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The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+(KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients’ outcome.

e-ASTROGAM (‘enhanced ASTROGAM’) is a breakthrough Observatory space mission, with a detector composed by a Silicon tracker, a calorimeter, and an anticoincidence system, dedicated to the study of the non-thermal Universe in the photon energy range from 0.3 MeV to 3 GeV – the lower energy limit can be pushed to energies as low as 150 keV for the tracker, and to 30 keV for calorimetric detection. The mission is based on an advanced space-proven detector technology, with unprecedented sensitivity, angular and energy resolution, combined with polarimetric capability. Thanks to its performance in the MeV–GeV domain, substantially improving its predecessors, e-ASTROGAM will open a new window on the non-thermal Universe, making pioneering observations of the most powerful Galactic and extragalactic sources, elucidating the nature of their relativistic outflows and their effects on the surroundings. With a line sensitivity in the MeV energy range one to two orders of magnitude better than previous generation instruments, e-ASTROGAM will determine the origin of key isotopes fundamental for the understanding of supernova explosion and the chemical evolution of our Galaxy. The mission will provide unique data of significant interest to a broad astronomical community, complementary to powerful observatories such as LIGO-Virgo-GEO600-KAGRA, SKA, ALMA, E-ELT, TMT, LSST, JWST, Athena, CTA, IceCube, KM3NeT, and LISA.

El linfoma primario del sistema nervioso central (LPSNC) es infrecuente y su manejo difiere significativamente del resto de los tumores malignos de esta localización. El texto desarrolla cómo los hallazgos radiológicos a menudo sugieren el diagnóstico precozmente. La imagen típica en los pacientes inmunocompetentes es una masa intraaxial supratentorial con realce homogéneo. Otros hallazgos que deben valorarse son la multifocalidad y el realce en anillo incompleto. En el diagnóstico diferencial del LPSNC deben considerarse principalmente otros tumores malignos del SNC, como el glioblastoma y las metástasis. El LPSNC suele tener menor edema y efecto masa, y respeta el córtex adyacente, siendo infrecuentes la necrosis, la hemorragia y la calcificación. Aunque los hallazgos en secuencias morfológicas son típicos, no son por completo específicos y pueden encontrarse formas atípicas. Las técnicas avanzadas, como la difusión y sobre todo la perfusión, muestran valores cualitativos y cuantitativos que desempeñan un papel importante al diferenciar el LPSNC de otros tumores cerebrales.

Context. Short supersoft X-ray source (SSS) states (durations ≤100 days) of classical novae (CNe) indicate massive white dwarfs that are candidate progenitors of supernovae type Ia.

Classical novae are phenomena caused by explosive hydrogen burning onto an accreting white dwarf. Only one classical nova had been identified in X-rays before the actual optical outburst occurred (V2487 Oph). The recently discovered nova, V2491 Cyg, is one of the fastest (He/N) novae observed to date. Using archival ROSAT, XMM-Newton, and Swiftdata, we show that V2491 Cyg was a persistent X-ray source during its quiescent time before the optical outburst. We present the X-ray spectral characteristics and derive X-ray fluxes. The pre-outburst X-ray emission is variable, and, at least in one observation, it exhibits a soft X-ray source.

Aims.The galactic black hole candidate XTE J1817-330was discovered in outburst by RXTE in January 2006. We present here the results of an XMM-Newton target of opportunity observation, performed on 13 March 2006 (44 days after the maximum), and an INTEGRAL observation performed on 15–18 February 2006 (18 days after the maximum).

Context.Optical novae have recently been identified as the major class of supersoft X-ray sources in M 31based on ROSAT and early XMM-Newton and Chandraobservations.

Aims.The galactic superluminal microquasar GRO J1655-40started a new outburst in February 2005, after seven years in quiescence, rising to a high/soft state in March 2005. In this paper we study the X-ray spectra during this rise.

We searched for X-ray counterparts of optical novae detected in M 31and M 33. We combined an optical nova catalogue from the WeCAPP survey with optical novae reported in the literature and correlated them with the most recent X-ray catalogues from ROSAT, XMM-Newton, and Chandra, and – in addition – searched for nova correlations in archival data. We report 21 X-ray counterparts for novae in M 31– mostly identified as supersoft sources (SSS) by their hardness ratios – and two in M 33. Our sample more than triples the number of known optical novae with a supersoft X-ray phase. Most of the counterparts are covered in several observations allowing us to constrain their X-ray light curves. Selected brighter sources were classified by their XMM-Newton EPIC spectra. We use the well-determined start time of the SSS state in two novae to estimate the hydrogen mass ejected in the outburst to ~$10^{-5}~M_{\odot}$and ~$10^{-6}~M_{\odot}$, respectively. The supersoft X-ray phase of at least 15% of the novae starts within a year. At least one of the novae shows a SSS state lasting 6.1 years after the optical outburst. Six of the SSSs turned on between 3 and 9 years after the optical discovery of the outburst and may be interpreted as recurrent novae. If confirmed, the detection of a delayed SSS phase turn-on may be used as a new method to classify novae as recurrent. At the moment, the new method yields a ratio of recurrent novae to classical novae of 0.3, which is in agreement (within the errors) with previous works.

This research deals with the investigation of the self-healing behavior after ballistic damage of ethylene-methacrylic acid ionomers and theirs blends with epoxidized natural rubber (ENR). The self-healing capability was studied by ballistic puncture tests under different experimental conditions as sample thickness, bullet speed, diameter and shape. Bullet speed ranging from few hundreds meters per second to few km/s were employed. The healing efficiency was evaluated by applying a pressure gradient trough the plates and by checking for possible flow at the damage zone. A morphology analysis of the impact area was made observing all samples by scanning electron microscope.

In the search for new deposits petrochemical extraction Companies are searching in challenging environments as deep sea-beds. At the same time, especially following the Gulf of Mexico disaster, there is a justified concern about the assessment of the installed asset condition. The Aerospace Engineering Department of the Politecnico di Milano and Prysmian Group R&D Department are currently carrying over a joint research project aiming to the development of new methods for the testing and evaluation of health status and conditions to be applied in the field of deep sub-sea umbilical normally employed for the petrochemical hydrocarbon extraction. The monitoring methods and the measurement system under joint development will enable Prysmian to validate vs. full scale measurement the design analytical tools currently utilized to analyze the developed elements versus the operational scenarios for which any particular umbilical is currently designed. Additionally, together with the Politecnico di Milano, Prysmian will develop a real-time measurement system to be utilized, during operational lifetime, for the asset management of the produced sub-sea umbilicals.

Glutamate is the major mediator of excitatory signaling in the mammalian central nervous system (CNS) and it has recently been described to have a central role in the transduction of sensory input in the peripheral nervous system (PNS), too. However, functional glutamatergic systems are expressed by peripheral non-neural tissues as well, such as heart, kidney, lungs, ovary, testis, blood and skin. Interestingly, glutamatergic alterations have been repeatedly described in these tissues in various neuropsychiatric diseases. Here we will review evidence suggesting that glutamate measurements obtained from sampling ex vivo peripheral cells can permit the assessment of the dynamics of glutamate release, uptake, receptor-mediated signaling, synthesis and degradation, and mirror homologous dysfunctions operative within the CNS in each single patient. Among all the available cell types we will focus on leukocytes, platelets and fibroblasts that can be easily obtained from patients multiple times without concerns related to post-mortem changes. Finally, we will briefly review another possibility, offered by testing plasma (and CSF) glutamate levels, allowing the indirect investigation of glutamatemediated crosstalk between central and peripheral compartments. Technical pitfalls of these biomarkers will be contextually emphasized.

Background:Persistent and multiple organ failure (POF and MOF) are predictive of death in acute pancreatitis (AP). Local complications without organ failure are associated with morbidity but a low risk of mortality. Aim:To design a three-category classification of AP severity and to compare it with the Atlanta Classification (AC) in terms of morbidity and mortality. Method:Severe AP was defined as death, POF (148 h) or MOF. Moderate AP was defined as the presence of acute collections and/or pancreatic necrosis. Mild AP was defined by exclusion. We compared this classification with AC in 144 episodes of AP. Results:In the three-category classification, severe AP was associated with significantly more frequent intensive care unit admission, invasive treatment and mortality than moderate and mild AP (p < 0.01). Severe AP patients required longer hospital stay and more nutritional support than mild AP patients (p < 0.01). Patients with moderate AP had significantly longer hospital stay and more need for nutritional support than patients with mild AP (p < 0.01). Five patients died, all of them with MOF and/or POF. Conclusions:A three-category classification distinguishes three homogeneous groups of severity.

Classical novae CNe have recently been reported to represent the major class of supersoft Xray sources SSSs in the central area of our neighbouring galaxy M 31. This paper presents a review of results from recent Xray observations of M 31 with XMMNewton and Chandra. We carried out a dedicated optical and Xray monitoring program of CNe and SSSs in the central area ofM 31. We discovered the first SSSs in M 31 globular clusters GCs and their connection to the very first discovered CN in a M 31 GC. This result may have an impact on the CN rate in GCs. Furthermore, in our optical and Xray monitoring data we discovered the CN M3 1N 200711a, which shows a very short SSS phase of 29–52 days. Short SSS states durations ≤ 100 days of CNe indicate massive white dwarfs WDs that are candidate progenitors of supernovae type Ia. In the case of M31N 200711a, the optical and Xray light curves suggest a binary containing a WD with MWD> 1.0 M. Finally, we present the discovery of the SSS counterpart of the CN M31N 200604a. The Xray light curve of M31N 200604a shows shorttime variability, which might indicate an orbital period of about 2 hours © 2010 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim

Nova V5116 Sgr 2005 No. 2, discovered on 2005 July 4, was observed with XMMNewton in March 2007, 20 months after the optical outburst. The Xray spectrum showed that the nova had evolved to a pure supersoft Xray source, indicative of residual Hburning on top of the white dwarf. The Xray lightcurve shows abrupt decreases and increases of the flux by a factor 8 with a periodicity of 2.97 h, consistent with the possible orbital period of the system. The EPIC spectra are well fit with an ONe white dwarf atmosphere model, with the same temperature both in the low and the high flux periods. This rules out an intrinsic variation of the Xray source as the origin of the flux changes, and points to a possible partial eclipse as the origin of the variable light curve. The RGS high resolution spectra support this scenario showing a number of emission features in the low flux state, which either disappear or change into absorption features in the high flux state. A new XMMNewton observation in March 2009 shows the SSS had turned off and V51 16 Sgr had evolved into a weaker and harder Xray source © 2010 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim

Detection of Xrays from classical novae, both in outburst and postoutburst, provides unique and crucial information about the explosion mechanism. Soft Xrays reveal the hot white dwarf photosphere, whenever hydrogen H nuclear burning is still on and expanding envelope is transparent enough, whereas harder Xrays give information about the ejecta andor the accretion flow in the reborn cataclysmic variable. The duration of the supersoft Xray emission phase is related to the turnoff of the classical nova, i.e., of the Hburning on top of the white dwarf core. A review of Xray observations is presented, with a special emphasis on the implications for the duration of postoutburst steady Hburning and its theoretical explanation. The particular case of recurrent novae both the “standard” objects and the recently discovered ones will also be reviewed, in terms of theoretical feasibility of short recurrence periods, as well as regarding implications for scenarios of type Ia supernovae © 2010 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim

We summarise our optical monitoring program of VY Scl stars with the SMARTS telescopes, and triggered Xray as well as optical observations afterduring state transitions of V504 Cen and VY Scl © 2010 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim

Context. Classical novae (CNe) have been found to represent the major class of supersoft X-ray sources (SSSs) in our neighbour galaxy M?31.Aims. We determine the properties and evolution of the two first SSSs ever discovered in the M?31 globular cluster (GC) system.Methods. We have used XMM-Newton, Chandra?and Swift?observations of the centre region of M?31 to discover both SSSs and to determine their X-ray light curves and spectra. We performed detailed analysis of XMM-Newton?EPIC PN spectra of the source in Bol 111 (SS1) using blackbody and NLTE white dwarf (WD) atmosphere models. For the SSS in Bol 194 (SS2) we used optical monitoring data to search for an optical counterpart.Results. Both GC X-ray sources were classified as SSS. We identify SS1 with the CN M31N?2007-06b?recently discovered in the M?31 GC Bol 111. For SS2 we did not find evidence for a recent nova outburst and can only provide useful constraints on the time of the outburst of a hypothetical nova.Conclusions. The only known CN in a M?31 GC can be identified with the first SSS found in a M?31 GC. We discuss the impact of our observations on the nova rate for the M?31 GC system.

Aims. On 28 February 2007 a new outburst of the previously known transient source XTE?J1856+053 was detected with RXTE/ASM. We present here the results of an XMM-Newton (0.5?10.0?keV) Target of Opportunity observation performed on 14?March 2007, aimed at constraining the mass of the compact object in this X-ray binary and determining its main properties.Methods. The EPIC-pn camera was used in Timing mode and its spectrum fit together with the RGS data. IR observations with GROND at the 2.2?m telescope in La Silla provide further information on the system.Results. The X-ray light curve shows that both the 1996 and the 2007?outbursts had two peaks. The X-ray spectrum is well fit with a thermal accretion disk model, with kTin= 0.75(?0.01)?keV and foreground absorption NH= 4.5(?0.1)?1022?cm-2. The low disk temperature favours a black-hole as accreting object, with an estimated mass in the range 1.3?4.2?M?. From the IR upper limits we argue that XTE?J1856+053 is a low mass X-ray binary. We estimate the orbital period of the system to be between 3 and 12?h.

Aims. The purpose of this study is to find transient X-ray sources in M?31 and to investigate and classify their nature. Methods. Three X-ray transients were observed with Swift. For each of the three X-ray transients, we used the Swift X-ray and optical data with observations from XMM-Newton and Chandra to investigate the lightcurves and the spectra of the outburst, thereby identifying the source types. Results. The outburst of XMMU J004215.8+411924 lasted about one month. The source had a hard power-law spectrum with a photon index of 1.6. It was previously identified as a Be/X-ray binary based on the optical identification with a star. However, we show that, with improved source coordinates it is clear that the optical source is not the counterpart to the X-ray source. The source SWIFT?J004217.3+411532 had a bright outburst, after which it slowly decayed over half a year. The spectrum was soft, corresponding to a thermal accretion disc with an innermost temperature of ~250-600?eV. The source was not seen in the optical, and the soft spectrum indicates that the source is most likely a black-hole low-mass X-ray binary. M31N 2006-11a is a nova that was previously observed in the optical. We detected it both in X-rays and UV with Swift ~half a year after the optical maximum, after which it decayed below the Swift detection threshold within a month. The spectrum of the X-ray transient can be modelled by a black-body with a temperature of 50 eV. We use catalogues of X-ray transients in M?31 to estimate their rate, and we find a lower limit of 9?yr-1.

Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin‐like growth factor binding protein (IGFBP)‐3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP‐3 plays a role in promoting angiogenesis. IGFBP‐3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up‐regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)‐2 and ‐9. IGFBP‐3 even induced membrane‐type 1 MMP (MT1‐MMP), which regulates MMP‐2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP‐3‐induced network formation and inhibited VEGF, MT1‐MMP but not IGF‐I up‐regulation. IGF‐I activated SphK, leading to sphingosine‐1‐phosphate (S1P) formation. The IGF‐I effect on SphK activity was blocked by specific inhibitors of IGF‐IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF‐I signaling prevented the IGFBP‐3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF‐I up‐regulation. Finally, IGFBP‐3 dose‐dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo. Thus, IGFBP‐3 positively regulates angiogenesis through involvement of IGF‐IR signaling and subsequent SphK/S1P activation.

Resveratrol, a natural product with a stilbene structure, exerts profound proapoptotic activity in human cancer cells, by triggering the accumulation of ceramide, a bioactive sphingolipid. We studied the biological effects of seven methoxylated and/or naphthalene-based resveratrol analogues and compared these compounds with resveratrol with the objective to identify an analogue with higher ceramide-mediated proapoptotic activity relative to resveratrol. Here we show that the compound with three hydroxyls and a naphthalene ring is the most effective in triggering apoptosis coupled to the induction of endogenous ceramide in human cancer cells.

A non-cytopathic strain of BVDV-2 was isolated from a batch of live infectious bovine rhinotracheitis (IBR) vaccine, and inoculated intranasally into four 3-month-old calves. Severe signs of disease developed by days 4 and 6 in three of the calves, free of BVDV and antibodies to BVDV, that had been exposed to the virus. These calves survived the acute phase of the infection and progressively recovered. BVDV was consistently isolated, or the respective viral RNA was detected, in the buffy coats from blood samples collected starting from days 2 or 4 up to days 11 or 14 after the experimental infection. Viral RNA was also detected in sera from these infected calves until the presence in the serum of virus neutralizing antibodies was demonstrated. By contrast, the only calf having pre-existing neutralizing antibodies to BVDV at the start of the study was protected from the disease. No virus was detected at any time after experimental inoculation of this calf. Genomic characterization of the BVDV-2 isolated in cell cultures, or detected in sera from the experimentally infected animals, revealed 100% homology in the nucleotide sequence with the BVDV-2 detected as a contaminant of the live IBR virus vaccine. These findings provided evidence of the infective nature of the contaminant BVDV-2 and of its potential to generate disease outbreaks when inoculated into susceptible animals.

Follicular fluid from women with endometriosis has been shown to induce a higher endometrial cell proliferation than that derived from women without the disease. To elucidate this issue further, the aims of the present study were to compare the ability of follicular fluid and peritoneal fluid to stimulate both endometrial and endometriotic cell proliferation and to verify whether the mitogenic effect was merely sex steroid-dependent. Endometrial and endometriotic cells were cultured in follicular fluid or peritoneal fluid diluted in serum-free media; the growth induced in these conditions was compared with that obtained by culturing these cells in medium supplemented with charcoal stripped calf serum and a correspondent content of 17-beta-oestradiol and progesterone. Follicular fluid was able to induce significantly higher cell proliferation than peritoneal fluid from controls, patients with endometriosis stage I-II and women with endometriosis stage III-IV (P < 0.05). Moreover, the growth in control media containing a corresponding amount of steroid hormones was significantly lower than that obtained with follicular or peritoneal fluids. This finding indicates that the stimulating effect is not simply related to the concentrations of 17-beta-oestradiol and progesterone present in these fluids. Finally, based on these results and on other previous observations, the hypothesis that follicular fluid may be involved in the development of endometriotic ovarian cysts is discussed.

Background and Purpose:Experimental evidence indicates cytokine and neurotrophin production in brain tissue after stroke. Since neurotrophins may also be released from blood cells, we measured nerve growth factor (NGF) and transforming growth factor (TGF)-β serum levels in 40 patients at various times after stroke and compared them to those in 20 healthy controls. Methods:Venous blood was obtained 1, 4, 10, 30 and 90 days after stroke and NGF and TGF-β serum levels were measured by commercial ELISA. Values at each time were correlated with stroke severity, assessed using the National Institute of Health Stroke Scale, and with lesion volume, calculated using Cavalieri’s direct estimator on a computerized tomography scan performed 5 days after stroke. Results and Conclusions:Although no significant differences between the two groups were demonstrated, in stroke patients, serum neurotrophins were significantly associated with clinical and neuroradiological parameters of brain injury and positively correlated with each other in the acute phases of stroke, suggesting that stroke may modulate peripheral neurotrophin levels.

Following the first official report of a clinically severe outbreak of bovine viral diarrhoea disease occurring in a farm in northern Italy, which had originated from the use of a live vaccine contaminated with a strain of BVD genotype II virus, a retrospective study on the prevalence of BVDV genotypes in Italy became highly relevant. For this purpose, the genotype of 78 BVDV-positive specimens, obtained in 1998–1999 from dairy cattle in an area near to where the outbreak occurred, was characterized by PCR technology. Two sets of primers, spanning the 5′ UTR of BVDV genome, were used sequentially in a first round of RT-PCR, performed on viral RNA extracted directly from 15 clinical samples and 63 BVDV-infected cell-culture fluids; a second PCR assay followed to selectively amplify only BVDV genotype II. All the viruses under study were characterized as BVDV genotype I. As well as contributing to a better understanding of the prevalence of BVDV genotypes in the field, the results of the present study illustrate the possibility that novel BVDV strains can emerge in susceptible animals through the use of contaminated immunobiological products for bovine use.

The aim of this study was to study the emotional impact of in-vitro fertilization (IVF) and any possible influence due to the type of diagnosis, duration of infertility, number of cycles and type of responses to treatment. The study was carried out on 200 patients admitted to hospital for the final stages of IVF (oocyte retrieval and embryo transfer). The psychological measures taken into consideration were: state and trait anxiety levels (Stait-Trait Anxiety), unconscious and symptomatic anxiety, perception of self and of others (EWI). Monitoring of anxiety levels during hospitalization highlighted significant differences with respect to the state anxiety values (P < 0.01) and general anxiety (P < 0.05), but not with respect to trait anxiety. The level of state anxiety of women with a diagnosis of infertility was significantly lower (P < 0. 05). Women who have experienced infertility of medium to long duration presented a significantly lower state anxiety value (P < 0. 01). The failure of oocyte fertilization determines a significant increase in state anxiety level (P < 0.01) There were no significant differences in anxiety values with respect to the cycle number. Perceptive functioning was normal.

Summary.: Defects in mitochondrial enzymes have been found not only in substantia nigra, but also in platelets from Parkinson's Disease (PD) patients, suggesting a systemic impairment of energy metabolism. Since platelets present an energy-dependent glutamate uptake similar to that described in central nervous system, glutamate uptake was determined in platelets from 34 PD patients and 21 age-related normal controls, as Na+-dependent [3H]glutamate influx; glutamate level was also analyzed by reverse-phase HPLC. A 50% reduction of glutamate uptake (p < 0.001) was observed in idiopathic PD patients, respect to controls and secondary parkinsonian syndromes. The decrease correlated with the severity of PD, measured by the UPDRS (r = −0.54; P < 0.05). Glutamate level was increased in platelets of PD patients, but was not correlated to the uptake decrease. Both phoenomena may be explained by the modifications of mitochondrial enzymes described in platelets, which could be used as a peripheral model of glutamatergic function in PD.

The aim of this study was to investigate inhibin B and follicle stimulating hormone (FSH) secretion in a large group of oligozoospermic subjects affected by different degrees of testicular damage, before and after FSH treatment. A total of 135 oligozoospermic subjects (sperm count < 20 x 10(6)/ml) were evaluated for seminal parameters and FSH, luteinizing hormone (LH), testosterone and inhibin B plasma concentrations. Testicular structure was analysed with bilateral fine needle aspiration cytology. Inhibin B showed an inverse correlation with FSH, no correlation with sperm concentration and a significant relationship with intratesticular spermatid number, demonstrating that testicular spermatids play an important role in the control of inhibin B production. Twenty-five subjects with sperm counts < 10 x 10(6)/ml were treated with FSH; 11 of these had basal FSH and inhibin B plasma concentrations in the normal range (group A), while in seven subjects FSH was elevated (> 7 IU/l) with normal inhibin B (group B), and in seven patients FSH was high and inhibin B reduced (< 80 pg/ml) (group C). During treatment, in group A patients inhibin B plasma concentrations increased significantly after 2, 3 and 4 weeks of FSH administration and declined thereafter to pre-treatment concentrations. Groups B and C did not show any modification during the treatment. In the same period, in group A FSH increased significantly after 2, 3 and 4 weeks and subsequently declined. In groups B and C, FSH increased significantly after 2 weeks and remained elevated during the following period. The results of the present study confirm the significant inverse correlation between inhibin B and FSH plasma concentrations in subjects with disturbed spermatogenesis, and demonstrate that inhibin B reflects Sertoli cell function and their interaction with spermatids. FSH and inhibin B concentrations are an expression of the spermatogenic status of seminiferous tubules. FSH treatment seems to modify inhibin B plasma concentrations only in subjects with normal basal FSH and inhibin B, independently from the effects of this therapy on sperm production.

Previous work from our laboratory has revealed that extracellular ATP is a rapid and potent activator of human sperm acrosome reaction and fertilizing ability. In the present study, we assessed the effects of in-vitro sperm incubation with ATP on fertilization and embryo development in couples undergoing in-vitro fertilization (IVF) for male factor infertility. Oocytes from 22 women undergoing ovulation induction were divided in two groups and inseminated in vitro either with selected spermatozoa from the corresponding partner suffering from male factor infertility pre-incubated with ATP (2.5 mM) for 1 h, or with spermatozoa incubated with 0.9% NaCl solution (control group). After insemination, fertilization was assessed by the presence of pronuclei and then by embryo cleavage. The fertilization rate in the group of oocytes inseminated with ATP-treated spermatozoa improved significantly with respect to the control group (65.7 versus 42.5%, P < 0.01). No significant differences were observed in embryo cleavage and embryo quality. Embryos from both treated and control groups were transferred together in 20 transfer procedures, and in two couples fertilization was not obtained. Nine pregnancies occurred: one biochemical, one miscarriage, and seven patients delivered 9 healthy babies. Two pregnancies were twin with an overall pregnancy rate of 40.9% per cycle and of 45% per transfer. In conclusion, the results of the present study demonstrate that, in humans, extracellular ATP induces a significant increase of sperm fertilizing potential, as these findings are a rationale for the use of ATP for in-vitro treatment of human spermatozoa during IVF.