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Newer paradigms in renal replacement therapy: will they alter cardiovascular outcomes?

Cardiovascular disease remains the leading cause of morbidity and mortality for patients with end-stage renal disease. Conventional hemodialysis has had limited impact on cardiovascular risk factors and mortality. Increasing evidence suggests that nocturnal home hemodialysis has beneficial effects on cardiovascular parameter outcomes. This article reviews the documented effects of nocturnal home hemodialysis on blood pressure control, cardiac geometry and left ventricular systolic function, lipid profiles, calcium-phosphate metabolism, parathyroid hormone levels, homocysteine levels, sleep apnea, and autonomic modulation of heart rate. It discusses possible mechanisms to explain these observed changes.

Cardiovascular Diseases↗

Effects of increased sea water concentrations of CO2 on growth of the bivalve Mytilus edulis L.

It has been proposed that emission of anthropogenic carbon dioxide to the atmosphere will lead to increased concentrations of CO(2) in sea water corresponding to a decrease of pH of several tenths of pH units. An experiment was performed to test the effects of increased sea water concentrations of CO(2) on shell growth of the blue mussel Mytilus edulis. The experiment was performed in aquaria continuously flushed with sea water spiked with CO(2) to provide five different levels of pH between 6.7 and control sea water with a pH of 8.1. The shell length of the mussels was measured at the start and end of the 44 days experimental period. No mortality was observed during the first 23 days of the experiment. The growth increment in mm was much larger for small mussels than for large mussels, but relative growth profile as function of pH was more similar in the two size groups; observed differences may be random variation between samples. The experiments showed that CO(2) induced reduction of pH affects the growth of M. edulis negatively. There was a strong and statistically significant decrease in growth at the lowest pH values, with virtually no growth at pH = 6.7 and reduced growth at pH = 7.1. The effect seems to set in between pH 7.4 and 7.1; at mean pH levels 7.4 and 7.6 the growth increments were not significantly different from growth at normal pH 8.1.

Animals↗

High-frequency ultrasound database profiling growth, development, and cardiovascular function in C57BL/6J mouse fetuses.

BACKGROUND: High-frequency ultrasound is effective for noninvasive phenotypic analysis of cardiovascular development and function in mutagenized fetal mice. However, lacking is a normative database of echocardiographic variables for monitoring growth and cardiovascular function. METHODS: C57BL/6J fetal mice were scanned in utero using an ultrasound system with a 15-MHz linear phased-array transducer. Pregnant mothers were anesthetized with 1% isoflurane mixed with 100% oxygen. Quantitative variables for monitoring fetal growth and cardiac function were obtained in several imaging planes and modalities. RESULTS: Fetal growth measurements increased linearly. Inflow velocities showed significant A-wave dominance. The E wave progressively increased during development. Cardiac function was best assessed through M-mode analysis, but short-axis images were difficult to obtain. Spectral Doppler was readily obtained and the myocardial performance index was calculated. CONCLUSIONS: These results provide an essential foundation for the evaluation of cardiovascular defects in mutagenized and transgenic mice.

Animals↗

Temporal profile of forced expiratory lung function in allergen-challenged Brown-Norway rats.

The Brown-Norway rat is often used to study the allergic pulmonary response. However, relatively little is known about the delayed phase reactions after allergen challenge in this species. To evaluate the temporal changes in lung function and elucidate the mechanisms involved in the delayed phase response, Brown-Norway rats were sensitized and challenged to aerosolized ovalbumin and lung functions were measured by forced expiratory maneuvers and forced oscillation for up to 10 days after a single antigen challenge. Statistically significant (P < 0.05) reductions in inspiratory capacity, forced vital capacity, functional residual capacity, peak expiratory flow and maximum mid-expiratory flow and increases in respiratory system resistance and elastance were seen by 1 to 3 days after ovalbumin challenge that returned to baseline by 10 days. The reductions in lung function after ovalbumin challenge were blocked by the corticosteroid, betamethasone (1 mg/kg, p.o.). Histological evaluation of lung tissue of sensitized rats demonstrated evidence of interstitial pulmonary edema, an increase in tissue eosinophils and an increase in Periodic Acid Schiff-positive cells in the airway epithelium. Bronchoalveolar lavage fluid samples showed large numbers of eosinophils and increased mucin content up to 6 days after antigen challenge. There was also an increase in wet-to-dry lung weight ratio in the lungs of sensitized rats after antigen. These results demonstrate that prolonged reductions in lung function occur after a single antigen challenge in Brown-Norway rats that is probably due to inflammatory processes producing interstitial pulmonary edema, mucus secretion and cellular influx into the lungs.

Allergens↗

The analysis of soil cores polluted with certain metals using the Box-Cox transformation.

To define the soil properties for a given area or country including the level of pollution, soil survey and inventory programs are essential tools. Soil data transformations enable the expression of the original data on a new scale, more suitable for data analysis. In the computer-aided interactive analysis of large data files of soil characteristics containing outliers, the diagnostic plots of the exploratory data analysis (EDA) often find that the sample distribution is systematically skewed or reject sample homogeneity. Under such circumstances the original data should be transformed. The Box-Cox transformation improves sample symmetry and stabilizes spread. The logarithmic plot of a profile likelihood function enables the optimum transformation parameter to be found. Here, a proposed procedure for data transformation in univariate data analysis is illustrated on a determination of cadmium content in the plough zone of agricultural soils. A typical soil pollution survey concerns the determination of the elements Be (16 544 values available), Cd (40 317 values), Co (22 176 values), Cr (40 318 values), Hg (32 344 values), Ni (34 989 values), Pb (40 344 values), V (20 373 values) and Zn (36 123 values) in large samples.

Agriculture↗

Spacial perception and spatial memory in children with benign childhood epilepsy with centro-temporal spikes (BCECTS).

Despite the benign prognosis regarding the response of seizures to treatment, some evidence now exists that patients with benign childhood epilepsy with centro-temporal spikes (BCECTS) may have neuropsychological deficits sometimes leading to academic underachievement. There is, however, no general agreement on the exact profile of functions disturbed. This study was designed to identify significant deficits in spatial perception and memory in children with BCECTS (ages 6-10 years) compared with healthy controls matched for age, sex and socioeconomic status. The neuropsychological test battery administered consisted of the HAWIK-III, the "Tübinger Luria Christensen Neuropsychological Test Set for Children", the "Kaufman Assessment Battery for Children" and the "Differential Neuropsychological Test". Twenty-two patients and 22 control subjects completed all tests. Children with BCECTS exhibited significant deficits in higher functions of spatial perception, including spatial orientation, as well as in basal and complex spatial memory. Deficits were independent of the lateralization of the epileptogenic foci and independent of anti-convulsive drug treatment.

Case-Control Studies↗

Suitability of the health and social care resources for persons requiring long-term care in Spain: an empirical approach.

The objective of this paper is to examine the suitability of specific facilities for dependent persons for meeting users' needs. A total of 1265 users of social and health facilities for dependent persons were interviewed in a study carried out in a typical southern European region with a Mediterranean welfare system: the Valencia Autonomous Region in Spain. Data were obtained on users' socio-demographic profile, health, functional dependence, cognition, social support and housing suitability. Based on these data and the institutional definitions of the specific facilities for dependent persons, the suitability index was drawn up for each facility and suitability was evaluated using discriminant analysis. The results give a high suitability index for most of the facilities (between 0.661 for Units for Home Hospitalisation and 1.000 for Units for Psychiatric Hospitalisation). But a significant percentage of patients (17% in Hospitals for Chronically Ill and Long-stay Patients) could be cared for in different facilities to the ones they actually use.

Aged↗

A randomized, double-blind, crossover study of the use of transcutaneous spinal electroanalgesia in patients with pain from chronic critical limb ischemia.

Transcutaneous spinal electroanalgesia (TSE) uses two electrodes placed over the skin of the dorsal spine to deliver pulses of short wavelength, high frequency, and relatively high voltage to the spinal cord without causing paresthesia. TSE has been used to treat pain and may improve limb blood flow. This randomized, double-blind, crossover study assessed the effect of TSE on microcirculation, pain, and activity in 8 patients (3 men, 5 women, median age 66.5 years, range 62-76 years) with chronic critical limb ischemia (CLI). After a one-week baseline period, patients used an active or inactive TSE machine for one hour daily for one week. Following a week of no stimulation, patients repeated the week of treatment with an identical matched machine. Daily use of TSE for one week did not improve microcirculatory perfusion (transcutaneous oxygenation), pain (verbal rating scale, McGill Pain Questionnaire), physical function (Functional Limitations Profile), mood (Beck Depression Inventory, Beck Anxiety Inventory), or sleep. There was no patient preference for the active TSE machines. This study showed that TSE administered daily for one week did not improve microcirculation, pain, or activity in patients with chronic CLI.

Aged↗

Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer's disease.

Mild cognitive impairment (MCI) defines a group of otherwise healthy elderly subjects with a markedly elevated risk of developing Alzheimer's disease (AD). In the search for biomarkers of MCI, we assessed whether MCI shares neurochemical abnormalities with AD in areas affected early in the course of the disease. As a secondary study aim, we tested to what extent neurochemical findings reflect neuropsychological deficits. Proton spectroscopy was performed in 19 MCI patients, 18 AD patients and 22 age and gender matched controls (CON) within the parietal gray and white matter (PWM and PGM) and the hippocampus (HIP). The cognitive test battery used included measures compiled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The N-acetyl-aspartate to creatine ratio (NAA/Cr) was significantly reduced in the HIP of MCI and AD compared with CON (p < 0.05). Only AD patients showed parietal abnormalities, namely significantly elevated myoinositol (mI/Cr and mI/NAA) in PGM, reduced NAA/Cr and elevated mI/NAA in PWM. MCI subjects were significantly impaired in categorical verbal fluency (VF) (p < 0.001) and delayed verbal recall (DVR) (p < 0.001). VF was positively correlated with hippocampal NAA/Cr (p < 0.05) and parietal mI/NAA (p < 0.05). In summary, this study demonstrates shared neurobiological hippocampal abnormalities in MCI and AD, whereas parietal lobe neurochemical profiles and functions were normal in MCI. Thus, biological evidence is provided that MCI represents a precursor stage of AD. Moreover, multivoxel 1H MRS may enable an objective staging of the neurodegenerative process underlying the age-dependent cognitive deficits eventually leading to dementia.

Aged↗

The functional expression of mu opioid receptors on sensory neurons is developmentally regulated; morphine analgesia is less selective in the neonate.

Opioid requirements in neonatal patients are reported to be lower than older infants and this may be a reflection of the developmental regulation of opioid receptors. In this study we have investigated the postnatal regulation of Mu opioid receptor (MOR) function in both rat lumbar dorsal root ganglion (DRG) cultures and behavioural mechanical and thermal reflex tests in rat pups. Immunostaining with MOR and selective neurofilament (NF200) antibodies was combined with calcium imaging of MOR function in cultured neonatal and adult rat dorsal root ganglion cells. Calcium imaging showed that a significantly greater number of neonatal DRG neurons expressed functional MOR compared to adult (56.5+/-3.4 versus 39.9+/-1.5%, n=8, mean+/-SEM, P<0.001). This expression is confined to the large, neurofilament positive sensory neurons, while expression in small, nociceptive, neurofilament negative neurons remains unchanged. Sensory threshold testing in rat pups showed that the analgesic potency of systemic morphine to mechanical stimulation is significantly greater in the neonate and declines with postnatal age. Morphine analgesic potency in thermal nociceptive tests did not change with postnatal age. These experiments show that the MOR expressed on large DRG neurons in neonates are functional and are subject to postnatal developmental regulation. This changing functional receptor profile is consistent with greater morphine potency in mechanical, but not thermal, sensory tests in young animals. These results have important clinical implications for the use of morphine in neonates and provide a possible explanation for the differences in morphine requirements observed in the youngest patients.

Age Factors↗

Trends in pharmacogenomics of drugs used in the treatment of asthma.

Pharmacogenetic studies of drugs used in the treatment of asthma have produced a few examples of reduced response in patients carrying specific genotypes in genes involved in the action of beta-2 agonists or leukotriene modifiers. Other candidate genes related to these drugs, as well as glucocorticoids, theophilline, anticholinergics, antihistaminics, and drug-metabolizing enzymes, may be proposed. Statistical power and population stratification may be issues of importance in case-control association studies. Future developments include expanded gene knowledge from asthma genetic and genomic studies, the development of new preventive and curative treatments, multiple contemporary genotyping methods for pharmacogenetically important genes in a given individual, and the construction of asthma functional pharmacogenomic profiles. In conclusion, it seems that asthma pharmacogenetic studies need to be replicated in prospective clinical trials in different populations with a large number of subjects being genotyped. It is suggested that large clinical trials which are proposed for asthma drugs experimentation should include a pharmacogenetic study as well.

Animals↗

Biochemical analysis of the TPS-b subfamily reveals a cineole-centered monoterpene biosynthetic module in Medicago truncatula.

Terpenoids constitute one of the largest and most structurally diverse classes of plant specialized metabolites, with diversity generated by terpene synthases (TPSs) and downstream tailoring enzymes. In Medicago truncatula, the TPS-b subfamily comprises five putative synthases, two of which are embedded within a previously uncharacterized genomic locus containing a cytochrome P450 (CYP) and a BAHD-type acyltransferase. Here, we present a comprehensive biochemical analysis of the M. truncatula TPS-b subfamily and define a cineole-centered monoterpene biosynthetic module. Heterologous expression and in vitro assays with multiple prenyl diphosphate substrates revealed three catalytically active TPS-b enzymes with distinct substrate preferences and product profiles. MtTPS4 functions as a dedicated (E)-&#x3b2;-ocimene synthase, whereas MtTPS15 exhibits substrate-dependent bifunctionality, producing (E)-&#x3b2;-ocimene from geranyl diphosphate and &#x3b1;-farnesene from farnesyl diphosphate. MtTPS36 generates 1,8-cineole as the predominant product alongside &#x3b1;-terpineol from geranyl and neryl diphosphate. Genome analysis revealed that MtTPS36 is colocalized with a cytochrome P450 belonging to the CYP736 family. Biochemical characterization of this CYP identified a previously undescribed plant cineole hydroxylase that catalyzes oxidation of 1,8-cineole to yield 2&#x3b1;-hydroxy-1,8-cineole (also known as 2-exo-hydroxy-1,8-cineole), establishing a TPS-CYP biosynthetic module. These results define the gene-to-metabolite relationships within the TPS-b subfamily in M. truncatula and expand the known enzymatic biosynthetic capacity underlying oxygenated monoterpene biosynthesis in plants.

1,8-Cineole↗

Comparative metabonomics of differential hydrazine toxicity in the rat and mouse.

Interspecies variation between rats and mice has been studied for hydrazine toxicity using a novel metabonomics approach. Hydrazine hydrochloride was administered to male Sprague-Dawley rats (30 mg/kg, n = 10 and 90 mg/kg, n = 10) and male B6C3F mice (100 mg/kg, n = 8 and 250 mg/kg, n = 8) by oral gavage. In each species, the high dose was selected to produce the major histopathologic effect, hepatocellular lipid accumulation. Urine samples were collected at sequential time points up to 168 h post dose and analyzed by 1H NMR spectroscopy. The metabolites of hydrazine, namely diacetyl hydrazine and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid (THOPC), were detected in both the rat and mouse urine samples. Monoacetyl hydrazine was detected only in urine samples from the rat and its absence in the urine of the mouse was attributed to a higher activity of N-acetyl transferases in the mouse compared with the rat. Differential metabolic effects observed between the two species included elevated urinary beta-alanine, 3-D-hydroxybutyrate, citrulline, N-acetylcitrulline, and reduced trimethylamine-N-oxide excretion unique to the rat. Metabolic principal component (PC) trajectories highlighted the greater degree of toxic response in the rat. A data scaling method, scaled to maximum aligned and reduced trajectories (SMART) analysis, was used to remove the differences between the metabolic starting positions of the rat and mouse and varying magnitudes of effect, to facilitate comparison of the response geometries between the rat and mouse. Mice followed "biphasic" open PC trajectories, with incomplete recovery 7 days after dosing, whereas rats followed closed "hairpin" time profiles, indicating functional reversibility. The greater magnitude of metabolic effects observed in the rat was supported by the more pronounced effect on liver pathology in the rat when compared with the mouse.

Administration, Oral↗

Involvement of cross-genus phages in bacterial resistance to chlorine disinfection.

Chlorine disinfection resistance in pathogenic microorganisms poses severe environmental concerns and public health risks. While phages play critical roles in host adaptation to environmental stress, how poly-host phages contribute to bacterial resistance to chlorine disinfectants remains poorly understood. Here, we investigated shifts in the population dynamics, transcriptional profiles, and function potentials of cross-genus phage-bacterial communities under exposure to chlorine disinfectants in a continuously operated anaerobic-anoxic-oxic system over a 92-day period, using integrated metagenomic and metatranscriptomic approaches. In the presence and absence of chlorine disinfectants, the genomic abundance and diversity of phage and bacterial communities showed similar variation trends, and the community structures of both exhibited clear differences. A strong significant positive correlation was observed between phage and bacterial diversity under chlorine exposure (R&#x202f;=&#x202f;0.975, p&#x202f;=&#x202f;0.00,057), whereas no significant correlation was detected in the absence of chlorine disinfection (R&#x202f;=&#x202f;-0.314, p&#x202f;=&#x202f;0.613), suggesting that chlorine disinfectants may enhance phage-bacteria interactions. Host-associated phages exhibited high consistency with their corresponding putative hosts in terms of genomic abundance (M2&#x202f;=&#x202f;0.0945, p&#x202f;=&#x202f;0.001) and transcript abundance (M2&#x202f;=&#x202f;0.3668, p&#x202f;=&#x202f;0.001), and they were also significantly correlated with cross-genus phages in both genomic abundance (R&#x202f;=&#x202f;0.97, p&#x202f;<&#x202f;2.2e-16) and transcript abundance (R&#x202f;=&#x202f;0.83, p&#x202f;<&#x202f;2.2e-16), which collectively suggests the critical role of cross-genus phages in the resistance of microbial communities to chlorine disinfectants. Bipartite association network analysis shows that cross-genus phages carry highly homologous genes to their putative hosts and may be involved in the horizontal transfer of these genes among bacteria. These homologous genes are involved in DNA repair, redox balance regulation, environmental stress adaptation and efflux pump functions, suggesting a synergistic role between cross-genus phages and their putative hosts in chlorine resistance. Our findings reveal that cross-genus phages can contribute to the resistance of bacterial communities to chlorine disinfectants, providing the theoretical foundation for evaluating the role of poly-host phages in microbial communities.

Chlorine resistance↗

Mammalian phospholipase Czeta induces oocyte activation from the sperm perinuclear matrix.

Mammalian sperm-borne oocyte activating factor (SOAF) induces oocyte activation from a compartment that engages the oocyte cytoplasm, but it is not known how. A SOAF-containing extract (SE) was solubilized from the submembrane perinuclear matrix, a domain that enters the egg. SE initiated activation sufficient for full development. Microinjection coupled to tandem mass spectrometry enabled functional correlation profiling of fractionated SE without a priori assumptions about its chemical nature. Phospholipase C-zeta (PLCzeta) correlated absolutely with activating ability. Immunoblotting confirmed this and showed that the perinuclear matrix is the major site of 72-kDa PLCzeta. Oocyte activation was efficiently induced by 1.25 fg of sperm PLCzeta, corresponding to a fraction of one sperm equivalent (approximately 0.03). Immunofluorescence microscopy localized sperm head PLCzeta to a post-acrosomal region that becomes rapidly exposed to the ooplasm following gamete fusion. This multifaceted approach suggests a mechanism by which PLCzeta originates from an oocyte-penetrating assembly--the sperm perinuclear matrix--to induce mammalian oocyte activation at fertilization.

Animals↗

Group A Streptococcus transcriptome dynamics during growth in human blood reveals bacterial adaptive and survival strategies.

The molecular basis for bacterial responses to host signals during natural infections is poorly understood. The gram-positive bacterial pathogen group A Streptococcus (GAS) causes human mucosal, skin, and life-threatening systemic infections. During the transition from a throat or skin infection to an invasive infection, GAS must adapt to changing environments and host factors. To better understand how GAS adapts, we used transcript profiling and functional analysis to investigate the transcriptome of a wild-type serotype M1 GAS strain in human blood. Global changes in GAS gene expression occur rapidly in response to human blood exposure. Increased transcription was observed for many genes that likely enhance bacterial survival, including those encoding superantigens and host-evasion proteins regulated by a multiple gene activator called Mga. GAS also coordinately expressed genes involved in proteolysis, transport, and catabolism of oligopeptides to obtain amino acids in this protein-rich host environment. Comparison of the transcriptome of the wild-type strain to that of an isogenic deletion mutant (DeltacovR) mutated in the two-component regulatory system designated CovR-CovS reinforced the hypothesis that CovR-CovS has an important role linking key biosynthetic, catabolic, and virulence functions during transcriptome restructuring. Taken together, the data provide crucial insights into strategies used by pathogenic bacteria for thwarting host defenses and surviving in human blood.

DNA, Complementary↗

The steady-state properties of an ion exchange membrane with mobile sites.

A study of the properties of the steady states of a system composed of two solutions separated by an ion exchange membrane having mobile sites is presented. It is assumed that the membrane is impermeable to coions; the solutions contain no more than two species of counterions, both of the same valence; and no flow of bulk solution occurs. Assuming that all ions are completely dissociated, behave ideally, and have constant mobilities throughout the membrane, explicit expressions are derived for the steady states of the electric current, individual fluxes, and concentration profiles as functions of the compositions of the solutions and of the difference of electric potential between them. The derived expressions are compared with those for an ion exchange membrane having fixed sites; and it is found that the expressions of certain quantities, such as the difference of electric potential between the two solutions for zero current or the ratio of the fluxes of the counterions as functions of the external parameters of the system, are the same for both types of membranes. On the other hand, differences in the behavior of the two types of membranes are found from other expressions-for example, the current-voltage relationship. In the mobile site ion exchanger the current asymptotically approaches finite limiting values for high positive and negative voltages while in the fixed site ion exchanger it is the conductance which approaches finite limiting values.

Biological Transport↗