954 research outputs found
The use of stable and radioactive sterol tracers as a tool to investigate cholesterol degradation to bile acids in humans in vivo
Alterations of cholesterol homeostasis represent important risk factors for atherosclerosis and cardiovascular disease. Different clinical-experimental approaches have been devised to study the metabolism of cholesterol and particularly the synthesis of bile acids, its main catabolic products. Most evidence in humans has derived from studies utilizing the administration of labeled sterols; these have several advantages over in vitro assay of enzyme activity and expression, requiring an invasive procedure such as a liver biopsy, or the determination of fecal sterols, which is cumbersome and not commonly available. Pioneering evidence with administration of radioactive sterol derivatives has allowed to characterize the alterations of cholesterol metabolism and degradation in different situations, including spontaneous disease conditions, aging, and drug treatment. Along with the classical isotope dilution methodology, other approaches were proposed, among which isotope release following radioactive substrate administration. More recently, stable isotope studies have allowed to overcome radioactivity exposure. Isotope enrichment studies during tracer infusion has allowed to characterize changes in the degradation of cholesterol via the “classical” and the “alternative” pathways of bile acid synthesis. Evidence brought by tracer studies in vivo, summarized here, provides an exceptional tool for the investigation of sterol metabolism, and integrate the studies in vitro on human tissue
Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway
Reduced cholesterol synthesis has been reported in patients with primary biliary cirrhosis but no data are available on changes in cholesterol catabolism induced by the disease. Serum levels of 7α-hydroxycholesterol and 27-hydroxycholesterol have been measured in 25 patients (either normocholesterolemic or hypercholesterolemic) with primary biliary cirrhosis and in control subjects. To evaluate cholesterol synthesis, serum levels of lathosterol were measured, and campesterol and sitosterol were considered to reflect intestinal absorption and biliary elimination of sterols. In normocholesterolemic patients with primary biliary cirrhosis, lathosterol was significantly lower than in normocholesterolemic controls (P < 0.05) whereas no difference was found between hypercholesterolemic patients and hypercholesterolemic controls. Serum concentrations of sitosterol were significantly higher in both normocholesterolemic and hypercholesterolemic patients with primary biliary cirrhosis as compared with the respective controls (P < 0.01). In patients with primary biliary cirrhosis, serum 7α-hydroxycholesterol was slightly higher than in controls. 27-Hydroxycholesterol was significantly higher in hypercholesterolemic compared to normocholesterolemic controls (P < 0.05) and a significant linear correlation (r = 0.771; P < 0.001) was found between 27-hydroxycholesterol and cholesterol. In contrast, in patients with primary biliary cirrhosis, high cholesterol concentrations were not associated with increased serum levels of 27-hydroxycholesterol. Our data confirm that in patients with primary biliary cirrhosis, cholesterol synthesis and biliary elimination of sterols are impaired and also suggest that both the feedback regulation of retained bile acids on cholesterol 7α-hydroxylase and the scavenger effect on elevated serum cholesterol by cholesterol 27-hydroxylase are deficient in these patients.—Del Puppo, M., M. Galli Kienle, M. L. Petroni, A. Crosignani, and M. Podda. Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway. J. Lipid Res. 1998. 39: 2477–2482
Neural bases of reward anticipation in healthy individuals with low, mid, and high levels of schizotypy
A growing body of research has placed the ventral striatum at the center of a network of cerebral regions involved in anticipating rewards in healthy controls. However, little is known about the functional connectivity of the ventral striatum associated with reward anticipation in healthy controls. In addition, few studies have investigated reward anticipation in healthy humans with different levels of schizotypy. Here, we investigated reward anticipation in eighty-four healthy individuals (44 females) recruited based on their schizotypy scores. Participants performed a variant of the Monetary Incentive Delay Task while undergoing event-related fMRI.Participants showed the expected decrease in response times for highly rewarded trials compared to non-rewarded trials. Whole-brain activation analyses replicated previous results, including activity in the ventral and dorsal striatum. Whole-brain psycho-physiological interaction analyses of the left and right ventral striatum revealed increased connectivity during reward anticipation with widespread regions in frontal, parietal and occipital cortex as well as the cerebellum and midbrain. Finally, we found no association between schizotypal personality severity and neural activity and cortico-striatal functional connectivity. In line with the motivational, attentional, and motor functions of rewards, our data reveal multifaceted cortico-striatal networks taking part in reward anticipation in healthy individuals. The ventral striatum is connected to regions of the salience, attentional, motor and visual networks during reward anticipation and thereby in a position to orchestrate optimal goal-directed behavior
Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population.
BACKGROUND:
The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols.
METHODS:
We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38-79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids).
RESULTS:
A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=-0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age.
CONCLUSION:
These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined
Age-related changes in bile acid synthesis and hepatic nuclear receptor expression
BACKGROUND:Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers.DESIGN:Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry.RESULTS:Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed.CONCLUSIONS:Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism
Displacement power spectrum measurement of a macroscopic optomechanical system at thermal equilibrium
The mirror relative motion of a suspended Fabry-Perot cavity is studied in
the frequency range 3-10 Hz. The experimental measurements presented in this
paper, have been performed at the Low Frequency Facility, a high finesse
optical cavity 1 cm long suspended to a mechanical seismic isolation system
identical to that one used in the VIRGO experiment. The measured relative
displacement power spectrum is compatible with a system at thermal equilibrium
within its environmental. In the frequency region above 3 Hz, where seismic
noise contamination is negligible, the measurement distribution is stationary
and Gaussian, as expected for a system at thermal equilibrium. Through a simple
mechanical model it is shown that: applying the fluctuation dissipation theorem
the measured power spectrum is reproduced below 90 Hz and noise induced by
external sources are below the measurement.Comment: 11 pages, 9 figures, 2 tables, to be submitte
Cholesterol metabolism after bariatric surgery in grade 3 obesity : differences between malabsorptive and restrictive procedures
OBJECTIVEdMalabsorptive bariatric surgery (biliopancreatic diversion and biliointestinal
bypass [BIBP]) reduces serum cholesterol levels more than restrictive surgery (adjustable gastric
banding [AGB]), and this is thought to be due to greater weight loss. Our aim was to evaluate the
changes of cholesterol metabolism induced by malabsorptive and restrictive surgery independent
of weight loss.
RESEARCH DESIGNANDMETHODSdIn a nonrandomized, self-selected, unblinded,
active-comparator, bicenter, 6-month study, glucose metabolism (blood glucose and serum insulin
levels and homeostasis model assessment of insulin resistance [HOMA-IR] index) and
cholesterol metabolism (absorption: serum campesterol and sitosterol levels; synthesis: serum
lathosterol levels; catabolism: rate of appearance and serum concentrations of serum 7-a- and
serum 27-OH-cholesterol after infusions of deuterated 7-a- and 27-OH-cholesterol in sequence)
were assessed in grade 3 obesity subjects undergoing BIBP (n = 10) and AGB (n = 10). Evaluations
were performed before and 6 months after surgery.
RESULTSdSubjects had similar values at baseline.Weight loss was similar in the two groups
of subjects, and blood glucose, insulin levels, HOMA-IR, and triglycerides decreased in a similar
way. In contrast, serumcholesterol, LDL cholesterol, non-HDL cholesterol, serum sitosterol, and
campesterol levels decreased and lathosterol levels increased only in BIBP subjects, not in AGB
subjects. A significant increase in 7-a-OH-cholesterol occurred only with BIBP; serum 27-OHcholesterol
decreased in both groups.
CONCLUSIONSdMalabsorptive surgery specifically affects cholesterol levels, independent
of weight loss and independent of glucose metabolism and insulin resistance. Decreased sterol
absorption leads to decreased cholesterol and LDL cholesterol levels, accompanied by enhanced
cholesterol synthesis and enhanced cholesterol catabolism. Compared with AGB, BIBP provides
greater cholesterol lowering
The variable finesse locking technique
Virgo is a power recycled Michelson interferometer, with 3 km long Fabry-Perot cavities in the arms. The locking of the interferometer has been obtained with an original lock acquisition technique. The main idea is to lock the instrument away from its working point. Lock is obtained by misaligning the power recycling mirror and detuning the Michelson from the dark fringe. In this way, a good fraction of light escapes through the antisymmetric port and the power build-up inside the recycling cavity is extremely low. The benefit is that all the degrees of freedom are controlled when they are almost decoupled, and the linewidth of the recycling cavity is large. The interferometer is then adiabatically brought on to the dark fringe. This technique is referred to as variable finesse, since the recycling cavity is considered as a variable finesse Fabry-Perot. This technique has been widely tested and allows us to reach the dark fringe in few minutes, in an essentially deterministic way
Virgo calibration and reconstruction of the gravitational wave strain during VSR1
Virgo is a kilometer-length interferometer for gravitational waves detection
located near Pisa. Its first science run, VSR1, occured from May to October
2007. The aims of the calibration are to measure the detector sensitivity and
to reconstruct the time series of the gravitational wave strain h(t). The
absolute length calibration is based on an original non-linear reconstruction
of the differential arm length variations in free swinging Michelson
configurations. It uses the laser wavelength as length standard. This method is
used to calibrate the frequency dependent response of the Virgo mirror
actuators and derive the detector in-loop response and sensitivity within ~5%.
The principle of the strain reconstruction is highlighted and the h(t)
systematic errors are estimated. A photon calibrator is used to check the sign
of h(t). The reconstructed h(t) during VSR1 is valid from 10 Hz up to 10 kHz
with systematic errors estimated to 6% in amplitude. The phase error is
estimated to be 70 mrad below 1.9 kHz and 6 micro-seconds above.Comment: 8 pages, 8 figures, proceedings of Amaldi 8 conference, to be
published in Journal of Physics Conference Series (JPCS). Second release:
correct typo
Reconstruction of the gravitational wave signal during the Virgo science runs and independent validation with a photon calibrator
The Virgo detector is a kilometer-scale interferometer for gravitational wave
detection located near Pisa (Italy). About 13 months of data were accumulated
during four science runs (VSR1, VSR2, VSR3 and VSR4) between May 2007 and
September 2011, with increasing sensitivity.
In this paper, the method used to reconstruct, in the range 10 Hz-10 kHz, the
gravitational wave strain time series from the detector signals is
described. The standard consistency checks of the reconstruction are discussed
and used to estimate the systematic uncertainties of the signal as a
function of frequency. Finally, an independent setup, the photon calibrator, is
described and used to validate the reconstructed signal and the
associated uncertainties.
The uncertainties of the time series are estimated to be 8% in
amplitude. The uncertainty of the phase of is 50 mrad at 10 Hz with a
frequency dependence following a delay of 8 s at high frequency. A bias
lower than and depending on the sky direction of the GW is
also present.Comment: 35 pages, 16 figures. Accepted by CQ
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