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At least 73 records · Page 4Linked to original sources

PubMed2006

Dual stretch responses of mHCN2 pacemaker channels: accelerated activation, accelerated deactivation.

Mechanoelectric feedback in heart and smooth muscle is thought to depend on diverse channels that afford myocytes a mechanosensitive cation conductance. Voltage-gated channels (e.g., Kv1) are stretch sensitive, but the only voltage-gated channels that are cation permeant, the pacemaker or HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, have not been tested. To assess if HCN channels could contribute to a mechanosensitive cation conductance, we recorded I(HCN) in cell-attached oocyte patches before, during, and after stretch for a range of voltage protocols. I(mHCN2) has voltage-dependent and instantaneous components; only the former was stretch sensitive. Stretch reversibly accelerated hyperpolarization-induced I(mHCN2) activation (likewise for I(spHCN)) and depolarization-induced deactivation. HCN channels (like Kv1 channels) undergo mode-switch transitions that render their activation midpoints voltage history dependent. The result, as seen from sawtooth clamp, is a pronounced hysteresis. During sawtooth clamp, stretch increased current magnitudes and altered the hysteresis pattern consistent with stretch-accelerated activation and deactivation. I(mHCN2) responses to step protocols indicated that at least two transitions were mechanosensitive: an unspecified rate-limiting transition along the hyperpolarization-driven path, mode I(closed)-->mode II(open), and depolarization-induced deactivation (from mode I(open) and/or from mode II(open)). How might this affect cardiac rhythmicity? Since hysteresis patterns and "on" and "off" I(HCN) responses all changed with stretch, predictions are difficult. For an empirical overview, we therefore clamped patches to cyclic action potential waveforms. During the diastolic potential of sinoatrial node cell and Purkinje fiber waveforms, net stretch effects were frequency dependent. Stretch-inhibited (SI) I(mHCN2) dominated at low frequencies and stretch-augmented (SA) I(mHCN2) was progressively more important as frequency increased. HCN channels might therefore contribute to either SI or SA cation conductances that in turn contribute to stretch arrhythmias and other mechanoelectric feedback phenomena.

Animals↗

PubMed1976

[Sugar consumption and prenatal acceleration. II. Studies on the etiology and pathophysiology of secular prenatal acceleration].

The pathophysiologic considerations support the causal relationship between the secular trend of sugar consumption in industrialized society and the development of prenatal acceleration, which is evident on the basis of epidemiological data. The excessive consumption of sugar and the other quickly absorbed "refined" carbohydrates enhances the hormonogenic effect of food which is also potentiated by the proteins. Together with the caloric overloading, provoked also by the excess in fat, characteristic for the affluent society, the excessive sugar consumption enhances in the pregnant women obesity and "protodiabetes" (PFEIFFER), in the predisposed child the tendency to hyperinsulinism with its consequences. In a prediabetic mother with normal glucose-tolerance the regularly repeated postprandial overfloating of the fetus with maternal glucose changes the feto-maternal hormonal regulation and enhances together with the overloading of substrate, i.e. energy and elements of biosyntheses, the accelerated fetal growth and especially the obesity of the large baby.

Birth Weight↗

PubMedDate not supplied

[Biological model of the accelerated aging. I. Dynamics of spontaneous mutation in spermatogenesis in SAM mice (senescence-accelerated mouse)].

We studied the dynamics of age-related cytogenetic changes in the developing male germ cells of mice prone to accelerated senescence (strain SAMP1) and mice resistant to accelerated senescence (strain SAMR1) by counting the spermatogonial and meiotic micronuclei and testing the defects of the spermatozoon head shape. In these animals, the accumulation of germinative mutations has a nonlinear pattern. During the entire ontogenesis of SAMP1 mice, the frequency of circular spermatids with micronuclei corresponded to the level observed upon induced mutagenesis.

Aging↗

PubMedDate not supplied

[Biological model of accelerated senescence. II. Age-related changes in the number of developing male germ cells and Sertoli cells in gonads of senescence-accelerated mice].

It was shown that in immature three- to four-week-old mice prone to accelerated senescence (SAMP1 strain), the number of spermatogonia, pachytene spermatocytes, and circular spermatids exceeded that in mice resistant to accelerated senescence (SAMR1 strain) by more than two times. Differences were found in the pattern of age-related changes in the number of meiotic and postmeiotic cells in the sexually mature SAMP1 and SAMR1 mice. In the gonads of SAMP1 and SAMR1 mice, the number of Sertoli cells was unstable.

Aging↗

PubMedDate not supplied

[A biological model of accelerated aging. III. Histological characteristics of age-related changes of spermatogenic epithelium in mice SAM (senescence-accelerated mouse)].

The data characterizing the age-related morphological changes in the spermatogenic epithelium of SAMP1 (senescence-accelerated prone) and SDAMR1 (senescence-accelerated resistant) mice are presented. In many tubules, "early spermatogenesis" was accompanied by the formation of many morphologically abnormal germ cells on histological sections of the gonads of sexually immature (three-four weeks) mice of both strains. At this stage, destructive processes in the spermatogenic epithelium were more pronounced in SAMR1 mice. In sexually mature (two-three months) SAMP1 and SAMR1 mice, spermatogenesis as a whole proceeded normally. The first signs of regressive changes in the inner structure of most tubules (disintegration, detachment of spermatogenic epithelium from basal membrane) and morphology of germ cells (pycnosis, nuclear and cytoplasmic vacuolization) were found in SAMP1 mice at the age of six-seven months. In the older age groups (9-10 and 12-15 months), all types of spermatogenic cells were represented in both SAMP1 and SAMR1 mice, but most of these cells were atypical. Mitotic figures were recorded in a population of highly differentiated Sertoli cells.

Aging↗

PubMed1994

Expression of a hybrid complement regulatory protein, membrane cofactor protein decay accelerating factor on Chinese hamster ovary. Comparison of its regulatory effect with those of decay accelerating factor and membrane cofactor protein.

C activation on the cell surface is supposedly regulated by membrane cofactor protein (MCP) and decay accelerating factor (DAF). These are complementary in function: MCP acts as a cofactor in factor I-mediated C3b and C4b inactivation, thus preventing the assembly of C3 convertases, whereas DAF accelerates spontaneous decay of the assembled C3 convertase. In this report, a hybrid MCP-DAF was expressed on Chinese hamster ovary cells by transfecting cDNA, and its regulatory activity was compared with those of MCP and DAF transfectants and with a transfectant expressing both MCP and DAF (MCP + DAF). The C3 deposition on sensitized CHO cells through activation of the classical pathway was blocked to a different degree with these transfectants, the order being MCP + DAF > DAF > hybrid MCP-DAF > MCP. Likewise, the C3 deposition via the alternative pathway was blocked efficiently in the order hybrid > MCP + DAF > MCP. The C-mediated cytolysis of CHO cells virtually reflected the degree of C3 fragment deposition. The MCP-DAF transfectant acquired additive protective activity against alternative pathway-mediated C3 deposition and cytolysis but was less potent in circumventing classical pathway attack than cells that expressed DAF alone or DAF + MCP. Hybrid MCP-DAF may be useful for alleviating C-mediated cell damage, especially via the alternative pathway.

Animals↗

PubMed1980

Thresholds for detection of constant rotary acceleration during vibratory rotary acceleration.

The effects of vibratory angular acceleration (aR) on detection thresholds for constant aR in a dynamic flight simulator are reported in three experiments. Detection thresholds were determined for 10 pilots and four nonpilots using a random, double-staircase procedure while the subjects sat erect in a device which rotated about an earth-vertical axis. Constant aRs were presented for 0.5 and 1.0 s with concurrent, vibratory aR at 1 and 5 Hz, and thresholds with no vibratory aR were established. The thresholds were obtained while the subjects observed a visual reference in the enclosed cockpit in two experiments and in total darkness in a third. The results confirmed earlier experiments showing an inverse relationship between the duration of constant aR and detection threshold and showed that the detection thresholds in darkness were higher than with a visual reference present. Two analyses of variance revealed no significant differences in thresholds across the three vibration conditions. These results indicate that vibratory aRs of fairly high levels can be present in a dynamic flight stimulator without masking the pilot's ability to detect either maneuver or disturbance motions.

Acceleration↗

PubMed1993

An acceleration of age-related increases in levels of the beta-subunit of nerve growth factor in selected tissues from senescence-accelerated mice (SAM-P/8).

An investigation was made of age-related changes in levels of the beta-subunit of nerve growth factor (beta-NGF) in selected tissues and of testosterone in serum in senescence-accelerated mice (SAM-P/8) and in the control mice (senesence-resistant mice; SAM-R/1). The concentrations of testosterone in serum were higher in SAM-P/8 than in SAM-R/1 at ages 2 and 4 mo. The level of beta-NGF in the thymus from SAM-R/1 increased with age, resulting in a statistically significant difference in its level between mice at ages 2 and 12 mo. By contrast, there was a transient increase in SAM-P/8 at around age 4 mo with a subsequent decrease. Consequently, significant differences were apparent in levels of beta-NGF between the two types of mouse at ages 2 and 4 mo. Similar results were obtained in the adrenal gland and testis. Compared to SAM-R/1 at age 2 mo, the average concentrations of beta-NGF in the hypophysis were higher in SAM-R/1 at ages 4 and 8 mo and in SAM-P/8 at all ages. In other tissues tested, no remarkable differences were detected. Our present results indicate that, in SAM-P/8, the elevation in levels of beta-NGF in the thymus, adrenal gland, testis, and hypophysis occurs in the early period of life compared to the control mice. Possible dysfunction of the disorder of hypophysis is discussed.

Adrenal Glands↗

PubMed2002

Dose-intensified accelerated vindesine-ifosfamide-cisplatin (VIP) chemotherapy followed by high-dose accelerated hyperfractionated radiotherapy in patients with pathologically proven stage IIIB non-small cell lung cancer: a feasibility study.

This study shows the feasibility of accelerated vindesine-ifosfamide-cisplatin chemotherapy, immediately followed by intensive radiotherapy to the residual tumour in responding patients, in 16 patients with pathologically proven stage IIIB non-small lung cancer. All toxicities were reversible, with only two of ten patients experiencing grade 3 oesophagitis, no treatment-related deaths and no serious late effects.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Attomole detection of 3H in biological samples using accelerator mass spectrometry: application in low-dose, dual-isotope tracer studies in conjunction with 14C accelerator mass spectrometry.

This is the first demonstration of the use of accelerator mass spectrometry (AMS) as a tool for the measurement of 3H with attomole (10(-18) mol) sensitivity in a biological study. AMS is an analytical technique for quantifying rare isotopes with high sensitivity and precision and has been most commonly used to measure 14C in both the geosciences and more recently in biomedical research. AMS measurement of serially diluted samples containing a 3H-labeled tracer showed a strong correlation with liquid scintillation counting. The mean coefficient of variation of 3H AMS based upon the analysis of separately prepared aliquots of these samples was 12%. The sensitivity for 3H detection in tissue, protein, and DNA was approximately 2-4 amol/mg of sample. This high sensitivity is comparable to detection limits for 14C-labeled carcinogens using 14C AMS and demonstrates the feasibility of 3H AMS for biomedical studies. One application of this technique is in low-dose, dual-isotope studies in conjunction with 14C AMS. We measured the levels of 3H-labeled 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 14C-labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in rat liver tissue and bound to liver DNA and protein 4.5 h following acute administration of individual or coadministered doses in the range of 4-5100 pmol/kg of body weight. Levels of PhIP and MeIQx in whole tissue and bound to liver protein were dose-dependent. MeIQx-protein and -DNA adduct levels were higher than PhIP adduct levels, which is consistent with their respective carcinogenicity in this organ. Coadministration of PhIP and MeIQx did not demonstrate any measurable synergistic effects compared to administration of these compounds individually. These studies demonstrate the application of AMS for the low-level detection of 3H in small biological samples and for its use in conjunction with 14C AMS for dual-labeling studies.

Animals↗

PubMed2004

Transgenic expression in pig hearts of both human decay-accelerating factor and human membrane cofactor protein does not provide an additional benefit to that of human decay-accelerating factor alone in pig-to-baboon xenotransplantation.

This study investigated whether the coexpression of human decay-accelerating factor (hDAF) and human membrane cofactor protein (hMCP) on porcine organs provides an additional benefit to that of hDAF alone to prevent rejection. Heterotopic heart xenotransplantation was performed in baboons with either hDAF (n=5) or hDAF/hMCP (n=5) transgenic pig organs. The only immunosuppression given was GAS914 (a soluble Gal [alpha1-3] Gal polymer) and cyclosporine A. With the exception of one hDAF organ that failed from a left atrium thrombosis, all xenografts developed acute humoral xenograft rejection. Acute humor xenograft rejection occurred at a median time of 152 hr in hDAF hearts and 162 hr in hDAF/hMCP organs. Recipients of hDAF or hDAF/hMCP hearts did not differ in their patterns of serum antiporcine antibodies or in plasma levels of the soluble terminal complement complex sC5b-9. It is concluded that in this pig-to-baboon heterotopic heart transplant, model expression of hDAF/hMCP does not provide an additional benefit in prevention of rejection to that of hDAF alone.

Animals↗

PubMed1988

Metabolism of senile amyloid precursor and amyloidogenesis. Age-related acceleration of apolipoprotein A-II clearance in the senescence accelerated mouse.

Serum clearance kinetics of murine senile amyloid-related high-density lipoprotein (HDL) apoprotein A-II (apo A-II) was examined in the senescence-accelerated mouse, prone (SAM-P/1) and resistant (SAM-R/1), with 125I-HDL purified from both strains. In SAM-R/1, with 125I-HDL purified from both strains. In SAM-R/1, the serum half-life of apo A-II was not altered with increasing age and was practically identical to that of apo A-I. In 2-month old SAM-P/1, the serum half-life of both apo A-I and apo A-II was generally the same as observed in SAM-R/1. However, at age 6 and 12 months, in SAM-P/1, the serum half-life of apo A-II decreased significantly and was less than that of apo A-I. These age-related changes in apo A-II clearance kinetics were observed regardless of the HDL donor. The authors also examined the tissue distribution of injected apo A-II, using 125I-apo A-II reconstituted HDL, and found that several organs trapped more 125I radioactivity in old SAM-P/1 than in young mice. This evidence strongly suggests that age-related changes in the metabolic environment of apo A-II might affect senile amyloidogenesis in SAM-P/1.

Aging↗

PubMedDate not supplied