Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology

The cardiac voltage-gated Na(+) channel Na(v)1.5 generates the cardiac Na(+) current (INa). Mutations in SCN5A, the gene encoding Na(v)1.5, have been linked to many cardiac phenotypes, including the congenital and acquired long QT syndrome, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. The mutations in SCN5A define a sub-group of Na(v)1.5/SCN5A-related phenotypes among cardiac genetic channelopathies. Several research groups have proposed that Na(v)1.5 may be part of multi-protein complexes composed of Na(v)1.5-interacting proteins which regulate channel expression and function. The genes encoding these regulatory proteins have also been found to be mutated in patients with inherited forms of cardiac arrhythmias. The proteins that associate with Na(v)1.5 may be classified as (1) anchoring/adaptor proteins, (2) enzymes interacting with and modifying the channel, and (3) proteins modulating the biophysical properties of Na(v)1.5 upon binding. The aim of this article is to review these Na(v)1.5 partner proteins and to discuss how they may regulate the channel's biology and function. These recent investigations have revealed that the expression level, cellular localization, and activity of Na(v)1.5 are finely regulated by complex molecular and cellular mechanisms that we are only beginning to understand.

High altitude, a natural research laboratory for the study of cardiovascular physiology and pathophysiology

High altitude constitutes an exciting natural laboratory for medical research. Although initially, the aim of high-altitude research was to understand the adaption of the organism to hypoxia and find treatments for altitude-related diseases, during the past decade or so, the scope of this research has broadened considerably. Two important observations led the foundation for the broadening of the scientific scope of high-altitude research. First, high-altitude pulmonary edema represents a unique model that allows studying fundamental mechanisms of pulmonary hypertension and lung edema in humans. Second, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary and systemic vascular dysfunction at an early stage. Here, we will review studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning lung edema and pulmonary hypertension and to the first direct demonstration of fetal programming of vascular dysfunction in humans.

Reticulate eruptions. Part 1: Vascular networks and physiology

Reticulate pattern is one of the most important dermatological signs of a pathological process involving the superficial vascular networks. Vascular malformations, such as cutis marmorata congenita telangiectasia and benign forms of livedo reticularis, and sinister conditions, such as meningococcal meningitis or Sneddon's syndrome, can all present with a reticulate pattern. The clinical presentation and morphology is determined by the nature and extent of the underlying pathology and the involvement of a particular vascular network. This review has been divided into four instalments. In the present paper, we discuss the anatomy and physiology of the complex network of vascular structures that support the function of the skin and subcutis.

The impact of body mass index on the physiology of patients with polytrauma

Obesity is a growing problem in industrial nations. The aim was to test the hypothesis that overweight patients face early physiologic impairment.

TRPM4 channels in the cardiovascular system: physiology, pathophysiology, and pharmacology

The transient receptor potential channel (TRP) family comprises at least 28 genes in the human genome. These channels are widely expressed in many different tissues, including those of the cardiovascular system. The transient receptor potential channel melastatin 4 (TRPM4) is a Ca(2+)-activated non-specific cationic channel, which is impermeable to Ca(2+). TRPM4 is expressed in many cells of the cardiovascular system, such as cardiac cells of the conduction pathway and arterial and venous smooth muscle cells. This review article summarizes the recently described roles of TRPM4 in normal physiology and in various disease states. Genetic variants in the human gene TRPM4 have been linked to several cardiac conduction disorders. TRPM4 has also been proposed to play a crucial role in secondary hemorrhage following spinal cord injuries. Spontaneously hypertensive rats with cardiac hypertrophy were shown to over-express the cardiac TRPM4 channel. Recent studies suggest that TRPM4 plays an important role in cardiovascular physiology and disease, even if most of the molecular and cellular mechanisms have yet to be elucidated. We conclude this review article with a brief overview of the compounds that have been shown to either inhibit or activate TRPM4 under experimental conditions. Based on recent findings, the TRPM4 channel can be proposed as a future target for the pharmacological treatment of cardiovascular disorders, such as hypertension and cardiac arrhythmias.

NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology

This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b(5) are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b(5) on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism.

Nutritional physiology of neonatal calves

The gastrointestinal tract of neonatal calves is relatively mature but still requires morphological and functional changes. The intake of colostrum with its nutrient and non-nutrient components exerts marked effects on gastrointestinal development and function. Colostrum intake provides immunoprotection (passive immunity by immunoglobulins) and is essential for survival of neonates of most species. Furthermore, there are important transient as well as long-lasting systemic effects on the nutritional status, on metabolism, and on various endocrine systems due to intake of nutrient and non-nutrient colostral components that contribute to survival in the stressful postnatal period. Colostrum is much more than just a supplier of immunoglobulins.

Incontinentia lactis: physiology and anatomy conducive to milk leakage in dairy cows

Incontinentia lactis is a possible predisposing factor for an elevated level of intramammary infection. The goal of the present study was to investigate possible causes of incontinentia lactis in dairy cows. Two farms that differed in breed composition, but that had similar average milk yields were studied: herd A, 28 kg/d, 31 Red Holstein cows; and herd B, 26 kg/d, 16 Brown Swiss cows. Herd A was classified into 2 groups: incontinentia lactis (ILA group) and control, whereas herd B was exclusively a control herd. Milk samples that represented foremilk and the main milk fraction were collected during 4 milking sessions. In addition, milk leakage samples from the ILA group were collected at different time intervals from 0 to 5 h before milking. Measurements of the teat, milk flow, fractions of cisternal and alveolar milk, intramammary pressure, and blood oxytocin pattern also were obtained. The ILA cows did not have differences in fat content between milk leakage and cisternal milk fraction. Milk fat content, however, increased during milking in response to continuous milk ejection (1.95, 1.99, and 4.61% for milk leakage, cisternal, and main milk samples, respectively). Teat canals were 9% shorter in the ILA cows, which showed greater milk yield, peak, and average flow rates. Quarter cisternal milk yield of ILA cows tended to be greater (0.50 vs. 0.23 and 0.28 kg for ILA and controls from herds A and B, respectively), whereas percentages of cistern milk and alveolar milk did not differ from controls. The greater pressure in the ILA group, both before and after manual udder stimulation (ILA: 4.0 and 6.4 kPa; control: 2.0 and 5.0 kPa, respectively), could be an important cause for the leakage. Nevertheless, the increase in IMP that occurred after udder preparation affirms that milk ejection occurred in response to the tactile teat stimulation, but not before the onset of leakage. Blood oxytocin concentration in ILA cows was low until the start of udder preparation and increased in response to the milking stimulus (reaffirming the hypothesis that milk leakage occurred in the absence of milk ejection). In conclusion, milk losses by leakage are likely due to the large amount of cisternal milk, which creates pressure and causes leakage, in the absence of milk ejection.

Quantitative proteome analysis in cardiovascular physiology and pathology. I. Data processing

Methodological evaluation of the proteomic analysis of cardiovascular-tissue material has been performed with a special emphasis on establishing examinations that allow reliable quantitative analysis of silver-stained readouts. Reliability, reproducibility, robustness and linearity were addressed and clarified. In addition, several types of normalization procedures were evaluated and new approaches are proposed. It has been found that the silver-stained readout offers a convenient approach for quantitation if a linear range for gel loading is defined. In addition, a broad range of a 10-fold input (loading 20-200 microg per gel) fulfills the linearity criteria, although at the lowest input (20 microg) a portion of protein species will remain undetected. The method is reliable and reproducible within a range of 65-200 microg input. The normalization procedure using the sum of all spot intensities from a silver-stained 2D pattern has been shown to be less reliable than other approaches, namely, normalization through median or through involvement of interquartile range. A special refinement of the normalization through virtual segmentation of pattern, and calculation of normalization factor for each stratum provides highly satisfactory results. The presented results not only provide evidence for the usefulness of silver-stained gels for quantitative evaluation, but they are directly applicable to the research endeavor of monitoring alterations in cardiovascular pathophysiology.

Linking physiology with behaviour: Functional specialisation of the visual field is reflected in gaze patterns during visual search

Based on neurophysiological findings and a grid to score binocular visual field function, two hypotheses concerning the spatial distribution of fixations during visual search were tested and confirmed in healthy participants and patients with homonymous visual field defects. Both groups showed significant biases of fixations and viewing time towards the centre of the screen and the upper screen half. Patients displayed a third bias towards the side of their field defect, which represents oculomotor compensation. Moreover, significant correlations between the extent of these three biases and search performance were found. Our findings suggest a new, more dynamic view of how functional specialisation of the visual field influences behaviour.

[Implantation: physiology, pathology and therapeutic options in disorders of implantation]

So far, implantation is a poorly understood process, which involves several paradoxical cell-biological mechanisms. First, 50% of the embryo is paternal and immunologically foreign material, and second, both the endometrium and embryo are covered by epithelial tissue to prevent cellular fusion. The adhesion and invasion of the blastocyst require an accurate coordination of embryonic and endometrial physiology and the modulation of maternal immune tolerance. Endometrial function plays an important role in assisted reproduction. Pathologies such as fibroids, hydrosalpinges, endometriosis and the polycystic ovary syndrome have a significant negative impact on implantation but can be treated in most cases. Therapeutic strategies to improve endometrial and embryonic function in recurrent implantation disorders are however still controversially discussed.