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Biomedical subjects

S Milano

Publications and source records attributed to S Milano.

At least 37 records · Page 2Linked to original sources
PubMed1997

Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood.

We have tested whether tetracyclines (TETs) are able to protect mice from lipopolysaccharide (LPS)-induced shock, a cytokine-mediated inflammatory reaction. Mice, injected with a single dose of tetracycline base (TETb; 1.5, 10 and 20 mg/kg of body weight) or doxycycline (DOXY; 1.5 mg/kg), were significantly protected from a lethal intraperitoneal injection of LPS (500 micrograms per mouse). TETs acted in early events triggered in response to LSP; in fact, they were no longer significantly protective if injected more than 1 h after the injection of endotoxin. LPS-treated mice protected by TETs showed a significant inhibition of tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and nitrate secretion in the blood, events that were directly related with the survival. In mice treated with TETs a significant decrease of inducible nitric oxide synthase (iNOS) activity was observed in spleen and peritoneal cells compared with that detected in mice treated with LPS alone. Furthermore, TETs were found to inhibit NO synthesis by peritoneal macrophages stimulated in vitro with LPS. On the contrary, TETs were unable to decrease the ability of the macrophages to synthesize IL-1 alpha and TNF-alpha in vitro. These results indicate that TETs are not able to act directly on the synthesis of these cytokines, but they may modulate other pathways that could in turn be responsible for the inhibition of IL-1 alpha and TNF-alpha synthesis. Altogether, these results indicate that TETs are advantageous candidates for the prophylaxis and treatment of septic shock in mice, having both antimicrobial activity and the ability to inhibit endogenous TNF-alpha, IL-1 alpha, and iNOS, hence, exerting, potent anti-inflammatory effects.

Animals↗
PubMed1996

Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or beta-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo.

In vivo microdialysis in rat ventral hippocampus was used (i) to verify the importance of 5-HT1A autoreceptors in the raphe as targets for drugs that enhance the citalopram-induced elevation of forebrain 5-hydroxytryptamine (5-HT), and (ii) to further examine the specificity of (-)-penbutolol in this regard. The selective 5-HT1A receptor antagonist WAY100635 (s.c., or intra-raphe) or the mixed 5-HT1A/1B/beta-adrenoceptor antagonist (-)-penbutolol (s.c.), potentiated the citalopram-induced 5-HT rise, whereas local "reverse' dialysis of WAY100635 into the ventral hippocampus did not. Furthermore, the (-)-penbutolol-induced augmentation proved stereoselective and not mediated by beta-adrenoceptors (no effect of s.c. (+)-penbutolol, or beta 1- and beta 2-adrenoceptor blockers (betaxolol, ICI118.551)). These data provide direct evidence that increased stimulation of 5-HT1A autoreceptors in the midbrain raphe impedes the effect of citalopram on forebrain extracellular 5-HT, whereas neither postsynaptic 5-HT1A receptors nor beta-adrenoceptors appear to be involved.

Adrenergic beta-Antagonists↗
PubMed1996

Activity of dorsal respiratory group inspiratory neurons during laryngeal-induced fictive coughing and swallowing in decerebrate cats.

Membrane potential changes and/or discharges from 36 inspiratory neurons were recorded intracellularly in the dorsal respiratory group (DRG; i.e., the ventrolateral subdivision of the nucleus tractus solitarii) in decerebrate, paralyzed, and ventilated cats. Electrical activities were recorded from both somata (n = 10) and axons (n = 26). Activities during quiet breathing were compared with those observed during fictive coughing and swallowing evoked by repetitive electrical stimulation of afferent fibers of the superior laryngeal nerve (SLN). These nonrespiratory behaviors were evident in paralyzed animals as characteristic discharge patterns of the phrenic, abdominal, and hypoglossal nerves. Twenty-six neurons exhibiting antidromic action potentials in response to electrical stimuli applied to the cervical (C3-5) spinal cord were classified as inspiratory bulbospinal neurons (IBSNs). These neurons were considered as premotoneurons. The remaining 10 inspiratory neurons (I-NAA) were not antidromically activated by electrical stimuli applied to either cervical spinal cord or ipsilateral cervical vagus. These neurons are thought to be propriobulbar neurons. We recorded the activity of 31 DRG inspiratory neurons (24 IBSNs and 7 I-NAA) during coughing. All but one (a late-recruited IBSN) discharged a burst of action potentials during the coughing-related phrenic nerve activity. Typically, ramp-like membrane depolarization trajectories and discharge frequencies during coughing were similar to those observed during inspiration. We recorded the activity of 33 DRG inspiratory neurons (23 IBSNs and 10 I-NAA) during swallowing. Most (28/33) neurons were briefly activated, i.e., discharged a burst of action potentials during swallowing, but peak discharge frequency decreased compared with that measured during inspiration. The membrane potentials of nine somata exhibited a brief bell-shaped depolarization during swallowing, the amplitude of which was similar to that observed during inspiration. These results suggest that some inspiratory premotoneurons and propriobulbar neurons of the DRG might be involved in nonrespiratory motor activities, even if clearly antagonistic to breathing (e.g., swallowing). We postulate the existence in the medulla oblongata of adult mammals of neurons exhibiting a "functional flexibility".

Action Potentials↗
PubMed1996

Histopathological grading of response to induction chemotherapy in non-small cell lung cancer: a preliminary study.

Management of locally advanced NSCLC is controversial. Induction chemotherapy followed by surgery has become an accepted approach for Stage III disease. However, the clinical assessment of the efficacy of preoperative treatment is inaccurate. We propose a four-grade histopathological evaluation of the response to chemotherapy based on the analysis of 20 evaluable cases and compared with clinical outcome. Follow-up ranged from 12 to 68 months. Correlation between different grading of necrosis and survival is statistically significant. Based on these preliminary results, we suggest that grading of response is a valid parameter to evaluate standard regimens and novel drug associations in larger trials.

Aged↗
PubMed1996

Synthesis and sulfatase inhibitory activities of non-steroidal estrone sulfatase inhibitors.

About one-third of breast cancers are classified as estrogen-dependent breast cancers. In the past 10 years, numerous reports have suggested the importance of estrone sulfate and estrone sulfatase in regulating the supply of estrogens to these cancers. Estrone sulfatase inhibitors may thus prove to be useful for the treatment of these diseases. Several research groups have reported the development of estrone sulfatase inhibitors, and estrone-3-O-sulfamate has been shown to be the most potent sulfatase inhibitor. However, a recent report indicated that estrone may be released during the inactivation of sulfatase by estrone-3-O-sulfamate and rendered the inhibitor to be estrogenic. Therefore, there is a need for a potent non-steroidal sulfatase inhibitor that is metabolically stable, more selective, and lacking estrogenic activity. We developed a series of (p-O-sulfamoyl)-N-alkanoyl tyramines, and they proved to be potent estrone sulfatase inhibitors. Using human placental microsome as the enzyme source, the best inhibitor in this series, compound 18, has an IC50 of 55.8 nM. Another potent inhibitor in this series, compound 17, exhibited time-dependent inactivation of sulfatase when incubated at various concentrations (0.2-1.0 microM) of the inhibitor. Estrone sulfate partially blocked the inactivation of the enzyme by the compound, indicating that the compound inactivated sulfatase at the active site. The irreversible nature of the enzyme-inhibitor interaction was supported by irreversibility studies. Thus, (p-O-sulfamoyl)-N-alkanoyl tyramines represent a new series of non-steroidal estrone sulfatase inhibitor.

Binding Sites↗
PubMed1996

Ex vivo evidence for PGE2 and LTB4 involvement in cutaneous leishmaniasis: relation with infection status and cytokine production.

Ex vivo culture of spleen cells from BALB/c mice infected with 2 x 10(6) Leishmania major (L. major) promastigotes were cultured with ConcanavalinA (ConA) or leishmanial antigen (L. Ag) and tested for prostaglandin E2 (PGE2) and for leukotriene B4 (LTB4), in order to study their involvement in the evolution of cutaneous leishmaniasis and the connexion with lymphokine-mediated responses. The data were compared with those obtained in BALB/c mice protected against L. major by sublethal irradiation (550 rad; cured mice). In the unprotected BALB/c mice the levels of PGE2 that were responsible for the depression of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF alpha) Th1-associated cytokines and for the relative increase in the interleukin-4 (IL-4) became higher and higher as the lesion progressed. On the contrary, the cured mice produced levels of PGE2 similar to normal uninfected controls, high levels of TNF alpha and IFN-gamma and low levels of IL-4. Elevated levels of LTB4 were detected in the early stage of infection in the unprotected mice compared to cured ones, a sign of more intense inflammation and a stimulus for the recruitment of inflammatory cells. The observation that exogenous LTB4 was able to enhance in vitro both Th1 cytokines in cured mice and Th2 cytokines in unprotected ones suggests that LTB4 could act in the recruitment of the T cells already committed to Th1 or Th2 phenotype.

Animals↗
PubMed1996

Depression of CD4 T cell subsets and alteration in cytokine profile in boutonneuse fever.

Interferon (IFN)-gamma, interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-alpha were significantly increased in sera from Sicilian patients with acute boutonneuse fever (BF) compared with those of healthy controls. IFN-gamma levels dropped sharply within the second week after infection. IL-6, IL-10, and TNF-alpha levels gradually declined; in convalescent patients only were they in the normal range. In contrast, peripheral blood mononuclear cells (PBMC) stimulated in vitro with phytohemagglutinin (PHA) produced low levels of IL-10 and IFN-gamma in acute BF that were compatible with the reduction in the levels of CD4+, CD4+/CD45RO+, and CD4+/CD45RA+ cells. In vitro production of TNF-alpha and IL-6 from PBMC stimulated with PHA was not significantly modified during the various phases of the infection compared with control PBMC, which could be due to the persistence of high levels of CD14+ monocytes compensating for the decrease in CD20+ B cells.

Adult↗
PubMed1996

Repeated administration of the 5-HT3 receptor antagonist granisetron reduces the incidence of delayed cisplatin-induced emesis in the piglet.

We analyzed the effects of the 5-HT3 receptor antagonist granisetron on both acute and delayed phases of cisplatin-induced emesis in the conscious piglet. Animals that received a high dose of cisplatin (5.5 mg/kg i.v.) were observed continuously for 60 h. Seventeen piglets were treated with cisplatin only and acted as controls. In experimental animals, granisetron (administered before cisplatin) was administered either as a single initial injection (7 mg/kg), alone or in combination with dexamethasone (40 mg), or as multiple injections (1 mg/kg) given every 5 h during the first 30 h of the experiment (cumulative dose: 7 mg/kg). Two other groups of piglets were treated with dexamethasone (40 mg) alone or with multiple injections of ondansetron (7 injections at 3.5 mg/kg), respectively. The latency to the first emetic episode was significantly increased in all groups that received a 5-HT3 receptor antagonist, whatever the agent and the protocol of administration. Piglets treated solely with dexamethasone exhibited a latency similar to that of controls. The total number of emetic events during the 60 h was significantly reduced only in the group of piglets treated repeatedly with granisetron and in the group that received an initial dose (7 mg/kg) of granisetron in combination with dexamethasone. We observed that 3 out of 8 piglets treated repeatedly with granisetron did not vomit throughout the experiment. These results demonstrate that granisetron, when administered repeatedly, is efficacious against delayed emesis. They also suggest that serotonin may be involved in the production of the delayed phase of cisplatin-induced emesis.

Animals↗
PubMed1996

[Pulsating tumor of the sternum: enlarged exeresis and reconstruction with marlex-methylmethacrylate prosthesis].

The authors report on a rare case of pulsating tumor of the sternum. En bloc resection was carried out with removal of the sternal manubrium and body, tracts of the I-II-III rib with the intercostal muscles and part of the left pectoralis major. Reconstruction of the thoracic wall was performed with a marlex MMA sandwich prosthesis. From a histological viewpoint, the carcinoma was well differentiated and compatible with thyroid primitivity. Non complementary antiblastic therapies were provided as all the examinations carried out were negative and the intervention was radical. The patient had been followed-up with serial controls and three complete stagings at one, three and five years after intervention (CT, echography and function tests of the thyroid, bone scintigraphy). At follow-up of more than six years the patient is doing well and is event free. The authors believe, even with the help of reports from the literature that, in sternal metastases from thyroid carcinomas, especially when single and large, surgical therapy is required.

Carcinoma↗
PubMed1995

In vivo and in vitro cytokine profiles and mononuclear cell subsets in Sicilian patients with active visceral leishmaniasis.

Sera from Sicilian patients with confirmed visceral leishmaniasis (Leishmania donovani infantum) were analysed at the moment of the diagnosis, during the course of the disease and after clinical recovery, for the concentration of IL-10, IFN-gamma, IL-4 and IL-2. The results show high concentrations of IL-10 and IFN-gamma in the sera at the beginning of infection that return to the normal range following successful chemotherapy. By contrast, PBMC stimulated in vitro with Ag and mitogen produced low levels of IL-10 and IFN-gamma when collected at the time of the diagnosis and normal levels when assayed after recovery. IL-2 was undetected in the sera and was significantly reduced in the supernatants of actively infected patients, returning to the normal level after recovery. IL-4 was absent in the sera and in high concentrations in the supernatants in all the phases of the disease. The levels of CD4+ and CD8+ T cells were within the normal range, but acute VL patients had markedly reduced levels of memory T cells (CD3+/CD45RO+) compared with healthy controls. These cells returned to the normal levels following successful chemotherapy. T cells are strongly activated in acute VL patients as indicated by the elevated number of CD3+ HLA-DR+ and by the increase in HLA-DR antigen on these cells. There was a significant reduction in the cell membrane DR antigen of the monocytes (CD 14+) during the acute phase of the disease, but it returned to the normal range after clinical recovery. These findings therefore suggest that in Sicilian patients with active VL the cytokine profile is not clearly characterized by Th2 phenotype as in mice, and both Th1-like and Th2-like cells appear to proliferate and to be activated. Furthermore, IL-10, rather than IL-4, could play an important part in the inhibition of IFN-gamma-induced macrophage activation and could reflect the levels of HLA-DR antigen expressed by the monocytes.

Animals↗
PubMed1995

Studies on the role of 5-HT1A autoreceptors and alpha 1-adrenoceptors in the inhibition of 5-HT release--I. BMY7378 and prazosin.

UNLABELLED: The present study utilized in vivo microdialysis to investigate the importance of 5-HT1A autoreceptors and alpha 1-adrenoceptors in the decreased 5-HT release obtained following administration of the mixed 5-HT1A autoreceptor partial agonist/alpha 1-adrenoceptor antagonist BMY7378, the selective 5-HT1A receptor agonist 8-OH-DPAT and the alpha 1-adrenoceptor antagonist prazosin. BMY7378 (0.25 mg/kg, s.c.), 8-OH-DPAT (0.025 mg/kg, s.c.) and prazosin (0.1-1.0 mg/kg, s.c.) all suppressed ventral hippocampal 5-HT efflux. The BMY7378- and 8-OH-DPAT-induced inhibition of 5-HT release were reversed by a 40 min pre-treatment with either (+/-)pindolol (8 mg/kg, s.c.) or WAY-100635 (0.3 mg/kg, s.c.), to block 5-HT1A autoreceptors. Neitehr of these antagonists altered the prazosin-induced (0.3 mg/kg, s.c.) 5-HT disease. THE RESULTS: (i) confirm that both an alpha 1-adrenoceptor antagonist (prazosin) and 5-HT1A autoreceptor stimulants (BMY7378 and 8-OH-DPAT) may reduce cerebral 5-HT release; (ii) support that the BMY7378-induced decrease in 5-HT release results from 5-HT1A autoreceptor agonism, rather than alpha 1-adrenoceptor blockade; and (iii) argue against "physiological" antagonism (i.e. via blockade of beta-adrenoceptors, 5-HT1B receptors or some other mechanism) as an explanation for the reversal by pindolol of 5-HT1A autoreceptor agonist-induced suppression of 5-HT release. These data support the usefulness of pindolol, as well as the more specific compound WAY-100635, to block 5-HT1A autoreceptors.

Animals↗
PubMed1995

Prostaglandin E2 regulates inducible nitric oxide synthase in the murine macrophage cell line J774.

We have evaluated the role of prostaglandin E2 (PGE2) in the synthesis of nitric oxide (NO) by the activation of the inducible form of nitric oxide synthase (NOS) in the murine macrophage cell line, J774, stimulated with different doses of lipopolysaccharide (LPS). The stimulation of the J774 line with suboptimal doses of LPS (0.1 microgram/mL) caused a production of endogenous PGE2 that was capable of stimulating NOS activity inducing an increase in the NO synthesis, as attested by the fact that cyclooxygenase enzyme inhibitor, indomethacin, significantly reduced NO secretion. On the contrary, a higher dose of LPS (1 microgram/mL) produced high levels of PGE2 that reduced the levels of NOS and, subsequently, NO production. Experiments carried out with exogenous PGE2 indicated that concentrations between 1 and 10 ng/mL are able to stimulate the expression of NOS and the release of NO, while higher concentrations (> 50 ng/mL) are inhibitory. Furthermore, our data indicate that there is a network of interaction which involves NO, PGE2, and tumor necrosis factor. High levels of PGE2 inhibited TNF alpha secretion, which in turn could exert inhibitory effects on NO synthesis.

Animals↗
PubMed1995

Effect of exogenous leukotriene B4 (LTB4) on BALB/c mice splenocyte production of Th1 and Th2 lymphokines.

The effect of exogenous leukotriene B4 (LTB4) on the production of cytokines typical of Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-10) lymphocytes was studied. Splenocytes were stimulated with concanavalin A (ConA) with or without different concentrations of LTB4 (3 x 10(-10) to 3 x 10(-7) M) for various times in the presence of BW 755C to inhibit the endogenous synthesis of eicosanoids. LTB4 was not able to induce cytokine secretion by itself. However, LTB4 augmented ConA spleen cell production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) from Th1 cells and interleukin-4 (IL-4) and interleukin-10 (IL-10) from Th2 cells more than the controls treated with ConA alone. The pre-exposition of splenocytes to LTB4 for 3 h made these cells more sensitive to ConA in terms of IL-2 and IL-10 production than those treated with LTB4 at the onset of the incubation and maintained during the whole culture period. The results suggest that LTB4 may participate as a component of the signal transduction process for ConA-induced Th1 and Th2 cytokine production in a time-dependent manner.

Animals↗
PubMed1995

Surgery of lung metastases in renal cell carcinoma.

OBJECTIVE: To examine the impact on survival of pulmonary resection in the treatment of renal cell carcinoma that has metastasized to the lung. PATIENTS AND METHODS: From June 1986 to July 1991, 19 patients were submitted to synchronous or asynchronous lung metastasectomy. Histological examination confirmed the presence of lung metastases from renal cell carcinoma in 16 cases (six synchronous and 10 asynchronous with a mean disease-free interval of 23 months). In the other three cases, histological examination revealed tuberculomas, chondroid hamartoma and foci of anthracosis. RESULTS: To date, among the six patients with synchronous lung metastases, three have died, two are progressing and one has no evident disease after a mean survival of 24 months. Among the 10 patients who underwent surgical resection of metachronous lung metastases, one has died, three are progressing and six have no evident disease (mean survival time, 43 months). CONCLUSION: While the presence of synchronous lung metastases is an unfavourable prognostic factor even after surgical removal (five out of six patients died or are in progression shortly after metastasectomy), the results after surgery of asynchronous lung metastases are encouraging, although the real efficacy of this treatment is still to be confirmed.

Carcinoma, Renal Cell↗
PubMed1995

The piglet as a suitable animal model for studying the delayed phase of cisplatin-induced emesis.

In 46 weaned piglets we surgically implanted a cannula in the jugular vein and electrodes for ECG and EMG recordings. After a 4- to 5-day recovery, piglets were hydrated, then dosed with cisplatin (5.5 mg/kg i.v.) and recorded continuously for the next 60 h. Thirteen piglets (i.e., controls) received only cisplatin. Twenty-three other piglets received, 15 min before cisplatin, an i.v. injection of granisetron (0.25, 0.5, 2 or 7 mg/kg) or ondansetron (0.5, 2 or 7 mg/kg). Ten other piglets received, in addition to cisplatin, multiple injections of granisetron (1 mg/kg) and ondansetron (3.5 mg/kg). All control piglets exhibited both acute and delayed emesis. The first vomiting occurred with a latency of 2.13 +/- 0.82 hr after cisplatin administration; emetic intensity reached a peak (5 vomits/hr) within 2 hr and then decreased rapidly. No vomiting was observed between the 16th and 18th hr. The mean number of vomits during the first 16th was 18.4 +/- 2. Delayed emesis started at the 18th hr and lasted until the 58th hr. The mean number of vomits during the whole of the delayed phase was 9.6 +/- 2.4; the highest emetic intensity (1.2 vomit/hr) occurred between the 21th and the 22th hr. Pretreatment with a 5-HT3 receptor antagonist increased significantly the latency of the first emetic event in a dose-dependent manner. However, the severity of the acute phase was reduced significantly only with granisetron at the dose of 7 mg/kg, although the severity of the delayed phase remained unchanged, irrespective of the dose of granisetron. Three about five piglets treated repeatedly with granisetron did not vomit throughout the chemotherapy course. In contrast, no complete control was observed with repetitive injections of ondansetron. Cisplatin inducing both acute and delayed vomiting in the piglet without any lethality; this animal is a suitable model in which to study the pathogenesis of delayed emesis.

Animals↗
PubMed1994

Protein kinase C activation and anti-amnesic effect of acetyl-L-carnitine: in vitro and in vivo studies.

Drugs belonging to different chemical classes having the ability to improve behavioral performance in animal learning and memory tests may share the common ability to stimulate protein kinase C activity in rat brain cortex. In vitro acetyl-L-carnitine (100 nM) promoted in rat brain cortex slices a significant increase in particulate activity associated with lower soluble protein kinase C activity and produced a direct stimulation of the enzyme in both the cortex and hippocampus. In vivo a significant increase in particulate protein kinase C activity was observed in the group of rats treated with 60 mg/kg acetyl-L-carnitine, a dose shown to be effective in improving the cognitive deficits induced by scopolamine in the Morris maze test. The results suggest that acetyl-L-carnitine increases particulate protein kinase C activity in the cortex both in vitro and in vivo. This effect in the in vivo experiments seems to be observed only with doses that are effective in improving the performance of rats in a spatial learning task.

Acetylcarnitine↗
PubMed1994

Brainstem neurons with projecting axons to both phrenic and abdominal motor nuclei: a double fluorescent labeling study in the cat.

The distribution of retrogradely doubly labeled brainstem neurons were analyzed in the cat after injection of two different fluorescent markers into the phrenic and abdominal motor nuclei. Diamidino Yellow (DY) was first injected either ipsilaterally or bilaterally into the ventral horn of lumbar spinal cord, and then Fast Blue (FB) into the right ventral horn of cervical spinal cord. Doubly labeled neurons were mainly found in the caudal ventrolateral medulla (retroambiguus region), in the dorsomedial and dorsolateral regions of the nucleus of the tractus solitarius (NTS) and in the raphe nuclei. In addition, doubly labeled neurons were found in the parabrachial and Kölliker-Fuse nuclei. Our results give anatomical evidence that pontine and medullary neurons are the source of a common pathway to both phrenic and abdominal motor nuclei. These neurons might be involved in strain efforts for expulsion such as vomiting or defecation.

Abdominal Muscles↗