A clinical approach to common electrolyte problems: 4. Hypomagnesemia.

Magnesium plays a critical role in many cell functions. Hypomagnesemia may occur because of decreased intake or absorption, internal redistribution or increased loss of this element through either renal or nonrenal routes. Manifestations of magnesium deficiency include alterations in calcium, phosphate and potassium homeostasis along with cardiac disorders such as malignant ventricular arrhythmias refractory to conventional therapy, enhanced sensitivity to digoxin and, possibly, coronary artery vasospasm and sudden death. Other features of magnesium deficiency include a host of neuromuscular and neuropsychiatric disorders. In this review we detail mechanisms that may lead to magnesium deficiency, summarize the clinical features of the deficiency and provide a clinical approach to the diagnosis and treatment of this electrolyte disorder.     

A clinical approach to common electrolyte problems: 2. Potassium imbalances.

A clinical approach to potassium imbalances is presented. Hypokalemia is rarely due solely to a reduced intake of potassium; instead, it usually results from a potassium flux into the cells or increased loss of the element, at times combined with a decreased intake. The clinician must seek the cause of the intracellular flux or the source of the gastrointestinal or renal loss. The causes of gastrointestinal losses are generally self evident. Renal potassium wasting, though, generally results from increased mineralocorticoid activity, an increased rate of urinary flow or of sodium delivery to the distal nephron, or both, hypomagnesemia or a combination of these factors. Hyperkalemia may be factitious, but usually it is caused by a flux of potassium from the cells or a decrease in the renal loss of potassium, the latter being mediated by a reduction in renal function, mineralocorticoid activity, or the rate of urinary flow or sodium delivery, or both. In both hypokalemia and hyperkalemia, treatment must be guided by the specific clinical circumstances.     

A quantum-theoretic approach to genetic problems

A quantum-theoretic picture of the transfer of genetic information is described. The advantage of such an approach is that a number of genetic effects appear to be explicable on the basis of general microphysical laws, independent of any specific model (such as DNA-protein coding) for the transmission of genetic information. It is assumed that the genetic information is carried by a family of numerical observables belonging to a specific microphysical system; it is shown that a single observable is theoretically sufficient to carry this information. The various types of structure that this observable can possess are then described in detail, and the possible genetic effects which can airse from each such structure are discussed. For example, it is shown how the assumption that the genetic observable possesses degenerate eigenvalues may lead to a theory of allelism. To keep the treatment self-contained, the basic quantum-theoretical principles to be used are discussed in some detail. Finally, the relation of the present approach to current biochemical ideas and to earlier quantum-theoretic treatments of genetic systems is discussed.     

A syndromic approach to common parasitic diseases

Standard textbooks discuss parasitic disease according to specific organisms. In contrast, patients with parasitic infections present to physicians with a variety of clinical manifestations that may involve any of several organ systems and that often mimic nonparasitic diseases. A syndromic approach to the clinical situation may help the physician in considering the most important parasitic agents. Many parasitic infections can be acquired in temperate climates. While often considered tropical or exotic, other parasitic diseases are now seen more frequently in developed countries because of immigration and increased world travel. In this review the clinical syndromes associated with common parasitic diseases in North America are discussed, with an emphasis on risk factors and diagnosis of specific infections.     

A diffusion approach to the electrolyte leakage from plant tissues

The exchange of ions between plant tissues and the external solution in vitro exhibits prominent biphasic kinetics. This is generally ascribed to the different contribution of the two compartments – apoplast and symplast – involved in the process. In this regard, an electro-diffusion model of the leakage is proposed in the paper. On the basis of the balance of fluxes through the plasmalemma and the cell wall, a system of differential equations describing the ion concentration in the outer solution is found. For a wide range of the system's coefficients, its behaviour is well approximated by a previously obtained analytical function. The values of the function's parameters, derived from the fit with experimental data, correlate adequately with the water deficit conditions of the samples. Hence, these parameters may be used to characterize the physiological status of the investigated plants.     

A rank-based mixed model approach to multisite clinical trials.

New rank-based methods for analyzing data from multisite clinical trials are presented in the context of "mixed" linear models. In contrast to current rank methods, the new procedures test for a drug main effect in the presence of a random drug by site interaction (or drug by investigator interaction when there is only one investigator per site). Analogous procedures are also provided for the "fixed-effects" situation, and comparisons are made with current methods. The rationale for an analysis that assumes random investigator effects is described.     

The average common substring approach to phylogenomic reconstruction.

We describe a novel method for efficient reconstruction of phylogenetic trees, based on sequences of whole genomes or proteomes, whose lengths may greatly vary. The core of our method is a new measure of pairwise distances between sequences. This measure is based on computing the average lengths of maximum common substrings, which is intrinsically related to information theoretic tools (Kullback-Leibler relative entropy). We present an algorithm for efficiently computing these distances. In principle, the distance of two l long sequences can be calculated in O(l) time. We implemented the algorithm using suffix arrays our implementation is fast enough to enable the construction of the proteome phylogenomic tree for hundreds of species and the genome phylogenomic forest for almost two thousand viruses. An initial analysis of the results exhibits a remarkable agreement with "acceptable phylogenetic and taxonomic truth." To assess our approach, our results were compared to the traditional (single-gene or protein-based) maximum likelihood method. The obtained trees were compared to implementations of a number of alternative approaches, including two that were previously published in the literature, and to the published results of a third approach. Comparing their outcome and running time to ours, using a "traditional" trees and a standard tree comparison method, our algorithm improved upon the "competition" by a substantial margin. The simplicity and speed of our method allows for a whole genome analysis with the greatest scope attempted so far. We describe here five different applications of the method, which not only show the validity of the method, but also suggest a number of novel phylogenetic insights.     

A rigorous approach to investigating common assumptions about disease transmission

Changing scale, for example, the ability to move seamlessly from an individual-based model to a population-based model, is an important problem in many fields. In this paper, we introduce process algebra as a novel solution to this problem in the context of models of infectious disease spread. Process algebra allows us to describe a system in terms of the stochastic behaviour of individuals, and is a technique from computer science. We review the use of process algebra in biological systems, and the variety of quantitative and qualitative analysis techniques available. The analysis illustrated here solves the changing scale problem: from the individual behaviour we can rigorously derive equations to describe the mean behaviour of the system at the level of the population. The biological problem investigated is the transmission of infection, and how this relates to individual interactions.     

A probabilistic approach to some problems in blood-tissue exchange

The problem of exchange of substances between circulating blood and tissue is discussed in terms of a model with continuously distributed tissue characteristics. Consideration is given to the distribution of perfusion rates, the distribution of metabolism coefficients for a substance consumed at a rate proportional to its concentration, and the distribution of permeability coefficients for a slowly penetrating inert substance. Equations are derived for obtaining crude estimates of the moments of these distributions from exchange data.     

A dynamic programming approach for finding common patterns in RNAs.

We developed a dynamic programming approach of computing common sequence structure patterns among two RNAs given their primary sequences and their secondary structures. Common patterns between two RNAs are defined to share the same local sequential and structural properties. The locality is based on the connections of nucleotides given by their phosphodiester and hydrogen bonds. The idea of interpreting secondary structures as chains of structure elements leads us to develop an efficient dynamic programming approach in time O(nm) and space O(nm), where n and m are the lengths of the RNAs. The biological motivation is given by detecting common, local regions of RNAs, although they do not necessarily share global sequential and structural properties. This might happen if RNAs fold into different structures but share a lot of local, stable regions. Here, we illustrate our algorithm on Hepatitis C virus internal ribosome entry sites. Our method is useful for detecting and describing local motifs as well. An implementation in C++ is available and can be obtained by contacting one of the authors.     

Computation of biopolymers: A general approach to different problems

A comparative analysis of some effective algorithms widely used in analysis, computation and comparison of chain molecules is presented. A notion of a stream in an oriented hypergraph is introduced, which generalizes a notion of a path in a graph. All considered algorithms looking over exponential sets of structures in polynomial time can be described as variants of a general algorithm of analysis of paths in graphs and of streams in oriented hypergraphs.     

An approach to inverse scattering problems

There are several reasons for investigating the inverse scattering problem in medical image processing. A typical case, that of ultrasonic fields, is considered. Assuming that a plane wave illuminates a weakly inhomogeneous two-dimensional object, the fundamental equation is derived for the scattered waves in integral as well as in differential forms. It is shown that the scattered waves observed on a circle surrounding the object is sufficient to specify the structure of the object. This information is summarized in a single term, which is a function of the wavenumber as well as the angles of incidence and observation. A successive approximation is applied to reconstruct the image of the object from this function. Since no analytic solution is available, several methods of approximations are proposed, and examples of computations are shown for the case of a cylindrical object.     

A fragment-like approach to PYCR1 inhibition

Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC₅₀ = 8.8 µM) and pathway relevant effects in cell-based assays.