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We present the clinical case of a 51-year-old male patient, affected by common variable immunodeficiency (CVID). In his history recurrent orbital cellulitis, exacerbation of chronic right dacryocystitis, lacrimal sac empyema with periodic episodes of dacryocutaneous fistolization. The coexistence of these particular immunological defects and the lack of literature about similar cases required an accurate evaluation of each step of the diagnostic and therapeutic approach. We performed an endoscopic endonasal dacryocystorhinostomy with “cold” instruments. No surgical complications were observed in the immediate postsurgical period. We balanced the necessity of a follow-up based on frequent office evaluation and the current pandemic emergency, in order to not expose the patient to an additional infectious risk. The discussion will focus on several aspects: the adequacy of radiological, the “cold” surgical technique, the choice of avoiding endocanalicular prostheses. We will discuss also about the use of oral and topical therapy, avoiding probable post-surgical infectious complications.

Background Inflammatory Bowel Disease (IBD), Crohn's Disease (CD) and Ulcerative Colitis (UC), are chronic and immune-mediated diseases with a relapsing-remitting trend. The overall incidence of these diseases is increasing. However, it is estimated that more than one third of patients experienced symptoms for more than one year before diagnosis. Delay in IBD diagnosis has several clinical, therapeutic and economic implications. Early diagnosis and proper treatment are the cornerstones for improving the standard of care for these patients.This study aims to evaluate the diagnostic delay in patients with IBD and to analyze the clinical and economic burden of the delay in IBD diagnosis in patients treated with biological drugs. Methods An observational and retrospective study was performed in IBD patients, regularly followed in our IBD Unit. Data regarding delay in IBD diagnosis were assessed through a questionnaire evaluating the disease course. Moreover, data about biologics dispensation were obtained from the medical records in the period 2014-2020. Results 606 IBD patients were enrolled. The median delay in IBD diagnosis was 5.0 months (IQR:1.0 11.0); it was statistically lower in UC patients (4 months (IQR: 1.0 12.0)) compared to CD (6 months (IQR: 2.0 12.0)) ( p =0.041). Of these 606, 229 patients were treated with biological therapy; in this subgroup 58.9% showed a diagnostic delay. The statistical analysis showed that the diagnostic delay was statistically significant associated with biological drugs (p=0.041). Conversely, there was no association with surgical treatment. Moreover, it has appeared that the diagnostic delay is associated, with a trend of statistical significance, with need to switch or swap to other biologics (p=0.058). Regarding economic burden, patients with delayed diagnosis have significantly higher median annual cost of biological therapy than patients without diagnostic delay (€7179.26 vs € 5131.51 p= 0.009). Conclusion The diagnostic delay in IBD represents a challenge with clinical, therapeutic and economic impact. It’s crucial to cooperate with general practitioner and gastroenterologists not dedicated to IBD in order to reduce the diagnostic delay and guarantee an effective, appropriate and early treatment that will improve the patients’ quality of life and meanwhile reduce the health care system costs.

Introduction: Stereotactic ablative radiotherapy (SABR) has been shown to increase survival in oligometastatic disease, but local control of colorectal metastases remains poor. We aimed to identify potential predictive factors of SBRT response through a multicenter large retrospective database and to investigate the progression to the polymetastatic disease (PMD). Material and methods: The study involved 23 centers, and was approved by the Ethical Committee (Prot. Negrar 2019-ZT). 1033 lung metastases were reported. Clinical and biological parameters were evaluated as predictive for freedom from local progression-free survival (FLP). Secondary end-point was the time to the polymetastatic conversion (tPMC). Results: Two-year FLP was 75.4%. Two-year FLP for lesions treated with a BED < 00 Gy, 100–124 Gy, and ≥125 Gy was 76.1%, 70.6%, and 94% (p = 0.000). Two-year FLP for lesion measuring ≤10 mm, 10–20 mm, and >20 mm was 79.7%, 77.1%, and 66.6% (p = 0.027). At the multivariate analysis a BED ≥125 Gy significantly reduced the risk of local progression (HR 0.24, 95%CI 0.11–0.51; p = 0.000). Median tPMC was 26.8 months. Lesions treated with BED ≥125 Gy reported a significantly longer tPMC as compared to lower BED. The median tPMC for patients treated to 1, 2–3 or 4–5 simultaneous oligometastases was 28.5, 25.4, and 9.8 months (p = 0.035). Conclusion: The present is the largest series of lung colorectal metastases treated with SABR. The results support the use of SBRT in lung oligometastatic colorectal cancer patients as it might delay the transition to PMD or offer relatively long disease-free period in selected cases. Predictive factors were identified for treatment personalization.

Somatostatin receptors (SSTR1–5) mediate antiproliferative effects. In C6 rat glioma cells, somatostatin is cytostatic in vitro via phosphotyrosine phosphatase-dependent inhibition of ERK1/2 activity mediated by SSTR1, -2, and -5. Here we analyzed the effects of SSTR activation on C6 glioma growth in vivo and the intracellular mechanisms involved, comparing somatostatin effects with selective agonists for SSTR1, -2, and -5 (BIM-23745, BIM-23120, BIM-23206) or receptor biselective compounds (SSTR1 and -2, BIM-23704; and SSTR2 and -5, BIM-23190). Nude mice subcutaneously xenografted with C6 cells were treated with somatostatin, SSTR agonists (50 μg, twice/day), or vehicle. Tumor growth was evaluated every 3 days for 19 days. The intracellular pathways responsible of SSTR effects in vivo were evaluated measuring Ki-67, phospho-ERK1/2, and p27kip1 expression by immunohistochemistry in sections from explanted tumors. Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation and induced upregulation of p27Kip1, whereas only a modest activation of caspase-3 was observed. Somatostatin (acting on SSTR1, -2, and -5) displayed the highest efficacy; SSTR5 selective agonist showed a stronger effect than SSTR1 agonist, and SSTR2 agonist was less effective. On the other hand, SSTR1 and -2 agonists maximally reduced tumor neovascularization. The combined activation of SSTR1 and -2 showed a synergistic activity, reaching a higher efficacy than BIM-23206, whereas the simultaneous activation of SSTR2 and -5 resulted in a response resembling SSTR5 effects. Thus the simultaneous activation of different SSTRs inhibits glioma cell proliferation in vivo through both direct cytotostatic and antiangiogenic effects.

Behavior of humpback whales was observed during the reproductive period off the northern coast of the state of Bahia (NB, n = 378 groups) and at the Abrolhos Bank (AB, n = 919) to compare patterns and group composition between the two locations. Alone individuals and dyads were most often encountered in both areas, although mother-calf pairs were more common in AB. While these two regions comprise distinct concentrations of humpback whales, with intrinsic environmental differences, behavior patterns were quite similar. The only behavioral differences found where for "tail up" and "resting". The patterns found here may reflect differences in the protection status of the areas or intrinsic environmental differences.Eventos e estados comportamentais de baleias jubarte durante a temporada reprodutiva foram observados no Litoral Norte da Bahia (LNB) e no Banco dos Abrolhos (BA), para identificar possíveis diferenças nos padrões comportamentais específicos a determinadas composições de grupo. Foram analisados 378 grupos de baleias jubarte no LNB e 919 no BA. Obteve-se uma predominância de duplas e animais solitários em ambas as áreas. No entanto, grupos de "fêmea e filhote" foram mais comumente observados no BA, quando comparados ao LNB. Apesar das duas áreas serem distintas quanto à concentração de baleias jubarte, com diferenças ambientais intrínsecas, obtiveram-se probabilidades de ocorrência das condutas bastante similares para ambas as áreas. Diferenças significativas na probabilidade de ocorrência foram obtidas apenas para as condutas "exposição da caudal" e "repouso". As diferenças obtidas neste estudo, comparando-se as duas regiões amostradas, possivelmente refletem diferenças no status de proteção da área e/ou características ambientais intrínsecas a cada área.

Solar hydrogen production via a two-step water-splitting thermochemical cyclic process is considered via MgO/Mg redox reactions. The first endothermic step is the production of Mg by carbothermal or methanothermal reduction of MgO, using concentrated solar energy as the source of high-temperature process heat. The second exothermic step is the steam-hydrolysis of Mg for the production of H 2 and MgO; the latter is recycled to the first step. Both reaction steps have been thermodynamically examined and experimentally investigated by means of thermogravimetric analysis. The carbothermal reduction of MgO was performed in the temperature range 1450–1550 °C using wood charcoal and petroleum coke as reducing agents. The steam-hydrolysis of Mg was studied in the temperature range 350–550 °C using various water vapor concentrations. Solid products were characterized via BET, XRD, and SEM. The rate laws of both reaction steps were determined by applying either a solid–solid diffusion kinetic model or the gas–solid shrinking core kinetic model.

The coordinated activity of estrogens and epidermal growth factor receptor (EGFR) family agonists represents the main determinant of breast cancer cell proliferation. Stromal cell-derived factor-1 (SDF-1) enhances extracellular signal-regulated kinases 1 and 2 (ERK1/2) activity via the transactivation of EGFR and 17beta-estradiol (E2) induces SDF-1 production to exert autocrine proliferative effects. On this basis, we evaluated whether the inhibition of the tyrosine kinase (TK) activity of EGFR may control different mitogenic stimuli in breast tumors using the EGFR-TK inhibitor gefitinib to antagonize the proliferation induced by E2 in T47D human breast cancer cells. EGF, E2, and SDF-1 induced a dose-dependent T47D cell proliferation, that being nonadditive suggested the activation of common intracellular pathways. Gefitinib treatment inhibited not only the EGF-dependent proliferation and ERK1/2 activation but also the effects of SDF-1 and E2, suggesting that these activities were mediated by EGFR transactivation. Indeed, both SDF-1 and E2 caused EGFR tyrosine phosphorylation. The molecular link between E2 and SDF-1 proliferative effects was identified because 1,1'-(1,4-phenylenebis(methylene))-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist, inhibited SDF-1- and E2-dependent proliferation and EGFR and ERK1/2 phosphorylation. EGFR transactivation was dependent on c-Src activation. E2 treatment caused a powerful SDF-1 release from T47D cells. Finally, in SKBR3, E2-resistant cells, EGFR was constitutively activated, and AMD3100 reduced EGFR phosphorylation and cell proliferation, whereas HER2-neu was transactivated by SDF-1 in SKBR3 but not in T47D cells. In conclusion, we show that activation of CXCR4 transduces proliferative signals from the E2 receptor to EGFR, whose inhibition is able to revert breast cancer cell proliferation induced by multiple receptor activation.

Incubation of hippocampal slices with different concentrations of creatine (0.5, 1, 10, 25 mM) results in a dose-dependent increase in intracellular phosphocreatine (PCr). Electrophysiological evidence suggests that this effect can protect neurons from anoxic damage by delaying the depletion of ATP during oxygen deprivation. In this paper we show that incubation of brain slices with varying doses of creatine increases intracellular phosphocreatine and delays anoxic depolarization (AD) in a dose-dependent way. Specifically, addition to the incubation medium of 1 mM creatine significantly increased AD latency during hypoxia and prevented irreversible neuronal damage. Adding 0.5 mM creatine had no significant effect. Higher concentrations of creatine (up to 25 mM) did not provide any better protection. Our data also suggest a linear correlation between intracellular PCr and AD latency. These data report neural protection by exogenous creatine at concentrations lower than those usually reported in the literature.

Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knock-in mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region- and time- specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2∷eGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.

Serotonin (5-HT) is a neurotransmitter involved in many aspects of the neuronal function. The synthesis of 5-HT is initiated by the hydroxylation of tryptophan, catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH (TPH1 and TPH2) have been identified, with TPH2 almost exclusively expressed in the brain. Following TPH2 discovery, it was reported that polymorphisms of both gene and non-coding regions are associated with a spectrum of psychiatric disorders. Thus, insights into the mechanisms that specifically regulate TPH2 expression and its modulation by exogenous stimuli may represent a new therapeutic approach to modify serotonergic neurotransmission. To this aim, a CNS-originated cell line expressing TPH2 endogenously represents a valid model system. In this study, we report that TPH2 transcript and protein are modulated by neuronal differentiation in the cell line A1 mes-c-myc (A1). Moreover, we show luciferase activity driven by the human TPH2 promoter region and demonstrate that upon mutation of the NRSF/REST responsive element, the promoter activity strongly increases with cell differentiation. Our data suggest that A1 cells could represent a model system, allowing an insight into the mechanisms of regulation of TPH2 and to identify novel therapeutic targets in the development of drugs for the management of psychiatric disorders. TPH2 is the rate-limiting enzyme for the synthesis of serotonin, expressed almost exclusively in the brain. We found, in a CNS-derived cell line (A1 cells) that endogenous TPH2 increases upon differentiation, and in undifferentiated cells upon knock down of REST/NRSF. A1 cells represent a model to study the regulation of TPH2 and to identify targets to modulate serotonin neurotransmission. © 2012 International Society for Neurochemistry.

A new method for evoking the tail flick reflex is introduced, using short duration or “impulsive” nociceptive stimuli, which allow synchronization and recording of electrophysiological responses. Ten adult rats were studied, by means of thermal (CO2 laser infrared pulse with 30 ms duration, 7.5 or 10 W), electric (a 25 ms train of five 0.2 ms pulses, with 5 or 10 mA intensity) or mechanical (pin pressed with 5 g force) stimuli. Both electromyographic and strain gauge mechanical responses were recorded from the tail. All three types of stimulation gave rise to three components, named early, late and ultralate, respectively occurring in the range of 19–97 ms, 190–519 ms, 1523–2765 ms. Conduction velocities of the underlying afferent fibres were calculated by moving the stimulation site. The early component could be linked to Aδ afferents, while late and ultralate components were due to unmylinated C afferents. Experiments with Fentanyl (20 μg/kg) showed that only the C linked components were depressed, with the ultralate component the most affected, possibly because supraspinally originated. Tail flick reflex evoked by impulsive stimuli is believed to be an important electrophysiological complement to behavioural procedures, useful in identifying the site of action of analgesics and other drugs upon the spinal and supraspinal centres involved in nociception.

We report the observation of Fano-like antiresonance lineshapes for ungerade modes in the low temperature spectra of Cu(DM-DCNQI)2 and its deuterated analog. Consideration of the existing structural and optical data leads us to conclude that the unusual vibronic coupling mechanism responsible for the observed lineshapes occurs via the effect of the vibrations on the pπ-d hybridization of the conduction bands. This brings further support to the existence of a mixed-valence Cu I / II state in the studied compounds. The observation of additional vibronic effects attributed to electron charge oscillations induced by the a g modes in Cu(DM-DCNQI-d8)2 suggests that the deuterium substitution favours the crossing of the border between the low temperature metallic and insulating phases.

{2,2′-bis-1,3-dithiole-1,2,4,5-tetracyanobenzene}, (TTF-TCNB), C6H4S4-C10H2N4,M=382.3, monoclinic,P21/a,a=9.194(3),b=12.342(3),c=7.426(2) A,β=95.12(3)°,Z=2,D x =1.52 Mg m−3, λ(MoKα)=0.71069 A,μ=0.51 mm−1,F(000)=776,T=293 K, finalR=0.039 for 1480 unique observed [F o >4σ(F 2 )] reflections. The complex represents a member of the series of crystal structures of molecular complexes containing TTF as an electron donor and TCNB as an electron acceptor. The structure was solved by direct methods and has been refined by full matrix least-squares calculations. The constituent molecules are stacked alternatively in infinite columns along thec axis. The mean separation of the molecular planes, which are inclined at the angle of 4.4°, is 3.48 A. There are no unusually short intermolecular contacts. Bond lengths and angles in the component molecules agree with values for neutral species; also the infrared and Raman spectra indicate a very slight degree of ionicity.

The results of a vibrational analysis of neutral N,N’‐dicyanoquinonediimine (DCNQI) and of 2,5‐X,Y‐DCNQI (X■Y■Cl; X■Cl, Y■CH3; X■Y■CH3 or CD3) are presented. A sound assignment of the in‐plane fundamental vibrational modes is discussed also in terms of a normal coordinate analysis (NCA) based on a modified valence force field. For light and deuterated 2,5‐dimethyl‐dicyanoquinonediimine (DMDCNQI) the vibrational analysis is extended to the corresponding radical anion. The comparison of the vibrational assignment of neutral and fully ionized species, together with the results of the NCA, leads to the identification of a strong Duschinsky effect, as well as of the frequency shifts relative to the ionization process. The buν47 fundamental mode (quinoid C■N stretch) is recognized as diagnostic of the degree of charge transfer (CT) for DMDCNQI component units of CT systems. The relative values of the linear electron–molecular vibration (e–mv) coupling constants for the neutral and ionized DMDCNQI molecular stru...

Wires and tapes of Bi-based superconductors have been produced by the standard powder in tube technique, using silver sheaths. Different geometries of samples have been processed, including single core wires, multi-filamentary wires and tapes. For each configuration both straight samples as well as coils have been prepared and electrically characterized at 77 K at zero field and at 4.2 K in magnetic fields up to 15 T. At 77 K straight samples exhibit critical current densities up to 8000 A/cm2 at zero magnetic field and up 75000 A/cm2 at 4.2 K. Due to a very weak field dependence, Jc at 4.2 K at 15 T is still higher than 20000 A/cm2.

To assess possible differences in dopamine metabolism that could parallel disease progression in Parkinson's disease (PD), we measured dopamine (DA) and its metabolites in the cerebrospinal fluid (CSF) in PD patients at different stages of disease: de novo (DEN), advanced not showing dyskinesias (ADV), and advanced with dyskinesias (DYS). DA, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly higher in DEN patients compared with other groups. A negative exponential correlation related DA level and disease duration. The HVA/DA ratio was significantly higher in the ADV and DYS group than that found in DEN group. Our data show that disease progression produces an early large decay of DA levels, followed by a stabilization. On the contrary, a late change in DA turnover (increased HVA/DA ratio) is documented in patients with longer disease duration. Our results suggest that the appearance of dyskinesia may not be related to a further loss of DA terminals but to a different, abnormal, DA turnover.

The results of a vibrational analysis of neutral N,N’‐dicyanoquinonediimine (DCNQI) and of 2,5‐X,Y‐DCNQI (X■Y■Cl; X■Cl, Y■CH3; X■Y■CH3 or CD3) are presented. A sound assignment of the in‐plane fundamental vibrational modes is discussed also in terms of a normal coordinate analysis (NCA) based on a modified valence force field. For light and deuterated 2,5‐dimethyl‐dicyanoquinonediimine (DMDCNQI) the vibrational analysis is extended to the corresponding radical anion. The comparison of the vibrational assignment of neutral and fully ionized species, together with the results of the NCA, leads to the identification of a strong Duschinsky effect, as well as of the frequency shifts relative to the ionization process. The buν47 fundamental mode (quinoid C■N stretch) is recognized as diagnostic of the degree of charge transfer (CT) for DMDCNQI component units of CT systems. The relative values of the linear electron–molecular vibration (e–mv) coupling constants for the neutral and ionized DMDCNQI molecular stru...

The ability of infrared spectra to selectively probe the temperature evolution of a 4kF modulation (dimerization) and a 2kF modulation (tetramerization) of the structure of quarter-filled organic conductors is demonstrated for the first time for the title compounds. A detailed analysis of the totally symmetric normal modes of DM-DCNQI and of their coupling to the radical electron for the isolated molecule is also reported.

Summary Aims of the study To assess the effect of temperature upon conduction velocity, amplitude and signal energy of the sensory and motor rat tail nerves. Materials and methods Sensory and motor responses were recorded from the tail nerves in 10 adult rats at different temperatures, starting from 40 °C and cooling down to 16 °C in steps of 2 °C. Results The conduction velocity of the various components of the orthodromic sensory response was directly and linearly related to temperature (fastest fibres ranged from 47.7 down to 19.7 m/s), with Q10 values of approximately 1.30, suggesting that all fibres, regardless of their diameter, were equally sensitive to changes in temperature. The motor conduction was similarly affected with a Q10 value of 1.28 and a velocity range from 24.2 down to 9.6 m/s. Amplitude and energy of the sensory responses were inversely related to temperature, reaching their maximum at 16 °C. Energy was by far the most temperature sensitive parameter, with a Q10 of approximately 3 both for fast or slow conducting fibres. Amplitude and energy of the motor responses also showed an inverse correlation with temperature, but were influenced by a more complex set of factors (neuromuscular synapse, muscle membrane) than the simple neural conduction. Conclusions Besides providing new normative data upon conduction in the rat tail nerves at different temperatures, our results suggest that this method may represent an excellent tool to study models of peripheral-nerve conduction in vivo under various physiological and pathological conditions.

Assessment of the conduction velocity of motor fibers of the rat tail nerves has been used by some authors in the past, but very little is known about the sensory fibers. In 10 adult rats, weighing between 320 and 380 g, responses from the nerves and muscles of the tail have been recorded after stimulation at its root and tip. It was found that stimulation of the tip involved mainly sensory fibers, of which two main groups could be identified. One faster group, conducting within the range of 38-27 m/s, and one slower group with range 14-7 m/s. The bipolar recording configuration was found to be optimal for sensory recording. Stimulation of the tail root evoked a motor response, which was preceded by a very small neurographic activity, due to the fastest sensory fibers conducting antidromically. The conduction velocity of motor fibers was calculated to be approximately 19 m/s. Distance traveled by the volley can be assessed with excellent precision on the tail nerves; hence the calculated conduction velocities are highly reliable and reproducible. We propose that the tail nerves may be a useful tool for evaluation of conduction velocity of Abeta and Adelta afferents. As the technique is just minimally invasive, the test can be repeated a number of times in animals under chronic experimental conditions.

Recent evidence indicates that cancer cells express chemokine (CK) receptors and that their signaling is crucial for tumor proliferation, migration, and angiogenesis. The profiles of expression of CXC CK receptors (CXCR1-5) and their main ligands (growth-related oncogene, GRO1-2-3/CXCL1-2-3; interleukin 8, IL-8/CXCL8; monokine-induced gamma-interferon MIG/CXCL9; gamma-interferon-inducible-protein-10, IP-10/CXCL10; stromal cell-derived factor-1, SDF1/CXCL12; B-cell activating CK-1, BCA-1/CXCL13) were analyzed by reverse transcription polymerase chain reaction (RT-PCR) in surgical samples of human meningiomas. All the five receptors displayed high percentages of positive cases: 92% CXCR1, 89% CXCR2, 83% CXCR3, 78% CXCR4, and 94% CXCR5. Conversely, their ligands showed a lower pattern of expression: 40% IL-8, 42% GRO1-3, 42% IP-10, 28% MIG, 53% SDF1, and 3% BCA-1. SDF1/CXCR4 interaction plays a pivotal role in cancer proliferation. Thus, the signaling mechanisms activated by the exclusive binding between SDF1 and CXCR4 was investigated in 12 primary cultures from meningioma tissues. CXCR4 was functionally coupled as demonstrated by the significant increase of DNA synthesis in meningioma cells in response to SDF1, measured by [3H]-thymidine uptake. In three primary cultures, the SDF1-dependent mitogenic activity was associated with a marked phosphorylation of extracellular signal-regulated kinase (ERK1/2) as evaluated by Western blots. PD98059 (a MEK inhibitor) significantly reduced ERK1/2 activation, thus linking the SDF1/CXCR4 pathway to meningioma cell proliferation via ERK1/2 signal transduction. We demonstrate, for the first time in human meningiomas, the simultaneous expression of CXCR1-5 and their CKs and the mitogenic activity of SDF1/CXCR4, suggesting a pivotal role of these receptor-ligand pairs in meningeal tumors.

Objective: To investigate if Helicobacter pylori ( HP ) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. Methods: In a group of 34 HP -infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. Results: Differently from the antioxidant-treated patients, the HP -eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged “on-time” duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. Conclusions: These data demonstrate a reversible Helicobacter pylori ( HP )–induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.

Hereditary creatine transporter deficiency causes brain damage, despite the brain having the enzymes to synthesize creatine. Such damage occurring despite an endogenous synthesis is not easily explained. This condition is incurable, because creatine may not be delivered to the brain without its transporter. Creatine-derived compounds that crossed the blood–brain barrier in a transporter-independent fashion would be useful in the therapy of hereditary creatine transporter deficiency, and possibly also in neuroprotection against brain anoxia or ischemia. We tested the double hypothesis that: (1) the creatine carrier is needed to make creatine cross the plasma membrane of brain cells and (2) creatine-derived molecules may cross this plasma membrane independently of the creatine carrier. In in vitro mouse hippocampal slices, incubation with creatine increased creatine and phosphocreatine content of the tissue. Inhibition of the creatine transporter with 3-guanidinopropionic acid (GPA) dose-dependently prevented this increase. Incubation with creatine benzyl ester (CrOBzl) or phosphocreatine–Mg-complex acetate (PCr-Mg-CPLX) increased tissue creatine content, not phosphocreatine. This increase was not prevented by GPA. Thus, the creatine transporter is required for creatine uptake through the plasma membrane. Since there is a strong indication that creatine in the brain is mainly synthesized by glial cells and transferred to neurons, this might explain why hereditary transporter deficiency is attended by severe brain damage despite the possibility of an endogenous synthesis. CrOBzl and PCr-Mg-CPLX cross the plasma membrane in a transporter-independent way, and might be useful in the therapy of hereditary creatine transporter deficiency. They may also prove useful in the therapy of brain anoxia or ischemia.

Background: Entacapone is a COMT inhibitor used in Parkinson's disease (PD) patients, as an adjunctive therapy to l-dopa in order to prolong its bioavailability and thus its clinical effect. However, previous studies reported entacapone-induced l-dopa to have lower Cmax and delayed tmax values, coupled with a delayed onset of the clinical effect, possibly suggesting an interference between the two drugs. The aim of our study was to evaluate whether a delayed entacapone administration in association with standard l-dopa/carbidopa, may in some subjects improve the entacapone effects on l-dopa AUC and thus on the clinical ‘on time’ duration. Methods: Twenty-eight idiopathic advanced PD patients were blindly evaluated in three different test days, following administration of carbidopa/l-dopa or carbidopa/l-dopa plus co-administered entacapone or plus entacapone administered with 30 min of delay. Results: The AUC, the ‘on time’ and UPDRS score of the whole group were improved by both modalities of entacapone administration. An ex post analysis showed that the delayed entacapone administration produced a significant improvement in a subgroup of 10 non-responding patients to the co-administration. Conclusion: We suggest that the delayed administration should be attempted in the subjects not improved by entacapone co-administration.

Low levels of lignans, namely enterolactone, have been reported to be associated with an increased risk of breast cancer in the general female population. We assessed, retrospectively, the relationship between serum enterolactone concentrations and the occurrence of breast cancer in women with palpable cysts. The levels of enterolactone in cryopreserved serum aliquots, obtained from 383 women with palpable cysts at the time of their first cyst aspiration, were measured using a time-resolved fluoroimmunoassay (TR-FIA). After a median follow-up time of 6.5 years (range 0.5–12.75 years), 18 women were found to have developed an invasive breast cancer. Median values of serum enterolactone were significantly lower in women who subsequently developed breast cancer: 8.5 nM/l versus 16.0 nM/l: P=0.04. Odd Ratios (OR) for breast cancer were: 0.36 (P=0.03), 0.57 (P=0.3) and 0.38 (P=0.25) for 25th (8 nM/l), 50th (16 nM/l) and 75th (24 nM/l) percentile values, respectively. The receiver operating characteristic (ROC) analysis showed a satisfactory accuracy for enterolactone as a breast cancer risk indicator (area under the curve (AUC)=0.64: P=0.04). Logistic regression analysis confirmed that the enterolactone concentration had a strong protective effect on the breast cancer risk. These findings may have important clinical implications with regard to interventional diet-focused chemo-preventive trials.

Procainamide protects mice bearing P388 leukemic cells against the toxicity of cisplatin without diminishing antitumor activity. The mechanism of action of procainamide protection was investigated both in vitro and in vivo. HPLC studies showed that procainamide forms a complex with cisplatin in vitro that has a UV spectrum similar to that of DPR, a triamine platinum complex that contains procaine as ligand. We report here the effect of the reaction product of cisplatin and procainamide on both cisplatin-induced DNA interstrand cross-links (ISCLs) and on the total DNA platination of isolated DNA. Total DNA platination in vitro of isolated DNA was increased by 113% (P.01) and 17% (P.05) after incubation times of 1.75 and 6 h, respectively, compared with products from the reaction of cisplatin with water. Furthermore, the reaction product of cisplatin and procainamide was bound to DNA to a significantly greater extent than was cisplatin itself. ISCLs were decreased by 41% when this drug combination was incubated with DNA for 1.75 h, but no changes were observed after incubation for 6 h. We also examined the influence of the time interval between administration of cisplatin and procainamide on normal kidney injury, the renal distribution and urinary excretion of platinum, and the formation of cisplatin-DNA adducts in renal tissue of Sprague-Dawley rats after i.p. administration of 7.5 mg/kg cisplatin either with or without procainamide. The plasma concentrations of urea and creatinine and kidney histology demonstrated that procainamide provided effective protection in vivo in the rat when administered either simultaneously or at 0.5 and 1 h before or after cisplatin. The protection was accompanied by both higher renal levels of platinum and cisplatin-DNA adducts and by an increase in the formation of ISCLs. Moreover, a dose-dependent reduction of urinary excretion and concentration of platinum was also observed. We propose that procainamide, after accumulation in the kidney, may coordinate with cisplatin to form a less toxic DPR-like complex that renders rats less susceptible to cisplatin-induced toxicity.

This paper reports on the effectiveness of oral lamotrigine in 15 patients suffering from “essential” trigeminal neuralgia and in five patients suffering symptomatic trigeminal neuralgia concomitant with multiple sclerosis. We recorded objective and subjective pain ratings and correlated them to daily dosage (400 mg maximum) and plasma levels of the drug. We detected pain relief proportional to daily dosage and to drug plasma levels. Eleven of the cases affected by the “essential” form of neuralgia showed complete pain relief on reaching their maximum daily dosage. All cases affected by the symptomatic form had complete pain relief. We could detect no changes from these results by the end of the follow-up period (3 to 8 months after the study ended).

An implication for Serotonin in the pathophysiology of epilepsy has been suggested in experimental and clinical papers.

The use of information technology is reduced in health area. Its introduction as a management tool and decision support can change the actual kinds of planning within health organizations. The purpose of this work is to develop a system in order to enable and process the nursing prescription. The system named DSSPPNC-Decision Support System in Planning and Prescription of Nursing Care-is a computational tool that enables the information access under the form of Nursing Assistance Protocols. The results of the present work will involve sensible changes in the nursing assistential practice, with repercussion in the type of assistance management and to care the individual hospitalized, making opportune and approaching the nurse to the patient, through raising of problems, aiming care planning and accomplishment, results valuation and supervision and control of the staff engaged to in assistance.

We report an unblinded, open-label, add-on trial of fluoxetine, a selective serotonin reuptake inhibitor, in 17 patients with complex partial seizures with and without secondary generalization (mean follow-up duration, 14 +/- 1.1 months). Six patients showed complete disappearance of their daily seizures; in the others the seizure frequency was lowered by 30%. No patient reported side effects.

Dendrosomes prepared from substantia nigra are able to take up and release [3H]dopamine in a CA(2+)-dependent manner. The Vmax values of [3H]dopamine uptake in substantia nigra dendrosomes was about 5 times lower than that in caudate putamen synaptosomes. The pattern of the K(+)-dependency of the [3H]dopamine release in substantia nigra dendrosomes was significantly different from that found in caudate putamen synaptosomes. The release of [3H]dopamine evoked by 15 mmol/l KCl from superfused dendrosomes was increased in a concentration-dependent manner by acetylcholine. The maximal potentiation produced by acetylcholine was about 40%. The potentiation of [3H]dopamine release by 10 mumol/l acetylcholine was insensitive to mecamylamine but antagonized by atropine and by pirenzepine. The effects of acetylcholine on the release of [3H]acetylcholine from substantia nigra nerve endings was also studied. Exogenous acetylcholine added to the superfusion medium decreased in a concentration-dependent manner the release of acetylcholine. This effect was not antagonized by mecamylamine or pirenzepine but fully antagonized by atropine. The data suggest the existence, in the substantia nigra of the rat, of two distinct muscarinic receptor subtypes regulating respectively dopamine release from dopamine dendrites and acetylcholine release from cholinergic nerve terminals.