In order to assess the hormonal determinants of insulin sensitivity and related components of the metabolic syndrome, we evaluated the effect of subcutaneous recombinant human chorionic gonadotropin ...(r-hCG; Ovidrel) on insulin sensitivity, vascular reactivity, leptin, insulin-like growth factor-I (IGF-I) and lipids in ambulant, community dwelling men >60 Years of age with serum testosterone <or= 15 nmol/l on two occasions.
Forty eligible men were randomized to receive 250 microg (5000 IU) r-hCG subcutaneously twice each week (n=20) or placebo (n=20) injections for 3 Months, and all subjects (mean age 67 (range 60-85) Years) completed the study.
Groups were well matched for height, weight, anthropometry and insulin sensitivity. Insulin sensitivity was assessed by homeostasis model (HOMA) and euglycemic hyperinsulinemic clamp at baseline and at the end of the treatment period in the first 30 men who did not have diabetes mellitus. Insulin sensitivity (HOMA and euglycemic clamp) or beta cell function (HOMA) were not significantly changed by r-hCG despite a significant increase in lean body mass (approximately 2 kg, P<0.001) and reduced fat mass (approximately 1 kg, P<0.05). Subcutaneous fat (skinfold measurements), abdominal girth and serum leptin all decreased and IGF-I tended to increase, but these changes were not significant. Recombinant hCG significantly reduced total and low density lipoprotein cholesterol, and triglycerides, but did not significantly alter high density lipoprotein cholesterol. Endothelial function (vascular reactivity) was not significantly worsened. We conclude that three-Months of treatment with r-hCG demonstrates expected hormonal effects, improved lipids and did not worsen vascular endothelial function. Insulin sensitivity was not altered despite suggestive changes in body composition.
These findings suggest short-term metabolic and cardiovascular safety and argue against an important role for androgens in the hormonal control of insulin sensitivity in older men.
The effect of mild closed head trauma, induced by the weight-drop method (450 g from a 1-m height), on lipid peroxidation and energy metabolism of brain tissue was determined at various times after ...cerebral injury in spontaneously breathing rats (1, 10, 30 minutes and 2, 6, 15, 24, 48, and 120 hours). Animals were continuously monitored for the evaluation of blood pressure, blood gases, heart rate, and intracranial pressure. Analysis of malondialdehyde (MDA) as an index of lipid peroxidation, ascorbic acid, high-energy phosphates, nicotinic coenzymes, oxypurines, and nucleosides was performed by high-performance liquid chromatography (HPLC) on neutralized perchloric acid extract of the whole brain. Data showed that MDA, undetectable in control, sham-operated rats, was already present within 1 minute of trauma (1.77 nmol/g wet weight; SD = 0.29) and reached maximal values by 2 hours (72.26 nmol/g w.w.; SD = 11.26), showing a progressive slow decrease thereafter. In contrast, ATP, GTP, and nicotinic coenzyme (NAD and NADP) concentrations showed significant reduction only by the second hour postinjury. Maximal decrease of the ATP and GTP concentrations were seen at 6 hours postinjury, whereas NAD and NADP concentrations showed maximum decline by 15 hours. Values recorded in mechanically ventilated rats did not differ significantly from those obtained in spontaneously breathing animals. These findings, supported by the absence of blood gas and blood pressure changes in the spontaneously breathing rats, strongly support the premise that biochemical changes (primarily lipid peroxidation) are not caused by secondary ischemic-hypoxic phenomena but rather are triggered by these forces acting on the brain at the time of impact. In addition, these results suggest that depression of energy metabolism might be caused by peroxidation of the mitochondrial membrane with a consequent alteration of the main mitochondrial function-that is, the energy supply.
On the basis of the contradiction between data on experimental head trauma showing oxidative stress-mediated cerebral tissue damage and failure of the majority of clinical trials using free radical ...scavenger drugs, we monitored the time-course changes of malondialdehyde (MDA, an index of cell lipid peroxidation), ascorbate, and dephosphorylated ATP catabolites in cerebrospinal fluid (CSF) of traumatic brain-injured patients.
CSF samples were obtained from 20 consecutive patients suffering from severe brain injury. All patients were comatose, with a Glasgow Coma Scale on admission of 6 +/- 1. The first CSF sample for each patient was collected within a mean value of 2.95 hours from trauma (SD=1.98), after the insertion of a ventriculostomy catheter for the continuous monitoring of intracranial pressure. During the next 48 hours, CSF was withdrawn from each patient once every 6 hours. All samples were analyzed by an ion-pairing high-performance liquid chromatographic method for the simultaneous determination of MDA, ascorbic acid, hypoxanthine, xanthine, uric acid, inosine, and adenosine.
In comparison with values recorded in 10 herniated-lumbar-disk, noncerebral control patients, data showed that all CSF samples of brain-injured patients had high values (0.226 micromol/L; SD=0.196) of MDA (undetectable in samples of control patients) and decreased ascorbate levels (96.25 micromol/L; SD=31.74), already at the time of first withdrawal at the time of hospital admission. MDA was almost constant in the next two withdrawals and tended to decrease thereafter, although 48 hours after hospital admission, a mean level of 0.072 micromol/L CSF (SD=0.026) was still recorded. The ascorbate level was normalized 42 hours after hospital admission. Changes in the CSF values of ATP degradation products (oxypurines and nucleosides) suggested a dramatic alteration of neuronal energy metabolism after traumatic brain injury.
On the whole, these data demonstrate the early onset of oxygen radical-mediated oxidative stress, proposing a valid explanation for the failure of clinical trials based on the administration of oxygen free radical scavenger drugs and suggesting a possible rationale for testing the efficacy of lipid peroxidation "chain breakers" in future clinical trials.
Objectives
The aim of this work was the evaluation of biodistribution and radiation dosimetry of
68
Ga-DOTANOC in patients affected by neuroendocrine tumors.
Materials and methods
We enrolled nine ...patients (six male and three female) affected by different types of neuroendocrine tumors (NETs). Each patient underwent four whole body positron emission tomography (PET) scans, respectively, at 5, 20, 60, and 120 min after the intravenous injection of about 185 MBq of
68
Ga-DOTANOC. Blood and urine samples were taken at different time points post injection: respectively, at about 5, 18, 40, 60, and 120 min for blood and every 40–50 min from injection time up to 4 h for urine. The organs involved in the dosimetric evaluations were liver, heart, spleen, kidneys, lungs, pituitary gland, and urinary bladder. Dosimetric evaluations were done using the OLINDA/EXM 1.0 software.
Results
A physiological uptake of
68
Ga-DOTANOC was seen in all patients in the pituitary gland, the spleen, the liver, and the urinary tract (kidneys and urinary bladder). Organs with the highest absorbed doses were kidneys
. The mean effective dose equivalent (EDE) was
.
Discussion and conclusions
The excretion of the compound was principally via urine, giving dose to the kidney and the urinary bladder wall. As SSTR2 is the most frequently expressed somatostatin receptor and
68
Ga-DOTANOC has high affinity to it, this compound might play an important role in PET oncology in the future. The dosimetric evaluation carried out by our team demonstrated that
68
Ga-DOTANOC delivers a dose to organs comparable to, and even lower than, analogous diagnostic compounds.
Somatostatin receptors 1–5 are over expressed in neuroendocrine tumours (NETs).
68Ga-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-1-Nal3-Octreotide (DOTA NOC), a recent ...synthesized somatostatin analogue, shows high affinity for those receptors. Herein, modifications of a commercial module for the labelling of DOTA NOC with
68Ga, as well as the assessment of time course of the radiochemical purity variation are described. The evaluation of radiochemical stability was done by two different chromatographic methods: reversed-phase radio HPLC and fast TLC analysis. Labelled compound has been found radiochemically stable within 3
h from the end of labelling (EOL) and radiochemical purity was always higher than 99%. After 73 labelling sessions the system showed great reproducibility and high radiochemical yield.
Background and aims: Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal ...barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability. Methods: The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers. Results: Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release. Conclusions: Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.
Context.
Markarian 501 (Mrk 501) is a very high-energy (VHE) gamma-ray blazar located at
z
= 0.034, which is regularly monitored by a wide range of multi-wavelength instruments, from radio to VHE ...gamma rays. During a period of almost two weeks in July 2014, the highest X-ray activity of Mrk 501 was observed in ∼14 years of operation of the
Neil Gehrels Swift
Gamma-ray Burst Observatory.
Aims.
We characterize the broadband variability of Mrk 501 from radio to VHE gamma rays during the most extreme X-ray activity measured in the last 14 years, and evaluate whether it can be interpreted within theoretical scenarios widely used to explain the broadband emission from blazars.
Methods.
The emission of Mrk 501 was measured at radio with Metsähovi, at optical–UV with KVA and
Swift
/UVOT, at X-ray with
Swift
/XRT and
Swift
/BAT, at gamma ray with
Fermi
-LAT, and at VHE gamma rays with the FACT and MAGIC telescopes. The multi-band variability and correlations were quantified, and the broadband spectral energy distributions (SEDs) were compared with predictions from theoretical models.
Results.
The VHE emission of Mrk 501 was found to be elevated during the X-ray outburst, with a gamma-ray flux above 0.15 TeV varying from ∼0.5 to ∼2 times the Crab nebula flux. The X-ray and VHE emission both varied on timescales of 1 day and were found to be correlated. We measured a general increase in the fractional variability with energy, with the VHE variability being twice as large as the X-ray variability. The temporal evolution of the most prominent and variable segments of the SED, characterized on a day-by-day basis from 2014 July 16 to 2014 July 31, is described with a one-zone synchrotron self-Compton model with variations in the break energy of the electron energy distribution (EED), and with some adjustments in the magnetic field strength and spectral shape of the EED. These results suggest that the main flux variations during this extreme X-ray outburst are produced by the acceleration and the cooling of the high-energy electrons. A narrow feature at ∼3 TeV was observed in the VHE spectrum measured on 2014 July 19 (MJD 56857.98), which is the day with the highest X-ray flux (>0.3 keV) measured during the entire
Swift
mission. This feature is inconsistent with the classical analytic functions to describe the measured VHE spectra (power law, log-parabola, and log-parabola with exponential cutoff) at more than 3
σ
. A fit with a log-parabola plus a narrow component is preferred over the fit with a single log-parabola at more than 4
σ
, and a dedicated Monte Carlo simulation estimated the significance of this extra component to be larger than 3
σ
. Under the assumption that this VHE spectral feature is real, we show that it can be reproduced with three distinct theoretical scenarios: (a) a pileup in the EED due to stochastic acceleration; (b) a structured jet with two-SSC emitting regions, with one region dominated by an extremely narrow EED; and (c) an emission from an IC pair cascade induced by electrons accelerated in a magnetospheric vacuum gap, in addition to the SSC emission from a more conventional region along the jet of Mrk 501.
Alcohol changes the progression of hepatitis C virus (HCV)-related chronic liver disease and may affect the outcome of interferon therapy. The ethanol intake of 245 patients with biopsy-proven ...chronic hepatitis C with or without cirrhosis, its interaction with laboratory and histological parameters common to alcohol and HCV-mediated liver damage, and its effects on therapy were evaluated. The results show that 60–70% of subjects regularly consumed alcohol (median intake >40 g/day in about 30%). Less than 50% stopped drinking after being diagnosed as having liver disease. Ethanol intake affected: fibrosis, especially in women, HCV RNA levels, which were significantly lower in abstainers than in drinkers (0.6 ± 0.3 vs 6.9 ± 5.9 Eq/ml x106; P < 0.01), and response to interferon therapy. The number of responders decreased as ethanol intake increased. There were less abstainers than drinkers among non-responders (10.7% vs 63.1% respectively; P < 0.001). Data indicate that alcohol will induce and worsen liver damage and, in subjects with chronic liver disease who continue to drink, adversely affect their response to treatment.
In Italy, cervical cancer screening programmes actively invite women aged 25-64 years. Programmes are hindered by low participation.
A sample of non-responder women aged 35-64 years, belonging to ...three different programmes (in Rome, Florence and Teramo), was randomly split into four arms: two control groups received standard recall letters to perform either Pap-test (first group) or human papillomavirus (HPV) test (second group) at the clinic. A third arm was sent letters offering a self-sampler for HPV testing, to be requested by phone, whereas a fourth group was directly sent the self-samplers home.
Compliance with standard recall was 13.9% (N619). Offering HPV test at the clinic had a nonsignificant effect on compliance (N616, relative risk (RR)=1.08; 95% CI=0.82-1.41). Self-sampler at request had the poorest performance, 8.7% (N622, RR=0.62; 95% CI=0.45-0.86), whereas direct mailing of the self-sampler registered the highest compliance: 19.6% (N616, RR=1.41; 95% CI=1.10-1.82). This effect on compliance was observed only in urban areas, Florence and Rome (N438, RR=1.69; 95% CI=1.24-2.30), but not in Abruzzo (N178, RR=0.95; 95% CI=0.61-1.50), a prevalently rural area.
Mailing self-samplers to non-responders may increase compliance as compared with delivering standard recall letters. Nevertheless, effectiveness is context specific and the strategy costs should be carefully considered.
Adriamycin (ADR), one of the major antitumor agents used for the clinical treatment of a wide variety of human cancers and its glutathione(GSH)-conjugated adduct, ADRIGLU, induced apoptosis in K562 ...erythroleukemia and TVM-A12 clone 2 melanoma human cell lines. We have previously reported that ADR has nuclear localization and that ADRIGLU localizes exclusively in the cytoplasm. During ADR or ADRIGLU treatment, significant depletion of the cell energy state, demonstrated by a reduction in high-energy phosphates (ATP and GTP) and a decrease in energy charge potential (ECP), were recorded between 2 hours and 24 hours, by HPLC analysis. Transmission electron microscopy also revealed that between 2 hours and 24 hours of ADR or ADRIGLU treatment, mitochondria underwent evident morphological changes, from an initial "high amplitude swelling state" to a "shrinkage state" and finally, in early apoptotic cells, to an "abnormal shrinkage state", in which a marked accumulation of pycnotic mitochondria was also observed. Confocal microscopic analysis, using the potential-sensitive dye JC-1, showed that inhibition of cell energy metabolism was preceded by a rapid decrease in mitochondrial transmembrane potential (delta psi m). With the progression of exposure time, the early depolarization of the mitochondrial membrane was followed by a transient reversion to normal delta psi m until, in apoptotic cells, almost all mitochondrial subpopulations appeared to be hyperpolarized. Our results indicated that mitochondria are actively involved in anthracycline-induced programmed cell death, suggesting a novel mechanism that may be common to all forms of apoptosis.
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