reproduce daily life activities and to reliably detect therapeutic benefits. CPET requires the patient's maximal effort and does not provide a reliable quality of life measure. It is, however, highly reproducible and provides remarkable insights into the pathophysiological mechanisms that lead to exercise intolerance. Due to the limited experience accumulated, CPET is not actually advised for the routine assessment and for the overall clinical decision making of PAH patients. In this review we critically address the knowledge currently acquired on these techniques.

Exercise Test↗

Diagnosis of pituitary adenomas on touch preparations assisted by immunocytochemistry.

Touch preparations from surgically removed pituitary adenomas were studied by both routine staining and immunocytochemistry for all anterior pituitary hormones. The results were correlated with the histologic, histochemical, immunohistochemical and ultrastructural findings. Several features were recognized, some of them applicable in diagnosing various adenoma types: high cellularity, cell monomorphism, nuclear irregularities and heterogeneity of immunoreactivity, all major diagnostic criteria of pituitary adenoma. The presence of numerous fibrous bodies associated with nuclear pleomorphism, multinucleation and peripheral displacement of nuclei, in association with growth hormone (GH) immunopositivity, represent diagnostic criteria for sparsely granulated GH cell adenoma. The "Golgi" pattern of prolactin (PRL) immunopositivity in conjunction with the small size of cell and nucleus and the presence of microcalcifications represents diagnostic features of PRL-secreting adenoma. Cytoplasmic accumulation of hyaline material in association with peripheral distribution of periodic acid-Schiff stain and adrenocorticotropic hormone immunoreactivity is characteristic of sparsely granulated corticotroph cell adenoma. Knowledge and application of the described features may contribute significantly to the diagnostic approach to pituitary adenomas.

Adenoma↗

[Development of nutrition science in veterinary medicine as an example of the School of Veterinary Medicine Hannover].

Animal nutrition is not a main subject in veterinary medicine training, nevertheless it has been taught in the Tierärztliche Hochschule Hannover since its foundation in 1778. In the very beginning only a few lectures about feedstuffs and toxic plants for horses and feeding technique have been presented. During the 19th century animal nutrition was taught about 20 h under the general topic: Gesundheitspflege or Dlätetik. Diätetik included in that time all factors which are important for health as soil, water, climate, stable, hamess and nutrition, too. Textbooks about "Gesundheitspflege" from that time, in particular HAUBNERs book (1st ed. 1845, 4th ed. 1881) give an impression about the extent and the level of the matter presented (table 2). The students had to learn about feedstuffs, feed deterioriation, poisonous plants or feeding techniques, accumulated by experiences during the last centuries. On the other side the informations about digestive physiology as well as the metabolism of nutrients were poor although the knowledge grew up very rapidly during the last part of the 19th century. The lectures touched mainly problems in horses, cattle and sheep, to a lesser extent to pigs. No other domesticated animals were mentioned. After the turn of the century the "Gesundheitspflege" was split in hygiene and feeding. The latter was then lectured by teachers for animal production, which included genetics, breeding, and housing, too. Altogether about 40 h (lectures and practicals) were given on animal nutrition (up to 1967). There was no time to demonstrate specific interactions to the tasks of a veterinarian. After a new training plan, established in 1967, students had to absolve about 120 h (lectures and practical courses) on animal nutrition. Parallelly the Tierärztliche Hochschule Hannover established an own chair and institute about animal nutrition. In the lectures basic informations on nutrition of all domesticated animals (including horses, dogs, cats, cage birds etc.) were presented as well as aspects related to clinical problems (nutritional induced diseases), food quality, diets or animal welfare. In the practical courses the student should gain experience in: judging feed quality (which presumes knowledge about standards of normal feeds and food), estimating nutrient content of feeds, controlling and correcting rations, diagnosis of nutritional shortcomings, calculating rations for sick animals etc. In future in veterinary animal nutrition the last mentioned aspects will become greater importance in lecturing and research. Furthermore the nutritionists have to look for parameters to control a species specific correct nutrition especially in food producing animals.

Animal Nutritional Physiological Phenomena↗

Primary hepatic low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) associated with primary biliary cirrhosis.

We describe a case of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the liver of a patient with early-stage primary biliary cirrhosis (PBC). The patient, a 62-year old woman, presented with abnormal liver function tests, a positive antimitochondrial antibody titer (1:160), and a liver mass. The resected mass, 6.0 x 5.0 x 4.0 cm, had the features of MALT-type lymphoma. The neoplastic cells were small lymphoid cells of B-cell lineage that surrounded reactive lymphoid follicles and infiltrated bile ductules to form lymphoepithelial lesions. The uninvolved liver had histologic evidence of early stage PBC, characterized by segmental duct destruction with granulomata and an inflammatory infiltrate in the portal triads composed of lymphocytes, plasma cells, and occasional eosinophils. A periportal lymph node showed histologic features of the hyaline-vascular type of Castleman's disease, without evidence of malignant lymphoma. Low-grade B-cell lymphomas of the MALT type rarely arise in the liver and, to our knowledge, have not been reported previously in association with PBC. The association in this case suggests that chronic antigenic stimulation as a result of PBC induced the accumulation of acquired MALT, which subsequently transformed to low-grade B-cell lymphoma.

Female↗