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L’obiettivo di questo lavoro è quello di valutare, in vitro, la fatica ciclica di ProFile, K3 e Twisted File, strumenti rotanti in nichel-titanio, in canali radicolari simulati aventi angoli di curvatura di 45°, 60° e 90°.

Migraine remains one of the most prevalent and disabling neurological disorders that often affects a person during their most productive years. Migraine afflicts approximately 11% of the adult population globally, causes substantial disability, which translates into lost productivity both at home and at work. Clearly there remains a need for new approaches to treat migraine and calcitonin gene-related peptide (CGRP) receptor antagonists have the potential to be a major advance in antimigraine therapy. CGRP was first proposed to play a role in migraine pathophysiology a little over 20 years ago and today there is considerable evidence that CGRP plays a key role in the pathogenesis of migraine. CGRP is a 37 amino acid vasoactive neuropeptide largely expressed in sensory neurons. It was observed that plasma levels of CGRP were elevated during the headache phase of migraine and the levels were normalized concomitantly with pain relief. This observation, along with other evidence, suggested that CGRP receptor antagonists might represent a novel approach to migraine treatment. The advent of small molecule CGRP receptor antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and effectiveness in treating migraine. This review will highlight the biology of CGRP as it pertains to migraine; discuss the CGRP receptor; spotlight the development of CGRP receptor antagonists; and examine site of action.

ABSTRACTMycoplasma pneumoniaeis one of the causative agents of atypical community-acquired pneumonia. Tigecycline belongs to a new class of glycylcycline antimicrobials that have activity against a wide range of microorganisms, including in vitro activity against M. pneumoniae. We investigated the effect of tigecycline on microbiologic, histologic, and immunologic indices in a murine model of M. pneumoniaepneumonia. BALB/c mice were inoculated intranasally with M. pneumoniaeand treated subcutaneously with tigecycline or placebo for 6 days. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniaeculture, lung histopathologic score (HPS), BAL cytokine and chemokine concentrations (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], interleukin 1β [IL-1β], IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 [p40/p70], granulocyte-macrophage colony-stimulating factor, MIP-1α, MIG, KC, MCP-1, and IP-10). BAL M. pneumoniaeconcentrations in mice treated with tigecycline (MpTige) tended to be reduced compared with mice treated with placebo (MpPl); however this did not reach statistical significance. The lung HPS was significantly lower, as well as the parenchymal-pneumonia subscore, in the MpTige mice than in the MpPl mice. MpTige mice had significantly lower BAL cytokine concentrations of IL-1β, IL-12 (p40/p70), IFN-γ, and TNF-α; of the chemokines, MIG, MIP-1α, and IP-10 were statistically lower in MpTige mice. While tigecycline treatment demonstrated a modest microbiologic effect, it significantly improved lung histologic inflammation and reduced pulmonary cytokines and chemokines.

Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentrations in respiratory secretions. We evaluated the effects of IL-12 therapy on microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in mice. BALB/c mice were inoculated with M. pneumoniae or SP4 broth. Mice were treated with intranasal IL-12 or placebo daily for 8 days, starting on day 1 after inoculation. Mice were evaluated at baseline and on days 1, 3, 6, and 8 after therapy. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic score (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-], gamma interferon [IFN-], IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and granulocyte-macrophage colony-stimulating factor), and plethysmography, both before and after methacholine treatment. M. pneumoniae-infected mice treated with IL-12 (MpIL12 mice) were found to have significantly higher BAL M. pneumoniae concentrations than those of M. pneumoniae-infected mice treated with placebo (MpP mice) (P < 0.001). MpIL12 mice had higher BAL concentrations of IL-12, IFN-, TNF-, and IL-6, with differences in IL-12 and IFN- concentrations reaching statistical significance (P < 0.001). Airway obstruction was statistically elevated in MpIL12 mice compared to that in MpP mice (P = 0.048), while airway hyperreactivity was also elevated in MpIL12 mice but did not reach statistical significance (P = 0.081). Lung parenchymal pneumonia subscores were significantly higher in MpIL12 mice (P < 0.001), but no difference was found for overall HPS, even though a strong trend was noticed (P = 0.051). Treatment of experimental M. pneumoniae pneumonia with intranasal IL-12 was associated with more severe pulmonary disease and less rapid microbiologic and histological resolution.

ABSTRACTMycoplasma pneumoniaeis a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniaerespiratory disease severity with interleukin-12 (IL-12) concentrations in respiratory secretions. We evaluated the effects of IL-12 therapy on microbiologic, inflammatory, and pulmonary function indices of M. pneumoniaepneumonia in mice. BALB/c mice were inoculated with M. pneumoniaeor SP4 broth. Mice were treated with intranasal IL-12 or placebo daily for 8 days, starting on day 1 after inoculation. Mice were evaluated at baseline and on days 1, 3, 6, and 8 after therapy. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniaeculture, lung histopathologic score (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and granulocyte-macrophage colony-stimulating factor), and plethysmography, both before and after methacholine treatment. M. pneumoniae-infected mice treated with IL-12 (MpIL12 mice) were found to have significantly higher BAL M. pneumoniaeconcentrations than those of M. pneumoniae-infected mice treated with placebo (MpP mice) (P< 0.001). MpIL12 mice had higher BAL concentrations of IL-12, IFN-γ, TNF-α, and IL-6, with differences in IL-12 and IFN-γ concentrations reaching statistical significance (P< 0.001). Airway obstruction was statistically elevated in MpIL12 mice compared to that in MpP mice (P= 0.048), while airway hyperreactivity was also elevated in MpIL12 mice but did not reach statistical significance (P= 0.081). Lung parenchymal pneumonia subscores were significantly higher in MpIL12 mice (P< 0.001), but no difference was found for overall HPS, even though a strong trend was noticed (P= 0.051). Treatment of experimental M. pneumoniaepneumonia with intranasal IL-12 was associated with more severe pulmonary disease and less rapid microbiologic and histological resolution.

Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniae respiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 107CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-], gamma interferon [IFN-], IL-1{szligbeta}, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniae were found to have significantly lower BAL M. pneumoniae concentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN- than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P = 0.065) and TNF- (P = 0.078). No differences were found for IL-1{szligbeta}, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniae pneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.

ABSTRACTMycoplasma pneumoniaeis a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniaerespiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniaepneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniaerespiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 107CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniaeculture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniaewere found to have significantly lower BAL M. pneumoniaeconcentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN-γ than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P= 0.065) and TNF-α (P= 0.078). No differences were found for IL-1β, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniaepneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.

Objectives/Hypothesis:To determine prognosis of primary sinonasal leiomyosarcomas after treatment.

Sabarubicin (MEN 10755) is the progenitor of a third generation of synthetic anthracycline oligosaccharides. Sabarubicin deamino analogues MEN 10959 and MEN 12297 were evaluated for topoisomerase II poisoning, cytotoxic potency and antitumor activity in human xenografts. The new analogues were able to induce DNA cleavage mediated by both DNA topoisomerase IIα and β and a good correlation was found regarding their cytotoxic activity. The two analogues possess also a different spectrum of antitumor activity, compared to sabarubicin.

Background/Aims:Liver sinusoids contain a large population of spontaneously cytotoxic cells (NK cells), CD8+T cells and macrophages. The physiological role of these leucocytes remains unclear. They may participate in immune surveillance and peripheral tolerance by deleting tumour cells, virus-infected cells and activated T cells as they traffic through the liver. In order to gain further information about the function of these leucocytes within the hepatic sinusoids, we examined their production of immunomodulatory cytokines and apoptosis-related molecules.

The A(3) adenosine receptor (A3AR) is one of four receptor subtypes for adenosine and is expressed in a broad spectrum of tissues. In order to study the function of A3AR, a mouse line carrying a mutant A(3) allele was generated. Mice homozygous for targeted disruption of the A3AR gene, A3AR(-/-), are fertile and visually and histologically indistinguishable from wild type mice. The lack of a functional receptor in the A3AR(-/-) mice was confirmed by molecular and pharmacological analyses. The absence of A3AR protein expression in the A3AR(-/-) mice was demonstrated by lack of N(6)-(4-amino-3-[(125)I]iodobenzyl)adenosine binding to bone marrow-derived mast cell membranes that were found to express high levels of A3AR in wild type mice. In A3AR(-/-) mice, the density of A(1) and A(2A) adenosine receptor subtypes was the same as in A3AR(+/+) mice as determined by radioligand binding to brain membranes. Additionally, A(2B) receptor transcript expression was not affected by ablation of the A3AR gene. A3AR(-/-) mice have basal heart rates and arterial blood pressures indistinguishable from A3AR(+/+) mice. Functionally, in contrast to wild type mice, adenosine and the A3AR-specific agonist, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-carboxamide (2-Cl-IB-MECA), elicit no potentiation of antigen-dependent degranulation of bone marrow-derived mast cells from A3AR(-/-) mice as measured by hexosaminidase release. Also, the ability of 2Cl-IB-MECA to inhibit lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo was decreased in A3AR(-/-) mice in comparison to A3AR(+/+) mice. The A(2A) adenosine receptor agonist, 2-p-(2-carboxyethyl)phenylamino)-5'-N-ethylcarboxamidoadenosine, produced inhibition of lipopolysaccharide-stimulated tumor necrosis factor-alpha production in both A3AR(-/-) and A3AR(+/+) mice. These results show that the inhibition in vivo can be mediated by multiple subtypes, specifically the A(3) and A(2A) adenosine receptors, and A3AR activation plays an important role in both pro- and anti-inflammatory responses.

Large cranial defects represent reconstructive challenges. Polyetheretherketone (PEEK) implants are preoperatively tailored to the exact size of the defect and exhibit an excellent combination of strength, durability, and environmental resistance. This study presents our experience with patient-specific PEEK implants with computer modeling.

In an attempt to better understand the role of the cyclohexene ring (ring A) in the biochemical and pharmacological properties of anthracyclines related to doxorubicin and daunorubicin, we investigated the effects of introduction of a fluorine atom at position 8 of idarubicin (4-demethoxydaunorubicin) on drug molecular conformation and biochemical and pharmacological activities. The study showed that the stereochemistry of the substituent at position 8 influenced the "half-chair" conformation, so that in the (8R)-fluoroepimer the A ring retained the alpha half-chair conformation, which is the most stable for natural compounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the beta half-chair conformation. The (8R)-fluoroepimer was more effective than the (8S)-fluoroepimer and idarubicin in stimulating topoisomerase II-mediated DNA cleavage. Similarly, the epimer with the alpha conformation was markedly more potent than the (8S)-epimer as a cytotoxic agent in a variety of human tumor cell lines and was more effective as an antitumor agent in the treatment of an ovarian carcinoma xenograft. In addition, 8-fluoro derivatives were able to overcome the resistance to doxorubicin in a number of human tumor cell lines expressing different mechanisms of resistance. In conclusion, these findings provide evidence that drug interactions involving the external (nonintercalating) moiety of the anthracycline chromophore play an important role in determining pharmacological properties, including drug ability to induce DNA cleavage, and therefore their antitumor efficacy.

Abstract: Cerebrospinal fluid (CSF) leakage after trans-sphenoidal surgery is a troublesome complication with a risk of meningitis and pneumocephalus. We suggest CT-guided intrasphenoidal injection of fibrin sealant through a 12-gauge needle as a simple alternative to surgical management of CSF fistulae. We treated eight patients, operated via the trans-sphenoidal route (five pituitary adenomas, three craniopharyngiomas), for a postoperative CSF leak by CT-guided intrasphenoidal injection of fibrin sealant alone in three cases and fibrin sealant and autologous blood in 5. CT was obtained 10 days after the procedure in all cases. In four patients, the CSF leak was closed successfully at the first attempt. The procedure was repeated on the four remaining patients because only a reduction in leakage was obtained at the first attempt. This procedure preserves olfaction and avoids the risk of frontal lobe damage. It could therefore represent the treatment of choice in many cases of anterior cranial fossa postsurgical CSF leaks.

Characterization of two mitochondrial proteins of M142 and 18 kDa, respectively, phosphorylated by the cAMP-dependent protein kinase of bovine heart mitochondria (mtPKA), is presented. A 42 kDa protein is found to be loosely associated to complexes I, III and IV of the respiratory chain and complex V (ATP synthase) in the inner mitochondrial membrane. An 18 kDa protein is associated to complex I in the inner membrane and in a purified preparation of this complex where it can be phosphorylated by the isolated catalytic subunit of PKA.

A study of bubble generation for constant gas‐flux condition by single‐nozzle injection in a coflowing liquid is reported. Focusing on single‐bubble generation in the dynamic and bubbly flow regime, the onset condition for bubble coalescence is investigated. The role of various forces involved in the bubble formation process is studied, and an overall force balance describing bubble dynamics is developed. Gas‐momentum flux and buoyancy in normal gravity enhance, while the surface‐tension force at the nozzle rim inhibits bubble detachment. On the other hand, liquid drag and inertia can act both as attaching or detaching forces, depending on the relative velocity of the bubble with respect to the surrounding liquid. Predictions of the theoretical model compare well with the present reduced‐gravity experiment and available normal‐gravity experiments. Effects of the fluid properties, injection geometry, and flow conditions on bubble size are investigated.

The human A3 adenosine receptor was cloned from a striatal cDNA library using a probe derived from the homologous rat sequence. The cDNA encodes a protein of 318 amino acids and exhibits 72% and 85% overall identity with the rat and sheep A3 adenosine receptor sequences, respectively. Specific and saturable binding of the adenosine receptor agonist N6-(4-amino-3-[125I]iodobenzyl)adenosine [125I]ABA was measured on the human A3 receptor stably expressed in Chinese hamster ovary cells with a Kd = 10 nM. The potency order for adenosine receptor agonists was N-ethylcarboxamidoadenosine (NECA) > or = (R)-N6-phenyl-2-propyladenosine [(R)-PIA] > N6-cyclopentyladenosine (CPA) > (S)-N6-phenyl-2-propyladenosine [(S)-PIA]. The human receptor was blocked by xanthine antagonists, most potently by 3-(3-iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine (I-ABOPX) with a potency order of I-ABOPX > 1,3-dipropyl-8-(4-acrylate)phenylxanthine > or = xanthine amino congener >> 1,3-dipropyl-8-cyclopentylxanthine. Adenosine, NECA, (R)- and (S)-PIA, and CPA inhibited forskolin-stimulated cAMP accumulation by 30-40% in stably transfected cells; I-ABA is a partial agonist. When measured in the presence of antagonists, the dose-response curves of NECA-induced inhibition of forskolin-stimulated cAMP accumulation were right-shifted. Antagonist potencies determined by Schild analyses correlated well with those established by competition for radioligand binding. The A3 adenosine receptor transcript is widespread and, in contrast to the A1, A2a, and A2b transcripts, the most abundant expression is found in the lung and liver. The tissue distribution of A3 mRNA is more similar to the widespread profile found in sheep than to the restricted profile found in the rat. This raises the possibility that numerous physiological effects of adenosine may be mediated by A3 adenosine receptors.

DIABETES insipidus is a rare complication of pregnancy. When this disease does happen to be associated with the pregnant state, however, considerable interest attaches to the combination, since there are implications both from the obstetrical and from the endocrine standpoint. To the obstetrician it is of importance to know whether an insufficient production of oxytocic hormone coincides with the inadequate elaboration of antidiuretic hormone, with the resultant possibility of dystocia. The obstetrician is interested also in the possibility that posterior pituitary extract administration, necessary for the treatment of the diabetes insipidus, might be responsible for the induction of premature labor. From an endocrine standpoint, further information is needed concerning the effect various normal hormonal shifts during pregnancy might have upon the function of the posterior lobe of the pituitary gland. That such shifts might well have an important effect is suggested by the well-known fact that in diabetes insipidus the

In bovine heart mitochondria a protein of Mr18 kDa, phosphorylated by mtPKA, is associated to the NADH-ubiquinone oxidoreductase in the inner membrane and is present in purified preparation of this complex. The 18 kDa phosphoprotein has now been isolated and sequenced. It is identified as the 18 kDa (IP) AQDQ subunit of complex I, a protein of 133 amino acids with a phosphorylation consensus site RVS at position 129–131.

Ovarian histology and function were assessed before and after total abdominal hysterectomy in 25 patients with symptomatic uterine myomata. Immediately before hysterectomy, bilateral ovarian biopsies were performed, and, 12 months later, all patients underwent a second ovarian biopsy through laparoscopy. Histologic study of the ovaries one year after total abdominal hysterectomy showed stromal cell hyperplasia, thickening of the tunica albuginea, and a significant decrease of follicular reserve, follicular cysts, and corpora albicantia. There was no significant difference in the number of atretic follicles and corpora lutea. The serum levels of all hormones studied were unchanged 12 months after the surgical procedures.

In bovine heart mitochondria a protein of Mr18 kDa, phosphorylated by mtPKA, is associated to the NADH‐ubiquinone oxidoreductase in the inner membrane and is present in purified preparation of this complex. The 18 kDa phosphoprotein has now been isolated and sequenced. It is identified as the 18 kDa (IP) AQDQ subunit of complex I, a protein of 133 amino acids with a phosphorylation consensus site RVS at position 129–131.

Abstract. The clinicopathological picture of 'isolated C3 mesangial nephritis' was studied in our case records. Focal and segmental or generalised deposits of C3 in the mesangium were found in 12 of 157 (7.6%) patients with primary glomerulonephritis. The clinical picture, similar to Berger's disease, was characterised by episodes of gross haematuria and/or persistent or recurrent micro-haematuria and/or proteinuria. Arterial hypertension and mild renal failure were observed in one case. Light-microscopy showed minor glomerular changes such as focal and segmental increase of mesangial matrix and mesangial hyperplasia. During the short-term follow-up (median 25.5 months) no deterioration of renal function was observed. The clinical course and short-term prognosis suggest that this form of glomerulonephritis is benign.

Il ruolo della Angio TC spirale nella valutazione diagnostica della biforcazione carotidea per la selezione di pazienti da sottoporre ad endo-arterectomia è ancora da definire.Lo scopo del nostro studio è quello di valutare l'accuratezza dell'Angio-TC spirale rispetto all'Angiografia carotidea. Abbiamo sottoposto ad Angio-TC spirale dei vasi epiaortici 46 pazienti (92 biforcazioni carotidee) entro 48 ore dall'esame angiografico, utilizzando un apparecchio TC spirale con tubo ad elevate prestazioni (Philips Tomoscan SR 7000). E' stato utilizzato un bolo di contrasto di circa 120 cc con 3 mm di spessore e 3 mm di avanzamento (Pitch=l) ottenendo immagini ricostruite sul piano assiale di 1 mm successivamente elaborate con algoritmo MIP.L'Angiografia carotidea è stata eseguita in almeno due proiezioni per ciascuna biforcazione carotidea ed il grado della stenosi valutato secondo i criteri NASCET.La concordanza tra Angio-TC spirale ed Angiografia carotidea è stata di circa il 90% con minore correlazione per le stenosi di grado lieve e moderato. L'Angio-TC è risultata superiore nella rilevazione di placche calcifiche.