Clarithromycin in the Management of Chronic Rhinosinusitis: Preliminary Results of a Possible Its New Use.

The aim of this study is to evaluate the efficacy and safety of prolonged therapy with low-dose clarithromycin in patients with chronic rhinosinusitis with polyps (CRSwP) after endoscopic sinus surgery (ESS). A total of 10 patients with CRSwP were identified and subjected to bilateral ESS. In post-operative patients they were treated with nasal wash with saline solution and steroid sprays (beclomethasone). During follow-up, after 30-40 days after the operation (M = 35.4 SD = +4.33), patients reported a worsening of symptoms with onset of nasal obstruction; reduction/loss of smell; headache; onset of viscous secretions and therefore all patients continued therapy with saline nasal irrigation, topical steroid therapy and started macrolide (clarithromycin 500 mg/pill: 1 pill/day for 3 days a week for 1 month). 22-item SinoNasal Outcome Test (SNOT-22) and a score to the endoscopic evaluation (endoscopic appearance score, EAS) before and after treatment were performed to evaluate efficacy of treatment. The results of the SNOT-22 and EAS showed statistically significant improvements (p < 0.05) for some parameters such as: the need to blow nose, sneezing, hyposmia, viscous mucous secretions about the SNOT-22 and reduction of secretions and edema of the nasal mucosa about the EAS. The preliminary results of our study show that the low-dose clarithromycin for a period of 1 month can improve patient complaints with CRSwP not only through the antibacterial properties but also for the immunomodulatory characteristics.

TNFα deficiency results in increased IL-1ß in an early onset of spontaneous murine colitis.

Inflammatory bowel disease (Crohn's disease (CD) and ulcerative colitis (UC)) is a multifactorial disease resulting from immune dysregulation in the gut. The underlying colitis is characterized by high levels of inflammatory cytokines, including TNFα. Biological intervention for IBD patients using anti-TNFα antibodies is often an effective therapeutic solution. However, TNFα neutralization fails to induce remission in a subgroup of IBD patients, primarily in UC patients. There is a dearth of suitable animal models representing TNFα non-responders. Here we have combined one of the best UC models currently available, namely Winnie and the TNFαKO mouse to generate a TNFα-deficient Winnie to study early onset colitis. The induced TNFα deficiency with underlying colitis does not influence general health (viability and body weight) or clinical parameters (colon weight, colon length and histological colitis) when compared with the Winnie genotype alone. The molecular characterization resulted in identification of Il1ß as the major elevated cytokine during early phases of colitis. Further, in vitro functional assay using bone marrow-derived dendritic cells confirmed IL-1ß as the major cytokine released in the absence of TNFα. This study has generated a successful model of colitis that remains TNFα non-responsive and has demonstrated that IL-1ß expression is a major pathway for the progression of colitis in this system. These data also suggest that IL-1ß can be a potential target for clinical intervention of UC patients who fail to respond to TNFα neutralization.

RNA editing signature during myeloid leukemia cell differentiation.

Adenosine deaminases acting on RNA (ADARs) are key proteins for hematopoietic stem cell self-renewal and for survival of differentiating progenitor cells. However, their specific role in myeloid cell maturation has been poorly investigated. Here we show that ADAR1 is present at basal level in the primary myeloid leukemia cells obtained from patients at diagnosis as well as in myeloid U-937 and THP1 cell lines and its expression correlates with the editing levels. Upon phorbol-myristate acetate or Vitamin D3/granulocyte macrophage colony-stimulating factor (GM-CSF)-driven differentiation, both ADAR1 and ADAR2 enzymes are upregulated, with a concomitant global increase of A-to-I RNA editing. ADAR1 silencing caused an editing decrease at specific ADAR1 target genes, without, however, interfering with cell differentiation or with ADAR2 activity. Remarkably, ADAR2 is absent in the undifferentiated cell stage, due to its elimination through the ubiquitin-proteasome pathway, being strongly upregulated at the end of the differentiation process. Of note, peripheral blood monocytes display editing events at the selected targets similar to those found in differentiated cell lines. Taken together, the data indicate that ADAR enzymes play important and distinct roles in myeloid cells.

Nasal packing in sphenopalatine artery bleeding: therapeutic or harmful?

The aim of this study is to present our management protocol of sphenopalatine artery bleeding, demonstrating that nasoendoscopic cautery (NC) was a more effective method than the nasal packing, in terms of shorter inpatient stay and reduced complications rate. We present ten posterior epistaxis not resolved by nasal packing. Tabotamp® was placed in the area of sphenopalatine foramen and/or in those parts of the posterior nasal cavity, where it was suspected that bleeding origins. In two cases, the bleeding was resolved in this way, instead eight cases needed of subperiosteal cauterization of sphenopalatine artery by Dessi bipolar forceps (MicroFrance®). 4 of these 8 patients evidenced a remarkable bleeding removing nasal packing (Hb before-nasal packing = 15 ± 0.69 versus Hb after-nasal packing = 13.3 ± 0.81; t student = 2.94; p value = 0.025). These four patients showed a deviation of the nasal septum ipsilateral to epistaxis, and according our experience, a traumatism of sphenopalatine area can be caused by Merocel® nasal packing in this condition. During follow-up, no recurrences of nasal bleeding have been observed in such patients. Nasal packing must be considered if posterior epistaxis is severe, but always taking into account the specific anatomy of patient and in particular septal spurs that can further compromise sphenopalatine artery. In our experience, the endoscopic endonasal cauterization of the sphenopalatine branches represented a safe and effective procedure.

Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections.

Flucytosine (5-fluorocytosine, 5-FC) is a fluorinated analogue of cytosine currently approved for the systemic treatment of fungal infections, which has recently demonstrated a very promising antivirulence activity against the bacterial pathogen Pseudomonas aeruginosa. In this work, we propose novel inhalable hyaluronic acid (HA)/mannitol composite dry powders for repositioning 5-FC in the local treatment of lung infections, including those affecting cystic fibrosis (CF) patients. Different dry powders were produced in one-step by spray-drying. Powder composition and process conditions were selected after in depth formulation studies aimed at selecting the 5-FC/HA/mannitol formulation with convenient aerosolization properties and drug release profile in simulated lung fluids. The optimized 5-FC/HA/mannitol powder for inhalation (HyaMan_FC#3) was effectively delivered from different breath-activated dry powder inhalers (DPI) already available to CF patients. Nevertheless, the aerodynamic assessment of fine particles suggested that the developed formulation well fit with a low-resistance DPI. HyaMan_FC#3 inhibited the growth of the fungus Candida albicans and the production of the virulence factor pyoverdine by P. aeruginosa at 5-FC concentrations that did not affect the viability of both wild type (16HBE14o-) and CF (CFBE41o-) human bronchial epithelial cells. Finally, pharmacokinetics of HyaMan_FC#3 inhalation powder and 5-FC solution after intratracheal administration in rats were compared. In vivo results clearly demonstrated that, when formulated as dry powder, 5-FC levels in both bronchoalveolar lavage fluid and lung tissue were significantly higher and sustained over time as compared to those obtained with the 5-FC solution. Of note, when the same 5-FC amount was administered intravenously, no significant drug amount was found in the lung at each time point from the injection. To realize a 5-FC lung concentration similar to that obtained by using HyaMan_FC#3, a 6-fold higher dose of 5-FC should be administered intravenously. Taken together, our data demonstrate the feasibility to deliver 5-FC by the pulmonary route likely avoiding/reducing the well-known side effects associated to the high systemic 5-FC doses currently used in humans. Furthermore, our results highlight that an appropriate formulation design can improve the persistence of the drug at lungs, where microorganisms causing severe infections are located.

Data in support of Gallium (Ga(3+)) antibacterial activities to counteract E. coli and S. epidermidis biofilm formation onto pro-osteointegrative titanium surfaces.

This paper contains original data supporting the antibacterial activities of Gallium (Ga(3+))-doped pro-osteointegrative titanium alloys, obtained via Anodic Spark Deposition (ASD), as described in "The effect of silver or gallium doped titanium against the multidrug resistant Acinetobacter baumannii" (Cochis et al. 2016) [1]. In this article we included an indirect cytocompatibility evaluation towards Saos2 human osteoblasts and extended the microbial evaluation of the Ga(3+) enriched titanium surfaces against the biofilm former Escherichia coli and Staphylococcus epidermidis strains. Cell viability was assayed by the Alamar Blue test, while bacterial viability was evaluated by the metabolic colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Finally biofilm morphology was analyzed by Scanning Electron Microscopy (SEM). Data regarding Ga(3+) activity were compared to Silver.

Gas what: NO is not the only answer to sexual function.

The ability to get and keep an erection is important to men for several reasons and the inability is known as erectile dysfunction (ED). ED has started to be accepted as an early indicator of systemic endothelial dysfunction and subsequently of cardiovascular diseases. The role of NO in endothelial relaxation and erectile function is well accepted. The discovery of NO as a small signalling gasotransmitter led to the investigation of the role of other endogenously derived gases, carbon monoxide (CO) and hydrogen sulphide (H2 S) in physiological and pathophysiological conditions. The role of NO and CO in sexual function and dysfunction has been investigated more extensively and, recently, the involvement of H2 S in erectile function has also been confirmed. In this review, we focus on the role of these three sister gasotransmitters in the physiology, pharmacology and pathophysiology of sexual function in man, specifically erectile function. We have also reviewed the role of soluble guanylyl cyclase/cGMP pathway as a common target of these gasotransmitters. Several studies have proposed alternative therapies targeting different mechanisms in addition to PDE-5 inhibition for ED treatment, since some patients do not respond to these drugs. This review highlights complementary and possible coordinated roles for these mediators and treatments targeting these gasotransmitters in erectile function/ED.

Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone.

BACKGROUND AND PURPOSE: Hydrogen sulphide (H2S) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilatation. Having previously shown that H2 S contributes to testosterone-induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect. EXPERIMENTAL APPROACH: H2 S biosynthesis was evaluated in rat isolated aortic rings following androgen receptor (NR3C4) stimulation. Co-immunoprecipitation and surface plasmon resonance analysis were performed to investigate mechanisms involved in NR3C4 activation. KEY RESULTS: Pretreatment with NR3C4 antagonist nilutamide prevented testosterone-induced increase in H2S and reduced its vasodilator effect. Androgen agonist mesterolone also increased H2S and induced vasodilatation; effects attenuated by the selective cystathionine-γ lyase (CSE) inhibitor propargylglycine. The NR3C4-multicomplex-derived heat shock protein 90 (hsp90) was also involved in this effect; its specific inhibitor geldanamycin strongly reduced testosterone-induced H2S production. Neither progesterone nor 17-ß-oestradiol induced H2S release. Furthermore, we demonstrated that CSE, the main vascular H2S-synthesizing enzyme, is physically associated with the NR3C4/hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H2S levels in human blood collected from male healthy volunteers were higher than those in female samples. CONCLUSIONS AND IMPLICATIONS: We demonstrated that selective activation of the NR3C4 is essential for H2S biosynthesis within vascular tissue, and this event is based on the formation of a ternary complex between cystathionine-γ lyase, NR3C4and hsp90. This novel molecular mechanism operating in the vasculature, corroborated by higher H2S levels in males, suggests that the L-cysteine/CSE/H2S pathway may be preferentially activated in males leading to gender-specific H2S biosynthesis.

Oral Syphilis: a retrospective analysis of 12 cases and a review of the literature.

OBJECTIVE: To present a retrospective analysis of multicentre case series of oral syphilis and a review of relevant literature. SUBJECTS AND METHODS: A PUBMED search was carried out from 1950 to 2011. Clinical records of patients with exclusive/prevalent oral manifestations of syphilis were collected and examined in three independent hospitals. RESULTS: Of 23 reports describing 34 patients were detected through the review (35% primary, 56% secondary, and 9% tertiary disease), describing unspecific ulcers (59%), mucosal patches (23%), keratosis (6%), pseudomembranes (3%), and gumma (9%). Multicentre case series revealed 12 patients with oral syphilis, of which 17%, 58%, and 25% with, respectively, primary, secondary, and tertiary lesions. Clinically, patients showed white patches (17%), blistering mucositis (8%), chronic unspecific ulcers with/without skin lesions (50%), gumma (17%), and necrosis of the dorsum of the tongue (8%). Oral bullae and tongue necrosis are never described in the current review. CONCLUSIONS: Diagnosis of syphilis remains a challenge because of the multiform and polymorphous clinical pattern at onset and its ability to imitate different diseases. It is mandatory to include syphilis in the differential diagnosis of unusual oral lesions. Diagnosis of oral lesions of syphilis is often difficult, and biopsy is required in controversial cases.

OS064. Contribute of the L-cysteine/ H2S pathway in placenta homeostasisin hypertensive disorders.

INTRODUCTION: Hydrogen sulfide (H2S) is considered the third endogenous gas transmitter besides nitric oxide and carbon monoxide [1]. It is produced from L-cysteine or L-methionine via the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). H2S is involved in the control of vascular homeostasis, having either relaxant or contractant effect on smooth muscle cells. The H2S involvement in rat and human intrauterine tissues has also been shown [2]. OBJECTIVES: The aim of our study was to investigate the L-cysteine/ H2S pathway in rat and human placenta in hypertensive state. METHODS: Placental samples were collected from spontaneous hypertensive rats (SHR) and normotensive rat (Wistar Kyoto; WKY). In parallel, placental samples were collected from 10 pre-eclamptic women and 5 controls after caesarean sections. Pre-eclamptic women were divided into two subgroups: Group1 (women who developed Early Preeclampsia, n=4); Group2 (women who developed Late Preeclampsia, n=6). The expression of CBS and CSE was evaluated in sample tissues by Western blotting analysis. The enzymatic activity was assessed in basal and stimulated (L- cysteine) condiction by a colorimetric assay. Statistical analysis was performed by using Student's t test. P<0,05 was considered as statistically significant. RESULTS: The expression of CBS and CSE in placenta of SHR rats were significantly reduced (p<0.05) compared to WKY. The H2S production resulted significantly (p<0,05) lower in SHR than WKY rats. In human placenta, the basal H2S production was similar in the three groups; interestingly the H2S production by adding L-cysteine, was higher in Late Preeclampsia compared to control group. CONCLUSION: H2S was produced in rat and human placenta. CBS and CSE, the enzymes involved in the production of H2S, were down-regulated in SHR rats and, as a consequence the H2S production was significantly reduced. Starting from these data, we tried to analyze the role of hydrogen sulfide in preeclampsia to assess the contribute of this gas transmitter in the development of this condition. Unexpectedly, preliminary data demonstrated that in women developing Late Preeclampsia there was an higher production of H2S after stimulation with L-cysteine, not revealed in Early Preeclampsia or in healthy control group. Our results indicated that the L-cysteine/H2S pathway could contribute to the development of preeclampsia condition.

First Report of Tomato spotted wilt virus on Tobacco in Campania, Italy.

During the spring and summer of 2010, a survey for viruses was conducted in two tobacco field trials at the Agricultural Research and Experimentation Council in Scafati, Campania, Italy. A total of 1,392 symptomatic and asymptomatic tobacco plants (cv. Burley) were sampled, and leaves were analyzed by double-antibody sandwich-ELISA using polyclonal antisera against five tobacco-infecting viruses: Tobacco mosaic virus, Potato virus Y, Cucumber mosaic virus, Alfalfa mosaic virus, and Tomato spotted wilt virus (TSWV) (Loewe, Munich, Germany). Only one plant was positive to TSWV. Symptoms on this plant were severe necroses on the stem with a few chlorotic/necrotic leaflets on the top of the plant. This result was subsequently confirmed by reverse transcription (RT)-PCR. The primers (5'-ATGTCTAAGGTTAAGCTC-3' forward and 5'-TTAAGCAAGTTCTGTGAG-3' reverse) targeted the nucleocapsid gene of TSWV and amplified the expected product of approximately 800 bp (2). The resultant sequence (GenBank Accession No. JF290419) was aligned and edited using BlastN, displaying 99.9% identity with deposited TSWV nucleocapsid gene sequences in GenBank, with no similarity to any other targets, which confirmed the presence of TSWV in tobacco. Leaf homogenate from the tobacco symptomatic plants was inoculated onto three plants of Nicotiana benthamiana, N. glutinosa, and Datura metel. All plants developed a systemic necrosis after 7 days. Inoculation from N. glutinosa back to cv. White Burley tobacco produced symptoms similar to those observed in the field. Two plants from each species were used as noninoculated controls, which remained asymptomatic. TSWV infection has been responsible for severe epidemics on tobacco throughout the United States and Greece, with losses estimated as much as 85% (1,3). The presence of TSWV in Italy could therefore represent a serious threat for tobacco in the region, especially considering that it is prevalent in other crops in the area and vectors are widespread. References: (1) E. K. Chatzivassiliou. Plant Dis. 92:1012, 2008. (2) R. K. Jain et al. Plant Dis. 82:900, 1998. (3) B. Mandal et al. Ann. Appl. Biol. 151:67, 2007.

Age-dependent association of idiopathic achalasia with vasoactive intestinal peptide receptor 1 gene.

Idiopathic achalasia is a rare disorder of the oesophagus of unknown aetio-pathogenesis characterized by a myenteric inflammation, aperistalsis and insufficient lower oesophageal sphincter relaxation. Vasoactive intestinal peptide (VIP), present in the myenteric plexus, is involved in smooth muscle relaxation and acts as an anti-inflammatory cytokine. The human VIP receptor 1 gene (VIPR1) is highly polymorphic and may play a role in idiopathic achalasia. One hundred and four consecutive patients and 300 random controls from the same geographic area were typed for five SNPs mapping in the VIPR1 gene. Patients with idiopathic achalasia show a significant difference in allele, genotype and phenotype distribution of SNP rs437876 mapping in intron 4. This association, however, was almost entirely due to the group of patients with late disease onset (P = 0.0005). These results strongly suggest that idiopathic achalasia is a heterogeneous disease with a different aetiology in cases with early or late disease onset.

Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study.

OBJECTIVE: Analysis of the association between psoriatic arthritis (PsA) clinical forms and MICA gene transmembrane polymorphisms. METHODS: Patients were classified as having peripheral asymmetric oligoarthritis (AO), peripheral symmetric poly-arthritis (PA) and spondylitis (SP), or disease combinations (PA/SP, OA/SP). Two hundred and twenty-six patients with PsA were typed for MICA exon 5 microsatellite (TM) by heteroduplex analysis and compared with 225 normal controls. RESULTS: MICA-TM microsatellite typing revealed that, among the different clinical forms of PsA, only the combined PA/SP subset shows a significant positive association with MICA-A9 and a lower frequency of MICA-A4, A5 genotype in PsA patients with a decrease, only in the PA/SP cohort, of all MICA-A5 combinations except MICA-A5, -A9. CONCLUSION: These results suggest a role for genes within the HLA region in the pathogenesis of PsA, and reinforce the idea that the different forms of PsA may have heterogeneous genetic basis.

A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B*2705 in Sardinia.

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B (*)2705 strongly associated with AS and B (*)2709 which is not, and show the co-occurrence of the B (*)2705 allele with a single nucleotide polymorphism (SNP) mapping at 3'-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B (*)2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a 'danger' signal might influence susceptibility to AS.

Pattern recognition receptors and interleukin-8 mediate effects of Gram-positive and Gram-negative bacteria on lung epithelial cell function.

BACKGROUND AND PURPOSE: Lung epithelial cells express pattern recognition receptors, which react to bacteria. We have evaluated the effect of Gram-positive and Gram-negative bacteria on interleukin-8 (CXCL8) release from epithelial cells and the integrity of the epithelial barrier. EXPERIMENTAL APPROACH: Primary cultures of human airway epithelial cells and the epithelial cell line A549 were used, and CXCL8 release was measured after exposure to Gram-negative or Gram-positive bacteria. Epithelial barrier function was assessed in monolayer cultures of A549 cells. RESULTS: Gram-positive bacteria Staphylococcus aureus or Streptococcus pneumoniae, induced release of CXCL8 from human airway epithelial cells. These bacteria also disrupted barrier function in A549 cells, an effect mimicked by CXCL8 and blocked by specific binding antibodies to CXCL8. Gram-negative bacteria Escherichia coli or Pseudomonas aeruginosa induced greater release of CXCL8 than Gram-positive bacteria. However, Gram-negative bacteria did not affect epithelial barrier function directly, but prevented disruption induced by Gram-positive bacteria. These effects of Gram-negative bacteria on barrier function were mimicked by FK565, an agonist of the nucleotide-binding oligomerization domain 1 (NOD1) receptor, but not by the Toll-like receptor (TLR) 4 agonist bacterial lipopolysaccharide. Neither the Gram-negative bacteria nor FK565 blocked CXCL8 release. CONCLUSIONS: These data show differential functional responses induced by Gram-negative and Gram-positive bacteria in human lung epithelial cells. The NOD1 receptors may have a role in preventing disruption of the epithelial barrier in lung, during inflammatory states.

HLA-B*2709 and lack of susceptibility to sacroiliitis: further support from the clinic.

Interferons (IFN) are well known triggers of immunomediated diseases in genetically predisposed subjects. We describe the unique case of a HLA-B*2709 positive subject who underwent IFN-alpha treatment for essential thrombocythemia and developed arthritis of the proximal interphalangeal joints of the hands but not sacroiliitis. The possible mechanisms of IFN-induced arthritis are discussed.

Phenotypic modifications of vascular smooth muscle cells could be responsible for vascular hyporeactivity to contracting agent in mechanically injured rat carotid artery.

Vascular smooth muscle cells (VSMCs) that accumulate in neointima after angioplastic injury show different phenotypic characteristics from those of medial layer and an impaired reactivity to contracting agents. The aim of the study was to correlate the vascular hyporesponsiveness to the changes in intracellular calcium concentration [Ca(2+)](i) and the expression of proteins necessary for its utilization in mechanically injured rat carotid arteries (IC) at 14 and 28 days after angioplastic balloon. IC showed a significant reduction (P<0.01) to PE- or KCl-induced contraction as compared to uninjured carotid (UC). Fura-2AM-loaded VSMCs isolated from IC revealed that this hyporeactivity to PE or KCl was accompanied by the impairment of the increase in [Ca(2+)](i) induced by contracting agents in both Ca(2+)-free or -containing medium. Similar results were observed following the ryanodine challenge in VSMC. Western blot analysis showed a significant (P<0.05) reduction in myosin heavy chain (MHC) and IP(3)-type III receptor expression in IC isolated at 14 days from injury compared to UC, while an improvement of these proteins expression was observed at 28 days after damage. On the other hand, in IC tissue, SERCA2 and alpha-actin expression, compared to UC was significantly higher at 14 days than at 28 days. These data indicate that vascular hyporeactivity induced by mechanical injury may be due to alterations of either [Ca(2+)](i) or contractile proteins. These modifications could be related to the changes of VSMC phenotypic characteristics, as supported by the observed modifications in MHC, SERCA2 and alpha-actin expression, proteins considered as biological markers of cellular differentiation.

Cloricromene in endotoxemia: role of NF-kappaB.

In this study we investigated, for the first time in vivo, the effect of cloricromene, a cumarine derivative, on NF-kappaB activation in endotoxin-treated rats. Endotoxemia was induced in male rats by the intravenous injection of Salmonella typhosa lipopolysaccharide (LPS; 2 mg/kg/i.v.). In vivo treatment with cloricromene (2 mg/kg/i.v.) 30 min before lipopolysaccharide administration reversed the LPS-induced loss in tone of the aortic rings, improved their reactivity to phenylephrine, decreased both nitric oxide (NO) and TNF-alpha serum levels by inhibiting LPS-induced inducible NO synthase and TNF-alpha mRNA expression, and interestingly inhibited LPS-induced NF-kappaB activation. Our data suggest that cloricromene protects rats from LPS by blocking LPS-induced NF-kappaB activation, leading to inhibition of NO and TNF-alpha overproduction and thereby reversing the LPS-induced vascular hyporeactivity.

Highly selective toxic and proapoptotic effects of two dimeric ribonucleases on thyroid cancer cells compared to the effects of doxorubicin.

The lack of selectivity of conventional antitumour drugs against cancer cells is responsible for their high toxicity. The development of new tumour-specific drugs is therefore highly needed. We tested the cytotoxic effects and the nature of cell death induced by a naturally dimeric bovine RNase and a newly engineered dimeric human RNase upon three genetically well-defined normal and malignant thyroid cell systems. RNases effects were compared with those of doxorubicin, a conventional antineoplastic drug. Our results show significant and selective proapoptotic effects exerted on tumour cells by both RNases, the strength of their cytotoxic and apoptotic activity being directly related to the degree of cell malignancy. No toxic effects were observed upon normal cells. Doxorubicin showed, instead, cytotoxic and apoptotic effects also against normal cells. The in vitro results were corroborated by the antitumour action of both dimeric RNases towards a malignant human thyroid tumour grown in nude mice. These results indicate a selective action of dimeric RNases against cancer cells and suggest the potential application of these molecules or their derivatives to the treatment of aggressive subtypes of thyroid cancer.

Sedation in gynaecologic oncology day surgery.

Gynaecologic oncology day surgery deals primarily with the diagnosis of endometrial, cervical, vulvar and vaginal tumors. Conscious sedation is an important technique used in gynaecologic oncology day surgery. It is often associated with regional anaesthesia. The goals of conscious sedation are to provide effective pain control with complete safety, reduction of the recovery time, of the infection risk and cost. Since the consequences of the immunosuppressive effects of the opiates and the surgical stress could lead to an increased susceptibility to post-operative infections and a possible lack of immunological defence in the cancer patients, we investigated the possibility of eliminating the administration of opiates during minor operations in gynaecologic oncology day surgery. In this study, 400 patients, aged between 35 and 77 years, underwent surgery using sedation at the day hospital annexed to the Gynaecology and Obstetrics Department of the 2nd University of Naples, Italy. The patients were randomized into two equal study groups, according to a computer-generated randomised list. All patients were seen by the consultant anaesthetist three days before surgery. In all cases, during surgery, we monitored the main vital parameters such as ECG, HR and RR, BT, BP and SO. The drugs commonly used were: opioids, hypnotics and benzodiazepines, associated or not, with local anaesthetics. By using these drugs, pain and anxiety were reduced, sedation and amnesia were accomplished. In our experience, conscious sedation seems to be the best choice in gynaecologic oncology day surgery because it presents low toxicity, is short acting and readily reversible, has a low cost and, finally, because it is more comfortable for the patients. Moreover, it is possible to eliminate the administration of opiates during conscious sedation for less invasive surgical procedures.