Stochastic epidemics in dynamic populations: quasi-stationarity and extinction

Empirical evidence shows that childhood diseases persist in large communities whereas in smaller communities the epidemic goes extinct (and is later reintroduced by immigration). The present paper treats a stochastic model describing the spread of an infectious disease giving life-long immunity, in a community where individuals die and new individuals are born. The time to extinction of the disease starting in quasi-stationarity (conditional on non-extinction) is exponentially distributed. As the population size grows the epidemic process converges to a diffusion process. Properties of the limiting diffusion are used to obtain an approximate expression for τ, the mean-parameter in the exponential distribution of the time to extinction for the finite population. The expression is used to study how τ depends on the community size but also on certain properties of the disease/community: the basic reproduction number and the means and variances of the latency period, infectious period and life-length. Effects of introducing a vaccination program are also discussed as is the notion of the critical community size, defined as the size which distinguishes between the two qualitatively different behaviours. Received: 14 February 2000 / Revised version: 5 June 2000 / Published online: 24 November 2000     

Polyamine contents in current foods: a basis for polyamine reduced diet and a study of its long term observance and tolerance in prostate carcinoma patients

Summary. Our aim was to develop a liquid chromatography and electrospray ionization tandem mass spectrometry (LCMS²) method to measure free amino acid (FAA) and dipeptide (DP) concentrations in biological fluids. We synthesized chloroformate derivatives of FAA and DP, identified the major precursor ions and used LCMS² to obtain the most intense product ions. Using serial dilutions of unlabeled and labeled standards ([²H₃]-L-Dopa, homoarginine, homophenylalanine, [¹⁵N]-Glutamine and [²H₃]-methionine), we observed linear relationships in MS response that we used to calculate the amounts of FAA and DP in biological samples. This method is sensitive with a limit of detection (LOD) for most of the FAAs and DPs tested in the 0.05–1 pmol range and is linear over 3–5 orders of magnitude when many metabolites were measured simultaneously. Reproducibility and between run or daily variations were <10% for most FAAs and DPs. We applied this method to human samples and quantitatively measured 21 FAAs and 2 DPs in 200 μl CSF, 31 FAAs and 6 DPs in 100 μl plasma, and 23 FAAs and 5 DPs in 200 μl urine. These data demonstrate the potential for using LCMS² to discover changes in FAA and DP metabolic pathways that occur during disease pathogenesis.     

Somatostatin analogues, a series of tissue transglutaminase inducers, as a new tool for therapy of mesenchimal tumors of the gastrointestinal tract

Summary. Imatinib, a tyrosine kinase inhibitor directed against the enzymatic domain of KIT protein, was found to produce dramatic clinical responses in metastatic gastrointestinal stromal tumors (GISTs). However, resistance usually develops thus determining treatment failure. The present study was performed to analyse the expression of somatostatin receptor (SSTR) subtypes, modulators of tissue transglutaminase, in a series of GISTs and leiomyosarcomas by immunohistochemistry to identify a new potential therapeutic target. Sixteen cases (8 males and 8 females, age range: 38–73; 11 GISTs, 4 leiomyosarcomas, 1 leiomyoma) were studied. Immunohistochemical detection of the relevant SSTRs was performed on paraffin-embedded tissue sections, stained with polyclonal antibodies directed against the five somatostatin receptor subtypes. We found 7 out of 16 (44%) tumors expressing all SSTRs and 14 out of 16 (87%) tumors positive for at least 3 subtypes. SSTR2_A was the most represented subtype in the tumors studied, being expressed in approximately 70% of cases exhibiting an intense labeling in most of these cases. The significant expression of SSTRs shown in this series of GISTs and gastrointestinal leiomyosarcomas suggests a potential therapeutic target to be explored alone and/or in combination with other therapeutic agents in the setting of refractory GI stromal tumors.     

Studies on the Holocene history of vegetation in the region of lake Srebarna (northeast Bulgaria)

The results of pollen analysis of two sediment cores from lake Srebarna (northeast Bulgaria) are presented. On the basis of the palynological data and the radiocarbon dates a reconstruction of the past flora and vegetation is made. For the first time a continuous palaeosuccession is established for the area of the Danubian Dobrudza and the Ludogorie district of northeast Bulgaria: a dominance of mixed xero- and mesophilous oak woods with Carpinus betulus, Ulmus, Tilia, Corylus during the Atlantic period; mixed oak woods with increasing importance of Tilia, Ulmus, Acer and a considerable presence of Carpinus betulus and Fagus during the Sub-boreal period; degradation of the woodland vegetation and transition to secondary plant communities with Carpinus orientalis and herbs during the Sub-atlantic period. Received January 5, 2001 / Accepted March 13, 2001     

The effect of glutamine supplementation and physical exercise on neutrophil function

Glutamine is the most abundant free amino acid in the body. Its primary source is skeletal muscle, from where it is released into the bloodstream and transported to a variety of tissues. Several studies have shown that glutamine is important for rat and human neutrophil function and that these cells utilize glutamine at high rates. Physical exercise has also been shown to induce considerable changes in neutrophil metabolism and function. As neutrophils represent 50-60% of the total circulating leukocyte pool and play a key role in inflammation, both physical exercise and glutamine might be expected to regulate the inflammatory process. In this review, the changes in neutrophil function induced by physical exercise and glutamine supplementation are compared.     

Stone Age to recent land-use history at Pegrema, northern Lake Onega, Russian Karelia

The village of Pegrema in Karelia may be regarded as a Stone Age innovation centre in the large Lake Onega area. Two pollen and plant macrofossil diagrams are presented which represent the first contribution to the study of human impact in the area using anthropogenic pollen indicators. A continuous but sporadic human presence from the Mesolithic onwards is demonstrated. While there is no archaeological evidence relating to the period 4200–3000 B.P., the pollen data suggest continuous, though rather sparse human presence. The data do not support any natural catastrophes in Pegrema as has been suggested elsewhere. Cerealia pollen is recorded earlier than expected (c. 5000 B.P.=. In the Bronce Age and Iron Age, the settlement of the Zaonezhye peninsula is reflected by a slight increase in herb pollen representation, sporadic Cerealia pollen and several periods of regression in Picea. The long introductory period of agriculture to the area, as well as the similarities and discrepancies between different sources of evidence (palaeoecological, archaeological and historical) are discussed at some length. The start of land clearance for permanent cultivation in the profile Pegrema S was dated to the late 13^th century. The beginning of more intensive field cultivation in the 15^th century is clearly seen in the pollen succession at both localities. The fluctuation in anthropogenic indicators can be related to population density based on historical data. The village of Pegrema was depopulated in 1956 which is reflected in a distinct decline in settlement indicators. Received February 17 / Accepted May 19, 2000     

Polyamine analogues – an update

Summary. The polyamines are growth factors in both normal and cancer cells. As the intracellular polyamine content correlates positively with the growth potential of that cell, the idea that depletion of polyamine content will result in inhibition of cell growth and, particularly tumour cell growth, has been developed over the last 15 years. The polyamine pathway is therefore a target for development of rationally designed, antiproliferative agents. Following the lessons from the single enzyme inhibitors (α-difluoromethylornithine DFMO), three generations of polyamine analogues have been synthesised and tested in vitro and in vivo. The analogues are multi-site inhibitors affecting multiple reactions in the pathway and thus prevent the up-regulation of compensatory reactions that have been the downfall of DFMO in anticancer chemotherapy. Although the initial concept was that the analogues may provide novel anticancer drugs, it now seems likely that the analogues will have wider applications in diseases involving hyperplasia.     

Primary kidney growth and its consequences at the onset of diabetes mellitus

Summary. Diabetes mellitus is a primary contributor to progressive kidney dysfunction leading to end-stage renal disease (ESRD). In the early phase of diabetes, prior to the onset of further complications, both kidney size and glomerular filtration rate (GFR) increase. Glomerular hyperfiltration is considered a risk factor for downstream complications and progression to ESRD. Abnormalities in vascular control have been purported to account for the glomerular hyperfiltration in early diabetes. In this review we discuss a tubulo-centric concept in which tubular growth and subsequent hyper-reabsorption contribute to the onset of glomerular hyperfiltration that demarks the early stage of diabetes. Kidney growth, in this concept, is no longer relegated to a compensatory response to hyperfiltration, but rather plays a primary and active role in its genesis and progression. As such, components of kidney growth, such as the polyamines, may provide a means of early detection of diabetic kidney dysfunction and more effective therapeutic intervention.     

Vegetation in the mountains of northwest Iberia during the last glacial-interglacial transition

A new core taken from a site in the Sierra de Courel range of mountains in the northwest Iberian peninsula, Spain, enables a palaeoenvironmental reconstruction to be made of the biological events resulting from climatic changes and human activities during the last 17,000 years in the area. The sequence begins with a phase characterised by the dominance of Gramineae (Poaceae) and Pinus. A markedly arid period with prevalence of Artemisia pollen occurred between 17,5000 and 15,500 uncal. B.P. Subsequently, a succession of woodlands with Betula, Pinus and other mesophilous and thermophilous trees was recognised during the period 15,500-13,500 uncal. B.P. Between 13,500 and 10,300 uncal. B.P. herbaceous vegetation formations indicating moister conditions dominated the pollen record, although a maximum of Gramineae has been dated during the period 11,300-10,300 uncal. B.P. Comparison with other pollen data from neighbouring mountains allows an interpretation of the vegetation changes during the glacial/interglacial transition in the mountains of northwest Iberia. The Holocene pollen record from the site does not differ markedly from other records in the area, tree expansion occurring before 10,000 uncal. B.P. and high values of deciduous Quercus mixed with other trees and shrubs persisting until 3500 uncal. B.P., when increased human activities are shown by a fall of the tree pollen percentages. Received July 7, 1999 / Accepted May 22, 2000     

A facile HPLC method for optical purity and quantitative measurements of phenylalanine from the hydrolyzed aspartame under different pH and temperature after its derivatization with a fluorescent reagent

Summary. In this paper, the artificial sweetener aspartame is deliberately hydrolyzed under different pH and temperature in the matrix, and time period for the hydrolysis. The HPLC analysis is then performed to quantitatively measure the amount and the optical purity of phenylalanine produced as a result of hydrolysis in the matrix after its functionalization with a fluorescent reagent. The results show that the amount of phenylalanine in the matrix is affected by the pH variation during the hydrolysis and found increased in low pH conditions. High temperature or long time periods for the decomposition also increases the amount, which indicates that beverages and foods containing aspartame as a sweetener may not be safe for phenylketonuria patients to consume if they are stored under these conditions. Conversely, the optical purity of phenylalanine, expressed as the percentage of d-enantiomer, is not affected by pH variations. However, it decreases as the length of time elapsed is increased or surrounding temperature is elevated during the decomposition.     

Effects of glucocorticoids on polyamine metabolism in liver and spleen of guinea pig during sensitization

Summary. Glucocorticoids are potent anti-inflammatory and immunosuppressive agents. As endogenous inhibitors of cytokine synthesis, glucocorticoids suppress immune activation and uncontrolled overproduction of cytokines, preventing tissue injury. Also, polyamine spermine is endogenous inhibitor of cytokine production (inhibiting IL-1, IL-6 and TNF synthesis). The idea of our work was to examine dexamethasone effects on the metabolism of polyamines, spermine, spermidine and putrescine and polyamine oxidase activity in liver and spleen during sensitization of guinea pigs. Sensitization was done by application of bovine serum albumin with addition of complete Freund’s adjuvant. Our results indicate that polyamine amounts and polyamine oxidase activity increase during immunogenesis in liver and spleen. Dexamethasone application to sensitized and unsensitized guinea pigs causes depletion of polyamines in liver and spleen. Dexamethasone decreases polyamine oxidase activity in liver and spleen of sensitized guinea pigs, increasing at the same time PAO activity in tissues of unsensitized animals.     

Two SIS epidemiologic models with delays

 The SIS epidemiologic models have a delay corresponding to the infectious period, and disease-related deaths, so that the population size is variable. The population dynamics structures are either logistic or recruitment with natural deaths. Here the thresholds and equilibria are determined, and stabilities are examined. In a similar SIS model with exponential population dynamics, the delay destabilized the endemic equilibrium and led to periodic solutions. In the model with logistic dynamics, periodic solutions in the infectious fraction can occur as the population approaches extinction for a small set of parameter values. Received: 10 January 1997 / 18 November 1997     

Polyamines in renal failure

Summary. The levels of polyamines (putrescine, spermidine and spermine) and polyamine oxidase in plasma of patients with chronic renal failure were determined. The level of putrescine was increased but the level of spermine was decreased in the plasma of these patients. The patients also had increased plasma polyamine oxidase activity leading to increased degradation of spermine. As acrolein was a major toxic compound produced from spermine by polyamine oxidase, the levels of free and protein-conjugated acrolein in plasma were also measured. Acrolein levels were enhanced in plasma of patients with chronic renal failure. The accumulated acrolein found as protein conjugates was equivalent to 170 μM, which was about 5-fold higher than in plasma of normal subjects. It was found that acrolein is mainly produced by spermine oxidase in plasma. An increase in putrescine, spermine oxidase and acrolein in plasma was observed in all cases such as diabetic nephropathy, chronic glomerulonephritis and nephrosclerosis. After patients with chronic renal failure had undergone hemodialysis, their levels of plasma polyamines, spermine oxidase and acrolein returned towards normal. It is likely that acrolein produced from spermine accumulates in the blood due to decreased excretion into urine and may function as a uremic “toxin”.     

Prediction of mutations engineered by randomness in H5N1 neuraminidases from influenza A virus

Summary. In this proof-of-concept study, we attempt to determine whether the cause-mutation relationship defined by randomness is protein dependent by predicting mutations in H5N1 neuraminidases from influenza A virus, because we have recently conducted several concept-initiated studies on the prediction of mutations in hemagglutinins from influenza A virus. In our concept-initiated studies, we defined the randomness as a cause for mutation, upon which we built a cause-mutation relationship, which is then switched into the classification problem because the occurrence and non-occurrence of mutations can be classified as unity and zero. Thereafter, we used the logistic regression and neural network to solve this classification problem to predict the mutation positions in hemagglutinins, and then used the amino acid mutating probability to predict the would-be-mutated amino acids. As the previous results were promising, we extend this approach to other proteins, such as H5N1 neuraminidase in this study, and further address various issues raised during the development of this approach. The result of this study confirms that we can use this cause-mutation relationship to predict the mutations in H5N1 neuraminidases. Authors’ address: Guang Wu, Computational Mutation Project, DreamSciTech Consulting 301, Building 12, Nanyou A-zone, Jiannan Road, Shenzhen, Guangdong Province CN-518054, China     

Taurine reduces caspase-8 and caspase-9 expression induced by ischemia in the mouse hypothalamic nuclei

Summary. Taurine is a sulphur-containing amino acid abundant in the nervous system. It protects cells from ischemia-induced apoptosis, but the mechanism underlying this is not well established. The aim of our study was to explore the effects of taurine on two main pathways of apoptosis induced by ischemia: receptor-mediated and mitochondrial cell death. Brain slices containing the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus were incubated in vitro under control and simulated ischemic (oxygen-glucose deprivation for 30 min) conditions in the absence and presence of 20 mM taurine. Brain slices were harvested after the 180-min “postischemic” period and fixed in 4% paraformaldehyde. To estimate apoptosis, immunostaining was done for caspase-8 and caspase-9 in paraffin-embedded sections. Immunoreactive caspase-8 and caspase-9 cells were observed in SON and PVN in all experimental groups, but in the “ischemic” group the expression of caspase-8 and caspase-9 and the number of immunoreactive cells was significantly increased in both hypothalamic nuclei. Addition of taurine (20 mM) to the incubation medium induced a marked decrease in caspase-8 and caspase-9 immunoreactivity after ischemia in SON and PVN when compared with the taurine-untreated “ischemic” group. Taurine reduces ischemia-induced caspase-8 and caspase-9 expression, the key inductors of apoptosis in SON and PVN. Authors’ address: Dr. Andrey Taranukhin, Tampere Brain Research Center, Medical School, University of Tampere, FI-33014 Finland     

Kidney growth,hypertrophy and the unifying mechanism of diabetic complications

Summary. Michael Brownlee has proposed a ‘Unifying Mechanism’ of hyperglycemia-induced damage in diabetes mellitus. At the crux of this hypothesis is the generation of reactive oxygen species (ROS), and their impact on glycolytic pathways. Diabetes is the leading cause of chronic kidney failure. In the early phase of diabetes, prior to establishment of proteinuria or fibrosis, comes kidney growth and hyperfiltration. This early growth phase consists of an early period of hyperplasia followed by hypertrophy. Hypertrophy also contributes to cellular oxidative stress, and may precede the ROS perturbation of glycolytic pathways described in the Brownlee proposal. This increase in growth promotes hyperfiltration, and along with the hypertrophic phenotype appears required for hyperglycemia-induced cell damage and the progression of downstream diabetic complications. Here we will evaluate this growth phenomenon in the context of diabetes mellitus.     

A unified hypothesis of coeliac disease with implications for management of patients

Summary. This mini-review presents the research carried out within the context of two of the main hypotheses of the aetiology of coeliac disease. The enzymopathic hypothesis of the disease has been placed clearly as the underlying deficiency causing increased levels of toxic peptides, while the immunological hypothesis has been implicated in the pathogenesis of the disorder as the result of the action of undigested peptides in the small intestine. As a consequence, we are proposing a unified hypothesis of coeliac disease, which takes into account the actions of these undigested peptides through their direct cytotoxicity and their immunoactivity. At the same time, work aimed at defining some of these biologically active peptides, which could be said to be involved in the aetiopathogenesis of coeliac disease, will be reported. The review also focusses on the use of enzyme therapy for management of the disease, which when used in conjunction with the gluten-free diet, offers a safeguard against damage to the small intestine caused by small amounts of gluten.     

A simple SIS epidemic model with a backward bifurcation

It is shown that an SIS epidemic model with a non-constant contact rate may have multiple stable equilibria, a backward bifurcation and hysteresis. The consequences for disease control are discussed. The model is based on a Volterra integral equation and allows for a distributed infective period. The analysis includes both local and global stability of equilibria.     

A new archaeobotanical database program

The available quantity of archaeobotanical data derived from the identification of macroremains has expanded considerably over the last few decades. In order to obtain a supraregional or even regional overview for a particular period of time, or of the distribution of a single species, a database is needed. At the Archaeobotanical Department of the Institute of the "Kommission für Arch?ologische Landesforschung in Hessen e.V." (KAL) such a database has been developed in the last few years. It is suitable for the handling of large quantities of archaeobotanical results, including a whole range of background information comprising archaeological, ecological and other related data, and offers various possibilities for the evaluation of these data. Received January 8, 2001 / Accepted April 9, 2002     

Gravity-directed calcium current in germinating spores of Ceratopteris richardii

 Gravity directs the early polar development in single cells of Ceratopteris richardii Brogn. It acts over a limited period of time during which it irreversibly determines the axis of the spore cell's development. A self-referencing calcium selective electrode was utilized to record the net movement of calcium across the cell membrane at different positions around the periphery of the spore during the period in which gravity orients the polarity of the spore. A movement of calcium into the cell along the bottom and out of the cell along the top was detected. This movement was specific, polarized, and strongest in a direction that opposed the vector of gravity. Treatment with nifedipine, a calcium-channel blocker, diminished the calcium current and caused the cell to lose its responsiveness to the orienting influence of gravity. Results shown suggest that calcium plays a crucial role in the ability of a single cell to respond to gravity and in the subsequent establishment of its polarity. Received: 13 June 1999 / Accepted: 1 September 1999