We have characterised the apoptotic defects in cells null for cytochrome c (cyt c-/-). Such cells treated with staurosporine (STS) exhibited translocation to the mitochondria and activation of the ...proapoptotic signalling molecule Bax but failed to release Smac/DIABLO from these organelles, judged by both confocal microscopy and Western blotting. While reference cells expressing cytochrome c released both it and Smac/DIABLO under a variety of conditions of apoptotic induction, we have never observed release of Smac/DIABLO from cyt c-/- cells. We eliminate the possibility that proteasomal degradation of cytosolically localised Smac/DIABLO is responsible for our failure to visualise the protein outside the mitochondria. Our findings indicate an unanticipated nexus between release of cytochrome c and Smac/DIABLO from mitochondria, previously thought to be a more or less synchronised event early in apoptosis. We suggest that the failure of cyt c-/- cells to release Smac/DIABLO after recruitment of Bax to mitochondria represents an extreme manifestation of some inherent difference in the regulation of release of these two proteins from mitochondria.
Although neural progenitor cells (NPCs) may provide a source of new neurons to alleviate neural trauma, little is known about their electrical properties as they differentiate. We have previously ...shown that single NPCs from the adult rat hippocampus can be cloned in the presence of heparan sulphate chains purified from the hippocampus, and that these cells can be pushed into a proliferative phenotype with the mitogen FGF2 Chipperfield, H., Bedi, K.S., Cool, S.M. & Nurcombe, V. (2002) Int. J. Dev. Biol., 46, 661–670. In this study, the active and passive electrical properties of both undifferentiated and differentiated adult hippocampal NPCs, from 0 to 12 days in vitro as single‐cell preparations, were investigated. Sparsely plated, undifferentiated NPCs had a resting membrane potential of ≈ −90 mV and were electrically inexcitable. In > 70%, ATP and benzoylbenzoyl‐ATP evoked an inward current and membrane depolarization, whereas acetylcholine, noradrenaline, glutamate and GABA had no detectable effect. In Fura‐2‐loaded undifferentiated NPCs, ATP and benzoylbenzoyl‐ATP evoked a transient increase in the intracellular free Ca2+ concentration, which was dependent on extracellular Ca2+ and was inhibited reversibly by pyridoxalphosphate‐6‐azophenyl‐2′‐4′‐disulphonic acid (PPADS), a P2 receptor antagonist. After differentiation, NPC‐derived neurons became electrically excitable, expressing voltage‐dependent TTX‐sensitive Na+ channels, low‐ and high‐voltage‐activated Ca2+ channels and delayed‐rectifier K+ channels. Differentiated cells also possessed functional glutamate, GABA, glycine and purinergic (P2X) receptors. Appearance of voltage‐dependent and ligand‐gated ion channels appears to be an important early step in the differentiation of NPCs.
We present a detailed abundance analysis of the three brightest member stars at the top of the giant branch of the ultrafaint dwarf (UFD) galaxy Grus II. All stars exhibit a higher than expected ...Mg/Ca ratio compared to metal-poor stars in other UFD galaxies and in the Milky Way (MW) halo. Nucleosynthesis in high-mass ( 20 M ) core-collapse supernovae has been shown to create this signature. The abundances of this small sample (three) stars suggests the chemical enrichment of Grus II could have occurred through substantial high-mass stellar evolution, and is consistent with the framework of a top-heavy initial mass function. However, with only three stars it cannot be ruled out that the abundance pattern is the result of a stochastic chemical enrichment at early times in the galaxy. The most metal-rich of the three stars also possesses a small enhancement in rapid neutron-capture (r-process) elements. The abundance pattern of the r-process elements in this star matches the scaled r-process pattern of the solar system and r-process enhanced stars in other dwarf galaxies and in the MW halo, hinting at a common origin for these elements across a range of environments. All current proposed astrophysical sites of r-process element production are associated with high-mass stars, thus the possible top-heavy initial mass function of Grus II would increase the likelihood of any of these events occurring. The time delay between the and r-process element enrichment of the galaxy favors a neutron star merger as the origin of the r-process elements in Grus II.
Abstract Background Degenerative hip disorders often coexist with degenerative changes of the lumbar spine. Limited data on this patient population suggests inferior functional improvement and pain ...relief after surgical management. The purpose of this study is to compare the rates of prosthetic-related complication following primary total hip arthroplasty (THA) in patients with and without prior lumbar spine arthrodesis (SA). Methods 811,601 Medicare patients undergoing primary THA were identified and grouped by length of prior SA (no fusion, 1-2 levels fused S-SAHA, ≥3 levels fused L-SAHA). Results Compared to controls, patients with prior SA had significantly higher rates of complications including dislocation (control:2.36%; S-SAHA:4.26%; L-SAHA:7.51%), revision (control:3.43%, S-SAHA:5.55%, L-SAHA:7.77%), loosening (control:1.33%, S-SAHA:2.10%, L-SAHA:3.04%) and any prosthetic-related complication (control:7.33%, S-SAHA:11.15% (RR 1.52), L-SAHA:14.16% (RR 1.93)) within 24 months (p<0.001). Conclusion The interplay of coexisting degenerative hip and spine disease deserves further attention of both arthroplasty and spine surgeons.
To investigate how moderate and/or high levels of DNA fragmentation (DFI), as measured by the sperm chromatin structure assay (SCSA), affect either IVF or IVF with intracytoplasmic sperm injection ...(ICSI) fertilization, cleavage, blastulation, implantation, and pregnancy.
Retrospective clinical study.
Academic human reproduction laboratory.
Eighty-nine couples undergoing IVF with conventional fertilization or ICSI.
Sperm chromatin structure assay testing (SCSA) of semen aliquot taken from ejaculate used for assisted reproductive technology (ART).
Related DFI to conventional semen parameters and cycle-specific outcomes after ART.
No patients achieved clinical pregnancy if SCSA values exceeded the DFI (27%,
P<.01), moderate DFI (15%,
P<.01), or high DFI (15%,
P<.05) thresholds. Dividing the DFI sperm population into moderate-fragmentation and high-fragmentation categories did not improve the prognostic value of the SCSA. No coefficient of determination (
r
2) between SCSA parameters and conventional parameters exceeded 0.29.
Sperm chromatin structure assay identified thresholds for negative pregnancy outcome after ART not identified using conventional semen parameters. This is the first study analyzing the clinical value of sperm DFI to 1 include a large number of ART patients (n = 89), 2 perform SCSA analysis on a semen aliquot from the ejaculate used for ART, and 3 examine how the extent (moderate and high DFI) of DFI influenced ART outcomes.
Mutations in Hnf-1α are the most common Mendelian cause of diabetes mellitus. To elucidate the molecular function of a mutational hotspot, we cocrystallized human HNF-1α 83–279 with a high-affinity ...promoter and solved the structure of the complex. Two identical protein molecules are bound to the promoter. Each contains a homeodomain and a second domain structurally similar to POU-specific domains that was not predicted on the basis of amino acid sequence. Atypical elements in both domains create a stable interface that further distinguishes HNF-1α from other flexible POU-homeodomain proteins. The numerous diabetes-causing mutations in HNF-1α thus identified a previously unrecognized POU domain which was used as a search model to identify additional POU domain proteins in sequence databases.
It is well known that reproductive capacity is lower in obese individuals, but what mediators and signals are involved is unclear. Kisspeptin is a potent stimulator of GnRH release, and it has been ...suggested that kisspeptin neurons located in the arcuate nucleus transmit metabolic signals to the GnRH neurons.
In this study, we measured body weight and plasma concentrations of leptin, insulin, testosterone, and triglycerides after high fat diet exposure and correlated these parameters with the number of kisspeptin-immunoreactive neurons in the arcuate nucleus of male rats. In this model, a high fat diet (45% or 60% energy from fat, respectively) or a control diet (10% energy from fat) was provided after weaning for three months.
We find a significant increase in body weight and plasma leptin concentration, but no change in the number of kisspeptin-immunoreactive cells with increased fat in the diet. Kisspeptin-immunoreactive cells are not correlated with body weight, testosterone, leptin or insulin. However, we find that the number of kisspeptin-immunoreactive cells is strongly and negatively correlated with the level of plasma triglycerides (R2=0.49, p=0.004).
We find a strong negative correlation between plasma triglyceride concentrations and the number of kisspeptin neurons in the rat arcuate nucleus regardless of the percentage of fat in the diet. In line with the lipotoxicity hypothesis, our results suggest that it is the level of hypertriglyceridemia per se that is a detrimental factor for kisspeptin expression in the arcuate nucleus.
Trends in vena caval interruption Moore, Phillip S., MD; Andrews, Jeanette S., MS; Craven, Timothy E., MSPH ...
Journal of vascular surgery,
07/2010, Letnik:
52, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Objective This study examined the national use of vena cava filters (VCFs) from 1998 to 2005. Methods Methods for complex surveys were used to examine hospital discharge data from the Nationwide ...Inpatient Sample (NIS) to determine the use of VCFs for the years 1998 to 2005. VCF placement in the absence of deep venous thrombosis (DVT) or pulmonary embolus (PE) was categorized as prophylactic. Results During the study period, the estimated rate of hospitalizations per year with a diagnosis of DVT (odds ratio OR, 1.025; 95% confidence interval CI, 1.019-1.032; P < .01) or PE (OR, 1.076; 95% CI, 1.069-1.083; P < .01) rose significantly. The estimated weighted frequency of VCF placement increased from 52,860 procedures in 1998 to 104,114 procedures in 2005 (0.15% and 0.27% of all discharges, respectively), representing an 80% increase. VCF placement significantly increased during hospitalizations with any diagnosis of DVT or PE, or both, and no DVT or PE ( P < .01 for each). Logistic regression models revealed that the rate of prophylactic VCF placement increased at a significantly higher rate than VCF placement associated with DVT or PE (157% vs 42%; P < .01), after adjusting for age, gender, and hospital characteristics. Prophylactic VCF placement in the setting of morbid obesity ( P < .01) and head injury ( P = .03) rose significantly over time. Conclusions From 1998 to 2005, the estimated rates of prophylactic VCF placement increased at a significantly higher rate than VCF placement in the setting of DVT or PE. Significant increases in the use of prophylactic VCFs were seen in the setting of morbid obesity and head injury.
Coplanar polychlorinated biphenyls (PCBs) cause adverse effects in developing and adult animals. Less is known about the effects of nonplanar ortho-substituted PCBs. We investigated the effects of 2 ...nonplanar PCB congeners, 95 (2,3,6-2',5'-penta CB) or 101 (2,4,5-2',5'-penta CB), and estradiol on selected endocrine parameters. In Study 1, weanling female Sprague-Dawley (S-D) rats were given a single dose of PCB 95 ip at 4, 8, 16, and 32 mg/kg/day for 2 consecutive days and killed 24 h after the last dose. PCB 95 exposure caused a dose-dependent (p < 0.001) decrease in serum thyroxine (T4) levels. Serum thyroid stimulating hormone (TSH) concentrations did not change, but prolactin (PRL) levels increased in a nonlinear (with dose) manner. No significant changes were seen in thyroid gland morphology and pituitary lactotroph number. In Study 2, progression or regression of effects was assessed by lengthening the time and a second congener was tested. Weanling female S-D rats received a single dose of PCB 95 or PCB 101 ip at 16 and 32 mg/kg/day for 2 days and were killed 48 h after the last dose. PCB 95 and PCB 101 both decreased serum T4 (p < 0.001) and hypothalamic dopamine (DA; p < 0.05) levels. No changes were seen in serum triiodothyronine (T3), TSH, and PRL concentrations. Morphological analysis of the thyroid gland showed a decrease (p < 0.05) in colloid area in rats treated with PCB 95 or 101. However, the epithelial cell height increased only in PCB 95 treated rats. Thyroid epithelial cell proliferation increased (p < 0.05) following exposure to estradiol and PCB 95. The results suggest that the HPT axis appears to be a target of ortho-substituted PCBs. PCB 95 was more effective than PCB 101 in causing these changes.
Since its introduction from Eurasia, smooth bromegrass (Bromus inermis Leyss.) has become an important cool‐season forage grass in North America. The objective of this study was to document breeding ...progress in smooth bromegrass between 1942 and 1995 in North America. Thirty cultivars or experimental populations were tested at up to seven sites in the eastern and central USA, with a range of soil types and climates. There have been small genetic changes in forage yield, brown leafspot resistance caused by Pyrenophora bromi (Died) Drechs., in vitro dry matter digestibility (IVDMD), and neutral detergent fiber (NDF) concentration. Brown leafspot resistance increased gradually, averaging 0.21 units decade−1. Mean forage yield did not change for cultivars developed after 1942, but was 0.54 Mg ha−1 (7.2%) higher for the post‐1942 group than in ‘Lincoln’, a direct representative of smooth bromegrass introduced into North America. Selection for increased IVDMD led to an average increase in IVDMD of 9 g kg−1 (1.4%), an increase in forage yield of 0.33 Mg ha−1 (5.0%), and a decrease in NDF of −8 g kg−1 (−1.2%) in the post‐1942 group. The slow rate of progress for smooth bromegrass forage yield is due to its complex polyploid inheritance, emphasis on traits other than forage yield, and relatively little concentrated attention from public and private breeders.
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