Results and predictors of outcome of endoscopic endonasal surgery in Cushing's disease: 20-year experience of an Italian referral Pituitary Center.

PURPOSE: To assess outcomes and predictors of early and long-term remission in patients with Cushing's disease (CD) due to ACTH-secreting adenomas treated via endoscopic endonasal approach (EEA). METHODS: This is a retrospective study. Consecutive patients operated for CD from 1998 to 2017 in an Italian referral Pituitary Center were enrolled. Clinical, radiological, and histological data at enrollment and follow-up were collected. RESULTS: 151 patients (107 F) were included; 88.7% were naïve for treatment, 11.3% had been treated surgically and 11.2% medically. At pre-operative magnetic resonance imaging (MRI), 35 had a macroadenoma and 80 a microadenoma, while tumor was undetectable in 36 patients. Mean age at surgery was 41.1 ± 16.6 years. Diagnosis was confirmed histologically in 82.4% of the cases. Patients with disease persistence underwent second surgery and/or medical and/or radiation therapy. Mean follow-up was 92.3 ± 12.0 (range 12-237.4) and median 88.2 months. Remission rate was 88.1% after the first surgery and 90.7% at last follow-up. One patient died of pituitary carcinoma. Post-surgical cortisol drop (p = 0.004), tumor detection at MRI (p = 0.03) and size < 1 cm (p = 0.045) increased the chance of disease remission; cavernous sinus invasion was a negative predictor of outcome (p = 0.002). Twenty-seven patients developed diabetes insipidus and 18 hypopituitarism. Surgery repetition increased the risk of hypopituitarism (p = 0.03), but not of other complications, which included epistaxis (N = 2), cerebrospinal fluid leakage (1), pneumonia (3), myocardial infarction (1), and pulmonary embolisms (2). CONCLUSIONS: Selective adenomectomy via EEA performed by experienced surgeons, supported by a multidisciplinary dedicated team, allows long-term remission in the vast majority of CD patients with low complication rate.

First Observation of P-odd γ Asymmetry in Polarized Neutron Capture on Hydrogen.

We report the first observation of the parity-violating gamma-ray asymmetry A_{γ}^{np} in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the Spallation Neutron Source at Oak Ridge National Laboratory. A_{γ}^{np} isolates the ΔI=1, ^{3}S_{1}→^{3}P_{1} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless effective field theory. We measured A_{γ}^{np}=[-3.0±1.4(stat)±0.2(syst)]×10^{-8}, which implies a DDH weak πNN coupling of h_{π}^{1}=[2.6±1.2(stat)±0.2(syst)]×10^{-7} and a pionless EFT constant of C^{^{3}S_{1}→^{3}P_{1}}/C_{0}=[-7.4±3.5(stat)±0.5(syst)]×10^{-11} MeV^{-1}. We describe the experiment, data analysis, systematic uncertainties, and implications of the result.

Two-Color Radiation Generated in a Seeded Free-Electron Laser with Two Electron Beams.

We present the experimental evidence of the generation of coherent and statistically stable two-color free-electron laser radiation obtained by seeding an electron beam double peaked in energy with a laser pulse single spiked in frequency. The radiation presents two neat spectral lines, with time delay, frequency separation, and relative intensity that can be accurately controlled. The analysis of the emitted radiation shows a temporal coherence and a shot-to-shot regularity in frequency significantly enhanced with respect to the self-amplified spontaneous emission.

Quality of maternal and neonatal care in Central Asia and Europe--lessons learnt.

In the World Health Organization (WHO) European region despite official high coverage of essential interventions for maternal and neonatal care, there are still significant gaps in the delivery of effective interventions. Since 2001, WHO designed and implemented the Making Pregnancy Safer programme, which includes hands-on training courses in effective perinatal care for maternity teams, development of clinical guidelines, maternal mortality and morbidity case reviews, and assessments of quality of care. This has contributed to enhancing capacity at country level to improve organisation and provision of care. This paper describes the programme's components, challenges, achievements and results.

Observation of time-domain modulation of free-electron-laser pulses by multipeaked electron-energy spectrum.

We present the experimental demonstration of a new scheme for the generation of ultrashort pulse trains based on free-electron-laser (FEL) emission from a multipeaked electron energy distribution. Two electron beamlets with energy difference larger than the FEL parameter ρ have been generated by illuminating the cathode with two ps-spaced laser pulses, followed by a rotation of the longitudinal phase space by velocity bunching in the linac. The resulting self-amplified spontaneous emission FEL radiation, measured through frequency-resolved optical gating diagnostics, reveals a double-peaked spectrum and a temporally modulated pulse structure.

Self-amplified spontaneous emission free-electron laser with an energy-chirped electron beam and undulator tapering.

We report the first experimental implementation of a method based on simultaneous use of an energy chirp in the electron beam and a tapered undulator, for the generation of ultrashort pulses in a self-amplified spontaneous emission mode free-electron laser (SASE FEL). The experiment, performed at the SPARC FEL test facility, demonstrates the possibility of compensating the nominally detrimental effect of the chirp by a proper taper of the undulator gaps. An increase of more than 1 order of magnitude in the pulse energy is observed in comparison to the untapered case, accompanied by FEL spectra where the typical SASE spiking is suppressed.

Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo.

The fungus Candida albicans behaves as a commensal as well as a true pathogen of areas highly enriched in dendritic cells, such as skin and mucosal surfaces. The ability of the fungus to reversibly switch between unicellular yeast to filamentous forms is thought to be important for virulence. However, whether it is the yeast or the hyphal form that is responsible for pathogenicity is still a matter of debate. Here we show the interaction, and consequences, of different forms of C. albicans with dendritic cells. Immature myeloid dendritic cells rapidly and efficiently phagocytosed both yeasts and hyphae of the fungus. Phagocytosis occurred through different phagocytic morphologies and receptors, resulting in phagosome formation. However, hyphae escaped the phagosome and were found lying free in the cytoplasm of the cells. In vitro, ingestion of yeasts activated dendritic cells for interleukin (IL)-12 production and priming of T helper type 1 (Th1) cells, whereas ingestion of hyphae inhibited IL-12 and Th1 priming, and induced IL-4 production. In vivo, generation of antifungal protective immunity was induced upon injection of dendritic cells ex vivo pulsed with Candida yeasts but not hyphae. The immunization capacity of yeast-pulsed dendritic cells was lost in the absence of IL-12, whereas that of hypha-pulsed dendritic cells was gained in the absence of IL-4. These results indicate that dendritic cells fulfill the requirement of a cell uniquely capable of sensing the two forms of C. albicans in terms of type of immune responses elicited. By the discriminative production of IL-12 and IL-4 in response to the nonvirulent and virulent forms of the fungus, dendritic cells appear to meet the challenge of Th priming and education in C. albicans saprophytism and infections.

Endogenous interleukin 4 is required for development of protective CD4+ T helper type 1 cell responses to Candida albicans.

Interleukin (IL)-4-deficient mice were used to assess susceptibility to systemic or gastrointestinal Candida albicans infections, as well as parameters of innate and elicited T helper immunity. In the early stage of systemic infection with virulent C. albicans, an unopposed interferon (IFN)-gamma response renders IL-4-deficient mice more resistant than wild-type mice to infection. Yet, IL-4-deficient mice failed to efficiently control infection in the late stage and succumbed to it. Defective IFN-gamma and IL-12 production, but not IL-12 responsiveness, was observed in IL-4-deficient mice that failed to mount protective T helper type 1 cell (Th1)-mediated acquired immunity in response to a live vaccine strain of the yeast or upon mucosal immunization in vivo. In vitro, IL-4 primed neutrophils for cytokine release, including IL-12. However, late treatment with exogenous IL-4, while improving the outcome of infection, potentiated CD4(+) Th1 responses even in the absence of neutrophils. These findings indicate that endogenous IL-4 is required for the induction of CD4(+) Th1 protective antifungal responses, possibly through the combined activity on cells of the innate and adaptive immune systems.

Experimental demonstration of emittance compensation with velocity bunching.

In this Letter we report the first experiments aimed at the simultaneous demonstration of the emittance compensation process and velocity bunching in a high brightness electron source, the SPARC photoinjector in INFN-LNF. While a maximum compression ratio up to a factor 14 has been observed, in a particular case of interest a compression factor of 3, yielding a slice current of 120 A with less than 2 microm slice emittance, has been measured. This technique may be crucial in achieving high brightness beams in photoinjectors aiming at optimized performance of short wavelength single-pass free electron lasers or other advanced applications in laser-plasma accelerators.

BriXS, a new X-ray inverse Compton source for medical applications.

MariX is a research infrastructure conceived for multi-disciplinary studies, based on a cutting-edge system of combined electron accelerators at the forefront of the world-wide scenario of X-ray sources. The generation of X-rays over a large photon energy range will be enabled by two unique X-ray sources: a Free Electron Laser and an inverse Compton source, called BriXS (Bright compact X-ray Source). The X-ray beam provided by BriXS is expected to have an average energy tunable in the range 20-180 keV and intensities between 1011 and 1013 photon/s within a relative bandwidth ΔE/E=1-10%. These characteristics, together with a very small source size (~20 µm) and a good transverse coherence, will enable a wide range of applications in the bio-medical field. An additional unique feature of BriXS will be the possibility to make a quick switch of the X-ray energy between two values for dual-energy and K-edge subtraction imaging. In this paper, the expected characteristics of BriXS will be presented, with a particular focus on the features of interest to its possible medical applications.

Analysis methodology of movable emittance-meter measurements for low energy electron beams.

The design of photoinjectors for modern free electron laser linac relies heavily on particular beam behavior in the few meters after the gun. To experimentally characterize it a movable emittance meter was proposed and built [L. Catani et al., Rev. Sci. Instrum. 77, 093301 (2006)] based on the beam slicing technique. This paper addresses all the aspects of analysis of the data acquired with the emittance meter and common to any slit based emittance measurement for low energy beams.

Application of intravoxel incoherent motion (IVIM) magnetic resonance imaging in the evaluation of primitive brain tumours.

Intravoxel incoherent motion is a potential non-invasive diagnostic tool in brain tumours, without any clear guidelines for its evaluation yet. In our study, we compare intravoxel incoherent motion with dynamic susceptibility contrast magnetic resonance imaging in the quantification of tumour tissue blood perfusion in 28 patients affected by brain tumours, highlighting the issues encountered during the acquisition set-up and post-processing steps. Intravoxel incoherent motion is a new imaging tool and an alternative technique to dynamic susceptibility contrast-magnetic resonance imaging which is of considerable interest at present. This is partly because it does not require the use of a contrast agent and relies on the intrinsic properties of motion in the capillaries of the spins. Compared to dynamic susceptibility contrast-magnetic resonance imaging, the intravoxel incoherent motion technique is also characterised by better resolution because the gadolinium-based contrast agent bolus used in the standard technique results in a variation by more than 50% of the signal coming from the brain. Finally, intravoxel incoherent motion is more sensitive to the incoherent motion that originates from small capillary vessels, while the dynamic susceptibility contrast signal is also contaminated by the input from larger arteries and veins, which may result in an overestimation of the blood volume. Although there are limitations due to the heterogeneity of the sample considered in our study, intravoxel incoherent motion has been shown to be an accurate noninvasive radiological biomarker, useful to distinguish between low and high grade glial tumours.

Metabolic findings on 3T 1H-MR spectroscopy in peritumoral brain edema.

BACKGROUND AND PURPOSE: Little is known about the metabolic properties of brain edema associated with tumors. This work was conducted on the basis of the assumption that, in the presence of intra-axial and extra-axial brain tumors, the white matter involved by the edema is a site of metabolic change that involves the structure of the myelin sheath. MATERIALS AND METHODS: Thirteen patients comprised our cohort affected by intra-axial and extra-axial cerebral tumors with a peritumoral T2-weighted MR signal hyperintensity as a result of edema, where MR spectroscopy showed no increase in choline-containing compounds. Measurements on proton MR spectroscopy (1H-MR spectroscopy) were performed with a 3T whole-body scanner with use of a point-resolved spectroscopy sequence for localization (TR, 2000 ms; TE, 35 ms), and the metabolites were quantified with the SAGE method. Peak intensities of the main metabolites were expressed as ratios of one another and were compared with values obtained in the white matter of the left frontal region in a control group of 16 healthy volunteers. RESULTS: Choline-to-creatine (Cho/Cr) and myo-inositol-to-creatine (mIns/Cr) signal intensity ratios were normal in all patients. N-acetylaspartate-to-creatine (NAA/Cr) and N-acetylaspartate-to-choline (NAA/Cho) ratios decreased in 4 patients. Glutamate plus glutamine-to-creatine (Glx/Cr) was increased in 10 patients. A resonance peak at 3.44 ppm, strongly suggesting the presence of glucose, was detected in all but 1 patient. Lactate was detected in 12 patients and lipids in 5. Moreover, the resonances that pertained to the aliphatic amino acids valine, leucine, and isoleucine were present in 12 patients. CONCLUSIONS: Our findings on MR spectroscopy confirmed the hypothesis that in the edema surrounding brain tumors, an energy-linked metabolic alteration was associated with injury to the myelin sheath.

Meeting the need for emergency obstetric care in Mozambique: work performance and histories of medical doctors and assistant medical officers trained for surgery.

OBJECTIVE: Nonphysicians in Mozambique have been performing major surgery for more than 20 years, with documented outcomes equivalent to those of specialists. The purpose of this study was to make an inventory of all government hospitals so as to document obstetric surgery performed by 'técnicos de cirurgia' (TCs) and to elucidate their retention at district level. DESIGN: Cross-sectional study of surgical procedures during 2002; longitudinal study of TCs and doctors graduating in 1987, 1988 and 1996. SETTING: All 34 hospitals with an operating theatre in Mozambique. POPULATION: Records of 12,178 major surgical obstetric operations were examined, and 59 medical officers and 34 TCs were interviewed. METHODS: Analysis of all surgical registers during 2002 in all government rural, provincial, general and central hospitals in Mozambique. TCs and doctors who had graduated in the specified years were traced and interviewed; health ministry records were reviewed to confirm assignments. MAIN OUTCOME MEASURES: Proportion of major obstetric surgeries performed by TCs. Proportion of TCs and medical doctors still at rural/district level at 7 years after graduation. RESULTS: Major obstetric surgery is conducted by nonphysicians in 57% of the 12,178 operations scrutinised. In district hospitals, they conducted 92% of 3246 operations. Retention of TCs and medical doctors at district hospital level differed markedly: after 7 years, 88% of the TCs remained in post compared with none of the medical doctors. CONCLUSION: Nonphysicians, trained in surgery, do most of the emergency obstetric surgery in Mozambique, and almost all of that performed in district hospitals. Nonphysicians, compared with physicians, stay longer in rural areas. After 7 years, around 90% of nonphysicians are still working in district hospitals, while almost no physicians remain there.

Tetanus toxin blocks the exocytosis of synaptic vesicles clustered at synapses but not of synaptic vesicles in isolated axons.

Recycling synaptic vesicles are already present in isolated axons of developing neurons (Matteoli et al., Zakharenko et al., 1999). This vesicle recycling is distinct from the vesicular traffic implicated in axon outgrowth. Formation of synaptic contacts coincides with a clustering of synaptic vesicles at the contact site and with a downregulation of their basal rate of exo-endocytosis (Kraszewski et al, 1995; Coco et al., 1998) We report here that tetanus toxin-mediated cleavage of synaptobrevin/vesicle-associated membrane protein (VAMP2), previously shown not to affect axon outgrowth, also does not inhibit synaptic vesicle exocytosis in isolated axons, despite its potent blocking effect on their exocytosis at synapses. This differential effect of tetanus toxin could be seen even on different branches of a same neuron. In contrast, botulinum toxins A and E [which cleave synaptosome-associated protein of 25 kDa. (SNAP-25)] and F (which cleaves synaptobrevin/VAMP1 and 2) blocked synaptic vesicle exocytosis both in isolated axons and at synapses, strongly suggesting that this process is dependent on "classical" synaptic SNAP receptor (SNARE) complexes both before and after synaptogenesis. A tetanus toxin-resistant form of synaptic vesicle recycling, which proceeds in the absence of external stimuli and is sensitive to botulinum toxin F, E, and A, persists at mature synapses. These data suggest the involvement of a tetanus toxin-resistant, but botulinum F-sensitive, isoform of synaptobrevin/VAMP in synaptic vesicle exocytosis before synapse formation and the partial persistence of this form of exocytosis at mature synaptic contacts.

Chronic blockade of glutamate receptors enhances presynaptic release and downregulates the interaction between synaptophysin-synaptobrevin-vesicle-associated membrane protein 2.

During development of neuronal circuits, presynaptic and postsynaptic functions are adjusted in concert, to optimize interneuronal signaling. We have investigated whether activation of glutamate receptors affects presynaptic function during synapse formation, when constitutive synaptic vesicle recycling is downregulated. Using primary cultures of hippocampal neurons as a model system, we have found that chronic exposure to both NMDA and non-NMDA glutamate receptor blockers during synaptogenesis produces an increase in miniature EPSC (mEPSC) frequency, with no significant changes in mEPSC amplitude or in the number of synapses. Enhanced synaptic vesicle recycling, selectively in glutamatergic nerve terminals, was confirmed by the increased uptake of antibodies directed against the lumenal domain of synaptotagmin. No increased uptake was detected in neuronal cultures grown in the chronic presence of TTX, speaking against an indirect effect caused by decreased electrical activity. Enhanced mEPSC frequency correlated with a reduction of synaptophysin-synaptobrevin-vesicle-associated membrane protein 2 (VAMP2) complexes detectable by immunoprecipitation. Intracellular perfusion with a peptide that inhibits the binding of synaptophysin to synaptobrevin-VAMP2 induced a remarkable increase of mEPSC frequency in control but not in glutamate receptor blocker-treated neurons. These findings suggest that activation of glutamate receptors plays a role in the downregulation of the basal rate of synaptic vesicle recycling that accompanies synapse formation. They also suggest that one of the mechanisms through which this downregulation is achieved is an increased interaction of synaptophysin with synaptobrevin-VAMP2.

Introducing Evidence-Based Medicine and guidelines for maternal and newborn care in the Republic of Moldova.

Familiarity with Evidence-Based Medicine (EBM) concepts is low amongst key maternal and newborn care clinicians in Moldova. Simple interventions can increase the knowledge of EBM concepts there.

Novel schemes for the optimization of the SPARC narrow band THz source.

A pulsed, tunable, narrow band radiation source with frequency in the THz region can be obtained collecting the coherent transition radiation produced by a train of ultra-short electron bunches having picosecond scale inter-distance. In this paper, we review the techniques feasible at the SPARC_LAB test facility to produce and manipulate the requested train of electron bunches and we examine the dynamics of their acceleration and compression. In addition, we show how the performances of the train compression and the radiation intensity and bandwidth can be significantly improved through the insertion of a fourth order harmonic cavity, working in the X-band and acting as a longitudinal phase space linearizer.

Antifungal type 1 responses are upregulated in IL-10-deficient mice.

C57BL/6 mice are highly resistant to infections caused by Candida albicans and Aspergillus fumigatus. To elucidate the role of IL-10 produced by C57BL/6 mice during these infections, parameters of infection and immunity to it were evaluated in IL-10-deficient and wild-type mice with disseminated or gastrointestinal candidiasis or invasive pulmonary aspergillosis. Unlike parasitic protozoan infection, C. albicans or A. fumigatus infection did not induce significant acute toxicity in IL-10-deficient mice, who, instead, showed reduced fungal burden and fungal-associated inflammatory responses. The increased resistance to infections as compared to wild-type mice was associated with upregulation of innate and acquired antifungal Th1 responses, such as a dramatically higher production of IL-12, nitric oxide (NO) and TNF-alpha as well as IFN-gamma by CD4+ T cells. Pharmacological inhibition of NO production greatly reduced resistance to gastrointestinal candidiasis, thus pointing to the importance of IL-10-dependent NO regulation at mucosal sites in fungal infections. These results are reminiscent of those obtained in genetically susceptible mice, in which IL-10 administration increased, and IL-10 neutralization decreased, susceptibility to C. albicans and A. fumigatus infections. Collectively, these observations indicate that the absence of IL-10 augments innate and acquired antifungal immunity by upregulating type 1 cytokine responses. The resulting protective Th1 responses lead to a prompt reduction of fungal growth, thus preventing tissue destruction and lethal levels of proinflammatory cytokines.

Cytokines in candidiasis and aspergillosis.

Both innate and T helper (Th) immunity play a central role in fungal infections. A bi-directional influence exists between the two compartments of the immune system, mainly occurring through cytokine production. On the one hand, protective Th1 or nonprotective Th2 cells mediate resistance or susceptibility to disseminated and localized fungal infections by secreting cytokines with activating or deactivating signals for effector phagocytic cells. On the other hand, cells of the innate immune system regulate the development of antifungal T helper responses by producing directive cytokines, such as interleukin (IL)-12 and IL-10. In experimental models of Candida albicans and Aspergillus fumigatus infections, the administration or neutralization of selective cytokines and the use of cytokine-deficient mice have revealed the existence of a hierarchical pattern of cytokine mediated regulation of antifungal Th cell development and effector function. A finely regulated balance of directive cytokines, rather than the relative absence of opposing cytokines, appears to be required for optimal development and maintenance of protective Th1 reactivity to fungi. Thus, it is conceivable that some cytokines may have beneficial or deleterious effects on infection, depending on the dose and timing of endogenous production or exogenous administration. A better understanding of the different, sometimes unexpected, roles of cytokines is required for their use in prophylaxis and therapy of fungal infections, either alone or in combination with antifungal agents.