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Aims. We report upper limits to the very high energy flux ($E>100$GeV) of the flat spectrum radio quasar 3C 454.3 ($z=0.859$) derived by the Cherenkov telescope MAGIC during the high states of July/August and November/December 2007. We compare the upper limits derived in both time slots with the available quasi-simultaneous MeV-GeV data from the AGILE γ-ray satellite and interpret the observational results in the context of leptonic emission models.

Ohne Zusammenfassung:

While rupture of the aorta is a leading cause of sudden death following motor vehicle crashes, the specific mechanism that causes this injury is not currently well understood. Aortic ruptures occurring in the field are likely due to a complex combination of contributing factors such as acceleration, compression of the chest, and increased pressure within the aorta. The objective of the current study was to investigate one of these factors in more detail than has been done previously; specifically, to investigate the in situintra-aortic pressure generated during isolated belt loading to the abdomen.Ten juvenile swine were subjected to dynamic belt loads applied to the abdomen. Intra-aortic pressure was measured at multiple locations to assess the magnitude and propagation of the resulting blood pressure wave. The greatest average peak pressure (113.6 ± 43.5 kPa) was measured in the abdominal aorta. Pressures measured in the thoracic aorta and aortic arch were 70 per cent and 50 per cent, respectively, that measured in the abdominal aorta. No macroscopic aortic trauma was observed.To the authors’ knowledge the present study is the first one to document the presence, propagation, and attenuation of a transient pressure wave in the aorta generated by abdominal belt loading. The superiorly moving wave is sufficient to generate hydrostatic and intimal shear stress in the aorta, possibly contributing to the hypothesized mechanisms of traumatic aortic rupture.

The synergism/antagonism between interleukin (IL)-1β and parathyroid hormone (PTH) has been the subject of in vitro and in vivo work, but a possible direct action of the cytokine on PTH release has not been reported. We have investigated the effect of a continuous infusion of human recombinant IL-1β (rIL-1β) on circulating PTH during a 14-day period in 7-week-old female rats. This time interval was chosen in order to exclude initial hypercalcemia and to enable data collection under steady-state conditions. Five groups of 20 animals each had miniosmotic pumps (Alzet 2002, 200 µl) implanted subcutaneously and primed to release either distilled water (controls) or 100, 500, 1,000 and 2,000 ng/24 h of rIL-1β. Blood was drawn on days 1 and 14 for PTH, corticosterone and Ca2+ determinations. Adequate biological activity of the infused rIL-1β was supported by elevated rectal temperature records and significant elevations of plasma corticosterone on day 14. The 100-ng dose had no effect but 500–2,000 ng rIL-1β/24 h significantly reduced plasma PTH in a dose-dependent manner down to 54% of basal value (20.4 ± 1.1 vs. 15.3 ± 1.4 pg/ml for 500 ng, p < 0.005; 20.5 ± 1.3 vs 12.3 ± 1.1 for 1,000 ng, p < 0.001, and 19.5 ± 2.0 vs. 10.6 ± 1.1 pg/ml for 2,000 ng, p < 0.0008). Despite these findings, no differences in blood Ca2+ could be detected between treated animals and controls. The following conclusions can be inferred from the foregoing: Systemic administration of rIL-1β to rats induced a dose-dependent fall in circulating PTH without altering calcemia, calling into question the biological relevance of the former finding. Although the recorded PTH depression may indeed not have been severe enough to cause hypocalcemia, it can be hypothesized that osteoclast activation by rIL-1β would enhance bone mineral release into the pool compensating for depressed PTH activity.

Zusammenfassung Die Langzeitverabreichung von synthetischen Gestagenen führt bei Affen und Hunden zu gutartigen hyperplastischen Veränderungen der Brustdrüse. Die ursächlichen Zusammenhänge könnten in der beobachteten erhöhten Wachstumshormonsekretion zu suchen sein. Andererseits wird vermutet, daß eine gesteigerte Prolaktinsekretion an der Genese des menschlichen Mammakarzinoms beteiligt ist. Aus diesen Überlegungen heraus haben wir den Einfluß von synthetischen Gestagenen auf die Prolaktin- und Wachstumshormonsekretion untersucht.

Abstract. The pharmacokinetics and the endocrine profile of a new low molecular somatostatin derivative, SMS 201–995, were investigated in a group of 35 normal subjects. Clearance studies (n = 6) for this peptide showed a prolonged half-life in plasma, 113 min, following single scinjections of 50 or 100 μg. Arginine stimulation tests (n = 6) were conducted immediately and 180 min after scinjection of 50 μg of SMS 201–995. The stimulatory effect of arginine on GH and insulin was counteracted by the peptide at the P< 0.001 and P< 0.02 significance level, respectively. Delayed arginine stimulation revealed a persistent blockade of the GH release (P< 0.02), whereas a recovery of the insulin response was observed. Plasma glucagon increments following a standard protein meal (n = 10) were significantly (P< 0.001) inhibited by previous scinjection of 50 μg of SMS 202–995. Pretreatment with 50 and 100 μ of SMS 202–995 sc(n = 9) inhibited (P< 0.001) the stimulatory effect of TRH (200 μg iv) on TSH without modifying basal levels. The injection of 100 μg/h during sleep completely abolished the nocturnal GH peak in 4 volunteers. No rebound rise after decline of the suppressive action on GH was recorded in any of the trials.Safety chemistries and blood coagulation studies remained normal and no side-effects or untoward reactions were recorded throughout the investigation.With its high potency, slow plasma clearance, and long action SMS 201–995 may represent a valuable tool in the long-term management of states of inappropriate GH secretion.

Bromocriptin (CB 154) has been found to suppress established lactation at a time when human plasma prolactin (HPRL) concentrations have already returned to the nonpregnant range. This action is due to inhibition of prolactin from the pituitary. It was then thought that a similar degree of inhibition induced during the menstrual cycle may help to uncover other possible biological actions of prolactin. In an attempt to elucidate this question eight breast-feeding mothers and seven normally menstruating volunteers underwent treatment with CB 154, including blood sampling during a sleep period. The dosage was 1 mg., three times daily, for 14 days in the first group and for a whole cycle in the normal volunteers. A control cycle preceded drug administration in the latter group. Prolactin (HPRL), growth hormone (HGH), luteotropin (LH), progesterone (PG), and estradiol (E2) were estimated (mean ± standard error) along the menstrual cycles in the normal volunteers. HPRL and milk volumes were measured in the breast-feeding women in the base-line period and during treatment. In the postpartum group, basal HPRL had already reached normal levels prior to therapy (10.8 ± 1.0 ng. per milliliter) and was significantly (p < 0.002) depressed to 3.7 ± 0.4 ng. per milliliter by CB 154. This degree of inhibition was effective in suppressing lactation within 24 to 48 hours in all of the subjects in that group. The fall in plasma HPRL from 9.5 ± 1.5 ng. per milliliter to 3.2 ± 0.2 ng. per milliliter observed in the normally menstruating women was similar to the one recorded in the breast-feeding group, but the sequence of hormonal changes during the menstrual cycle was not altered by treatment. The overnight study ensured around-the-clock prolactin inhibition. Results indicate no action of prolactin in the regulation of the human menstrual cycle at levels of inhibition at which a biological action of this hormone is clearly suppressed.

Summary The effects of several calcium antagonists (verapamil, nicardipine and two diltiazem isomers, d-cis and l-cis diltiazem) alone and associated to non-depolarizing (pancuronium) and depolarizing (succinylcholine) neuromuscular blockers, were evaluated on sciatic nerve-tibialis anterior muscle preparations from cats in vivo. The calcium antagonists used (at 0.1 and 0.5mg/kg iv) did not modify the height of muscular twitches elicited indirectly. However, these agents potentiated in a dose-dependent way the neuromuscular blockade induced by iv pancuronium (2–40µg/kg) and succinylcholine (6–200µg/kg). The order of potency in increasing the effects of pancuronium was nicardipine » d-cis diltiazem ? verapamil, whereas the order of potency in enhancing succinylcholine effects was d-cis diltiazem ? verapamil » nicardipine. The effects of diltiazem were stereoselective, thus the potentiation induced by d-cis diltiazem was significantly greater in all cases than that induced by l-cis diltiazem, which suggests that calcium channel blockade plays a role in these interactions. However, other mechanisms such as calcium antagonists-induced nicotinic receptor desensitization may also be involved.

Abstract. The purpose of the present work was to study the effect of a methionine-enkephalin analogue (FK 33-824) on glucose tolerance in man. Groups of 5 to 8 normal subjects were given a 0.5 mg im injection of the drug or placebo just before a 100 g oral glucose load or a 0.5 g/kg iv glucose load. In the enkephalin analogue treated subjects, diminished insulin response to glucose was observed following the oral glucose load, with insulin values significantly lower than in the controls from time 10 to 90 min, but no corresponding change in the glucose curve. This effect was not observed when glucose was given iv in another group of 5 subjects in whom the significant blunting of the insulin response was accompanied by a significant decrease in glucose tolerance.These observations demonstrate that in man, enkephalin produces a decrease in insulin secretion in response to both oral and iv glucose loads. The absence of any marked impairment in glucose tolerance in the oral test in spite of the decreased insulin response suggests that enkephalin might have an additional effect in delaying glucose absorption.

In order to elucidate the role of prolactin (PRL) in the regulation of the human corpus luteum, a study was conducted in a series of female volunteers. Following a control cycle, two groups of five and four women were treated with bromocriptine, a prolactin (PRL) inhibitor; they received 5 and 7.5 mg. daily, respectively, for the length of another cycle. In two other subjects both doses were administered in consecutive cycles, whereas in two additional cases treatment was restricted to the postovulatory period until the onset of the next menses. Parameters examined were plasma PRL, LH, FSH, estradiol (E2-17β), and progesterone (PG), the latter being elaborated to a luteal index. Initiation of therapy at the onset of menstruation was followed by an immediate and significant (p < 0.001) fall in plasma PRL concentration. FSH, LH, and E2-17β were not modified by treatment, but a marked decrease in luteal PG in three out of five women receiving 5 mg. and in the four women receiving 7.5 mg. (p < 0.05) was recorded. This effect was only observed when treatment was extended to the entire length of the menstrual cycle, and was reversible on discontinuation of therapy. When administered in two consecutive cycles to the same person, 7.5 mg. induced a more marked fall in plasma PG when compared with the control and the 5 mg. dose. These results suggest that PRL physiologically influences the function of the human corpus luteum since its suppression to below-normal levels may cause defective PG synthesis by the ruptured follicle. The possible biological implications of this effect are discussed.

Summary In rats a chronic uremic syndrome was induced by 5/6 resection and subsequent irradiation of the kidneys. After 5 weeks 45Ca and 89Sr were injected simultaneously, and the different metabolic handling of the two elements was determined applying an open two-compartment model of Calcium kinetics. The uremic animals were compared with two groups of rats which were pairfed, and fed ad libitum, respectively. Besides an elevenfold faster urinary excretion when calculated with Sr, and which was reduced to about one half in the uremic rats, a significant discrimination by bone in favour of Ca was found, with a rather stable factor of 1.2 in the three groups. This is considered to evidence that urinary excretion and bon uptake of Sr are independent processes.

A female child was admitted to the hospital few days after birth with severe hypoglycemia and convulsive episodes. Plasma insulin levels were elevated and oral and intravenous administration of glucose were unable to keep blood glucose above 2 mmol/l limit. Intravenous infusion of a long acting somatostatin analog, SMS 201-995, at a dosage gradually increasing from 2 to 50 μg/24 hr, was accompanied by a dramatic fall in circulating insulin levels. Normality of glucose homeostasis was restored and convulsive spells ceased. Fasting blood glucose levels stabilized between 3.4 and 4.7 mmol/l. No rebound phenomenon was observed during short term interruptions of the SMS 201-995 infusion. A subtotal pancreatectomy was performed during SMS treatment, and the diagnosis of nesidioblastosis was confirmed by immunocytologic and electron-microscopic studies. It is concluded that this new potent and long acting somatostatin derivative may be useful in the management of hyperinsulinism in the neonate.

Summary This study examined the effects of the long-acting selective mini somatostatin analogue (SMS) 201-995 in two acromegalic patients who were treated for 3 and 6 months, respectively. During treatment the mean growth hormone levels (25.3 and 20.8 ng/ml vs 5.9 and 10.6 ng/ml) and somatomedin C levels (6.2 and 6.2 IU/ml vs 3.3 and 3.8 IU/ml) decreased and the patients reported an improvement in their symptoms. The main side effect was an increase in stool fat excretion which did exceed the normal range (<7 g/day) in one patient. Five acromegalics who received 2 × 50 µg SMS 201-995/day for 5 days showed a significant increase of stool fat excretion (1.7 vs 3.5 g/day;p<0.05). Fasting blood glucose levels, glucose tolerance, and glycosylated hemoglobin were not essentially effected. It is concluded that SMS 201-995 offers new possibilities in the treatment of acromegaly. The gastrointestinal and diabetogenic side effects of this substance, however, should be carefully monitored.

The antigalaclic action of Br-ergocryptine (CB 154 was studied in a group of women in the postpartum period who were compared with another two groups of normal breast-feeding mothers and estrogen-treated women. Treatment with Br-ergocryptine induced a fall in blood prolaclin concentrations to below the basal values found in nonlactaling women. No milk secretion was recorded in this group. This compound also inhibited the prolactin peak that normally occurs in response to suckling. Lactation suppression was also effective once it had been initiated, regardless of the prolactin concentrations at the time therapy was started. Inhibition of milk secretion by Brergocrypline also was observed in 2 women at a time when serum prolactin had reached normal levels and despite breast stimulation. Since treatment depressed serum prolactin values even further, it cannot be clearly explained whether the antigalaclic action was due simply to the fall in serum prolactin concentrations to a level below the normal range or to the abolition of the postsuction response. Exogenous administration of estrogen failed to inhibit prolactin secretion but was effective in suppressing lactation, thus suggesting a peripheral action on the mammary gland

Three women with the galactorrhea-amenorrhea syndrome experienced return of menstruation while receiving treatment with Br-ergocryptine (CB 154), a specific prolactin inhibitor. Ovulation could be substantiated in all 3 patients by demonstrating elevated urinary pregnanediol during the luteal phase of the cycle. Furthermore, one of the patients conceived during treatment and gave birth to a healthy baby. There is evidence that the re-establishment of ovulation occurs because of the fall in circulating prolactin induced by Br-ergocryptine. This would in turn enable the hypothalamic center to restore normal cycling activity.

Summary Plasma LH fluctuations reflect pulsatile hypothalamic GnRH activity. In order to investigate a possible interaction between opiate and dopaminergic pathways in the control of LH and PRL release, a met-enkephalin analogue (FK 33-824) was administered intravenously to female volunteers at a rate of 0.01 mg/kg/h for 4 h. LH pulses as recorded by plasma measurements every 20' were significantly (p < 0.01) inhibited whereas PRL concentrations were increased. Pre-treatment with bromocriptine, 1.25 mg b.i.d. for 3 days, counteracted the stimulatory effect of FK 33-824 on PRL secretion but the inhibitory effect on LH episodic release was not modified by this dopamine agonist.

There is little information about the action of ergot derivatives other than bromocriptine (CB 154) on plasma prolactin and milk secretion in human beings. In a recent report it has been suggested that ergonovine might interfere with lactation when administered post partum. The present study shows that methyl-ergonovine (Methergine), a closely related compound, has no action on prolactin or milk secretion as measured in a group of 10 breast-feeding mothers in comparison with another 10 untreated puerperas.

Context.3C 279, the first quasar discovered to emit VHE γ-rays by the MAGIC telescope in 2006, was reobserved by MAGIC in January 2007 during a major optical flare and from December 2008 to April 2009 following an alert from the Fermi space telescope on an exceptionally high γ-ray state.Aims.The January 2007 observations resulted in a detection on January 16 with significance 5.4σ, corresponding to a F(>150 GeV) (3.8 ± 0.8) × 10-11ph cm-2s-1while the overall data sample does not show significant signal. The December 2008–April 2009 observations did not detect the source. We study the multiwavelength behaviour of the source at the epochs of MAGIC observations, collecting quasi-simultaneous data at optical and X-ray frequencies and for 2009 also γ-ray data from Fermi.Methods.We study the light curves and spectral energy distribution of the source. The spectral energy distributions of three observing epochs (including the February 2006, which has been previously published) are modelled with one-zone inverse Compton models and the emission on January 16, 2007 also with two zone model and with a lepto-hadronic model.Results.We find that the VHE γ-ray emission detected in 2006 and 2007 challenges standard one-zone model, based on relativistic electrons in a jet scattering broad line region photons, while the other studied models fit the observed spectral energy distribution more satisfactorily.

Context.Part of the very high energy γ-ray radiation coming from extragalactic sources is absorbed through the pair production process on the extragalactic background light photons. Extragalactic magnetic fields alter the trajectories of these cascade pairs and, in turn, convert cosmic background photons to γ-ray energies by inverse Compton scattering. These secondary photons can form an extended halo around bright VHE sources.

Context. Wide-range spectral coverage of blazar-type active galactic nuclei is of paramount importance for understanding the particle acceleration mechanisms assumed to take place in their jets. The Major Atmospheric Gamma Imaging Cerenkov (MAGIC) telescope participated in three multiwavelength (MWL) campaigns, observing the blazar Markarian (Mkn) 421 during the nights of April 28 and 29, 2006, and June 14, 2006.Aims. We analyzed the corresponding MAGIC very-high energy observations during 9 nights from April 22 to 30, 2006 and on June 14, 2006. We inferred light curves with sub-day resolution and night-by-night energy spectra.Methods. MAGIC detects γ-rays by observing extended air showers in the atmosphere. The obtained air-shower images were analyzed using the standard MAGIC analysis chain.Results. A strong γ-ray signal was detected from Mkn 421 on all observation nights. The flux (E>250 GeV) varied on night-by-night basis between (0.92±0.11) × 10-10cm-2s-1(0.57 Crab units) and (3.21±0.15) × 10-10cm-2s-1(2.0 Crab units) in April 2006. There is a clear indication for intra-night variability with a doubling time of 36±$10_{\rm stat}$min on the night of April 29, 2006, establishing once more rapid flux variability for this object. For all individual nights γ-ray spectra could be inferred, with power-law indices ranging from 1.66 to 2.47. We did not find statistically significant correlations between the spectral index and the flux state for individual nights. During the June 2006 campaign, a flux substantially lower than the one measured by the Whipple 10-m telescope four days later was found. Using a log-parabolic power law fit we deduced for some data sets the location of the spectral peak in the very-high energy regime. Our results confirm the indications of rising peak energy with increasing flux, as expected in leptonic acceleration models.

Context. Wide-range spectral coverage of blazar-type active galactic nuclei is of paramount importance for understanding the particle acceleration mechanisms assumed to take place in their jets. The Major Atmospheric Gamma Imaging Cerenkov (MAGIC) telescope participated in three multiwavelength (MWL) campaigns, observing the blazar Markarian (Mkn) 421 during the nights of April 28 and 29, 2006, and June 14, 2006.

Context. Gamma-ray bursts are cosmological sources emitting radiation from the gamma-rays to the radio band. Substantial observational efforts have been devoted to the study of gamma-ray bursts during the prompt phase, i.e. the initial burst of high-energy radiation, and during the long-lasting afterglows. In spite of many successes in interpreting these phenomena, there are still several open key questions about the fundamental emission processes, their energetics and the environment.Aims. Independently of specific gamma-ray burst theoretical recipes, spectra in the GeV/TeV range are predicted to be remarkably simple, being satisfactorily modeled with power-laws, and therefore offer a very valuable tool to probe the extragalactic background light distribution. Furthermore, the simple detection of a component at very-high energies, i.e. at ~100 GeV, would solve the ambiguity about the importance of various possible emission processes, which provide barely distinguishable scenarios at lower energies.Methods. We used the results of the MAGIC telescope observation of the moderate resdhift (z~ 0.76) GRB 080430 at energies above about 80 GeV, to evaluate the perspective for late-afterglow observations with ground based GeV/TeV telescopes.Results. We obtained an upper limit of F95% CL= 5.5 × 10-11erg cm-2s-1for the very-high energy emission of GRB 080430, which cannot set further constraints on the theoretical scenarios proposed for this object also due to the difficulties in modeling the low-energy afterglow. Nonetheless, our observations show that Cherenkov telescopes have already reached the required sensitivity to detect the GeV/TeV emission of GRBs at moderate redshift (z≲ 0.8), provided the observations are carried out at early times, close to the onset of their afterglow phase.

Context. Gamma-ray bursts are cosmological sources emitting radiation from the gamma-rays to the radio band. Substantial observational efforts have been devoted to the study of gamma-ray bursts during the prompt phase, i.e. the initial burst of high-energy radiation, and during the long-lasting afterglows. In spite of many successes in interpreting these phenomena, there are still several open key questions about the fundamental emission processes, their energetics and the environment.

The blazar PG 1553+113 is a well known TeV γ-ray emitter. In this paper we determine its spectral energy distribution through simultaneous multi-frequency data to study its emission processes. An extensive campaign was carried out between March and April 2008, where optical, X-ray, high-energy (HE) γ-ray, and very-high-energy (VHE) γ-ray data were obtained with the KVA, Abastumani, REM, RossiXTE/ASM, AGILE and MAGIC telescopes, respectively. We combine the data to derive the source's spectral energy distribution and interpret its double-peaked shape within the framework of a synchrotron self-Compton model.

The blazar PG 1553+113 is a well known TeV γ-ray emitter. In this paper we determine its spectral energy distribution through simultaneous multi-frequency data to study its emission processes. An extensive campaign was carried out between March and April 2008, where optical, X-ray, high-energy (HE) γ-ray, and very-high-energy (VHE) γ-ray data were obtained with the KVA, Abastumani, REM, RossiXTE/ASM, AGILE and MAGIC telescopes, respectively. We combine the data to derive the source's spectral energy distribution and interpret its double-peaked shape within the framework of a synchrotron self-Compton model.

The effects were studied of several calcium channel blocking agents on muscle twitch, and possible interactions between these drugs and pancuronium and suxamethonium, using a rat phrenic-hemidiaphragm preparation. Nicardipine, verapamil and diltiazem each caused a concentration-related depression of muscle response. Nicardipine had the most, and diltiazem the least, potent effect. Verapamil and diltiazem 5 and 10μmol litre−1 caused a concentration-dependent enhancement of suxamethonium-induced neuromuscular blockade, but increased the effect of pancuronium only at 10 μmol litre−1. Nicardipine 10μmol litre−1 significantly enhanced pancuronium-induced neuromuscular blockade, but not that produced by suxamethonium.

Abstract. The pharmacokinetics and the endocrine profile of a new low molecular somatostatin derivative, SMS 201–995, were investigated in a group of 35 normal subjects. Clearance studies (n = 6) for this peptide showed a prolonged half-life in plasma, 113 min, following single scinjections of 50 or 100 μg. Arginine stimulation tests (n = 6) were conducted immediately and 180 min after scinjection of 50 μg of SMS 201–995. The stimulatory effect of arginine on GH and insulin was counteracted by the peptide at the P< 0.001 and P< 0.02 significance level, respectively. Delayed arginine stimulation revealed a persistent blockade of the GH release (P< 0.02), whereas a recovery of the insulin response was observed. Plasma glucagon increments following a standard protein meal (n = 10) were significantly (P< 0.001) inhibited by previous scinjection of 50 μg of SMS 201-995. Pretreatment with 50 and 100 μg of SMS 201-995 sc(n = 9) inhibited (P< 0.001) the stimulatory effect of TRH (200 μg iv) on TSH without modifying basal levels. The injection of 100 μg/h during sleep completely abolished the nocturnal GH peak in 4 volunteers. No rebound rise after decline of the suppressive action on GH was recorded in any of the trials.Safety chemistries and blood coagulation studies remained normal and no side-effects or untoward reactions were recorded throughout the investigation.With its high potency, slow plasma clearance, and long action SMS 201–995 may represent a valuable tool in the long-term management of states of inappropriate GH secretion.