Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin II type I receptor antagonists

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) type 1 receptor antagonists have strong cytostatic properties on in vitro cultures of many normal and neoplastic cells. They are effective, in particular, in reducing the growth of human lung fibroblasts, renal canine epithelial cells, bovine adrenal endothelial cells, simian T lymphocytes, and of neoplastic cell lines derived from human neuroblastomas, a ductal pancreatic carcinoma of the Syrian hamsters, human salivary glands adenocarcinomas, and two lines of human breast adenocarcinomas. ACE inhibitors are also effective in protecting lungs, kidneys and bladders from the development of nephropathy, pneumopathy, cystitis, and eventually fibrosis in different models of organ-induced damage such as exposure to radiation, chronic hypoxia, administration of the alkaloid monocrotaline or bladder ligation. ACE inhibitors and AII type 1 receptor antagonists are also effective in reducing excessive vascular neoformation in a model of injury to the cornea of rats and rabbits, and in controlling the excessive angiogenesis observed in the Solt-Farber model of experimentally induced hepatoma, in methylcholantrene or radiation-induced fibrosarcomas, in radiation-induced squamous cell carcinomas and in the MA-16 viral-induced mammary carcinoma of the mouse. Captopril was, in addition, effective in controlling tumor growth in a case of Kaposi's sarcoma in humans. The inhibition of AII synthesis and/or its blockade by AII receptors is likely to be an important mechanism for this cytostatic action. The mitogenic effect of AII is well established and a reduction of AII synthesis may well explain cell and neoplasm delayed growth. Moreover, AII regulates and enhances the activity of several growth factors including transforming growth factor B (TGFB) and smooth muscle actin (SMA); and many of these factors are reduced in tissues of animals treated with ACE inhibitors and AII type 1 receptor antagonists. These processes seem to be particularly relevant in the control of fibroblast growth and in the control of the ensuing fibrosis. The ACE inhibitors containing a sulphydril (SH) or thiol radical in their moiety (Captopril and CL242817) seemed to be more effective in controlling fibrosis and the growth of some neoplastic cells than those ACE inhibitors without this thiol radical in their structure, even if the second group of these drugs show in vitro a stronger inhibitory effect on converting enzyme activity. Pharmacologically it is known that ACE inhibitors containing a thiol radical also have antioxidant properties and they are efficient in controlling metalloproteinase action. However, although these additional properties are pharmacologically relevant, the blockade of AII synthesis plays an essential role in the cytostatic activity of these two categories of drugs. These observations underline that in addition to the beneficial effect of these drugs on the cardiovascular system, new potential applications are opening for their wider deployment.     

Magnetic Resonance enteroclysis imaging in Crohn's disease

PURPOSE: To assess the role of magnetic resonance enteroclysis (MRE) in patients with Crohn's disease, in order to identify involved segments, define the extension and evaluate transmural alterations. MATERIALS AND METHODS: Eighteen patients with known Crohn's disease were studied with MR (1.5 T), with breath-hold T2-weighted TSE, T2-weighted TSE SPIR and 3D T1-weighted sequences before and after gadolinium injection (0.2 mmol/kg) in the coronal and axial planes. The small bowel was distended by the administration of 2 l of methylcellulose through a nasojejunal tube and drug induced hypotony. Typical patterns of Crohn's disease, such as mucosal abnormalities, parietal thickening and narrowing of the bowel, prestenotic dilation, fibrofatty proliferation and enlarged lymph nodes were analysed on radiological and MRE images. MRE was performed within 30 days from conventional radiological studies (conventional enteroclysis and small bowel follow-through). RESULTS: Good distension of the bowel wall was obtained in all cases. MRE assessed the presence of parietal thickening and narrowing of the bowel wall (14/18 cases) and the presence of prestenotic dilatation (12/18 cases). Vascular enhancement (14/18 cases), transmural abnormalities (8/18 cases), fibrofatty proliferation (3/18 cases), abscess formation (2/18 cases) and enlarged mesenteric lymph nodes (6/18 cases) were also observed. MRE missed small fistulas which were visible in radiological studies in two patients. CONCLUSIONS: MRE appears to be a promising technique in patients with Crohn's disease. Due to limited spatial resolution MRE could be a useful adjunct to radiological studies and in following up selected groups of patients with prior known disease.     

Feedback inhibition by RALT controls signal output by the ErbB network

The ErbB-2 interacting protein receptor-associated late transducer (RALT) was previously identified as a feedback inhibitor of ErbB-2 mitogenic signals. We now report that RALT binds to ligand-activated epidermal growth factor receptor (EGFR), ErbB-4 and ErbB-2.ErbB-3 dimers. When ectopically expressed in 32D cells reconstituted with the above ErbB receptor tyrosine kinases (RTKs) RALT behaved as a pan-ErbB inhibitor. Importantly, when tested in either cell proliferation assays or biochemical experiments measuring activation of ERK and AKT, RALT affected the signalling activity of distinct ErbB dimers with different relative potencies. RALT deltaEBR, a mutant unable to bind to ErbB RTKs, did not inhibit ErbB-dependent activation of ERK and AKT, consistent with RALT exerting its suppressive activity towards these pathways at a receptor-proximal level. Remarkably, RALT deltaEBR retained the ability to suppress largely the proliferative activity of ErbB-2.ErbB-3 dimers over a wide range of ligand concentrations, indicating that RALT can intercept ErbB-2.ErbB-3 mitogenic signals also at a receptor-distal level. A suppressive function of RALT deltaEBR towards the mitogenic activity of EGFR and ErbB-4 was detected at low levels of receptor occupancy, but was completely overcome by saturating concentrations of ligand. We propose that quantitative and qualitative aspects of RALT signalling concur in defining identity, strength and duration of signals generated by the ErbB network.     

Probable dengue virus infection among Italian troops,East Timor, 1999-2000

To investigate the attack rate and risk factors for probable dengue fever, a cross-sectional study was conducted of an Italian military unit after its deployment to East Timor. Probable dengue was contracted by 16 (6.6%) of 241 army troops and caused half of all medical evacuations (12/24); no cases were detected among navy and air force personnel.     

(-)-Linalool produces antinociception in two experimental models of pain

Linalool is a monoterpene compound commonly found as a major component of the essential oils of several aromatic plant species, many of which are used in traditional medical systems as analgesic and anti-inflammatory remedies. We previously reported that (-)-linalool, the natural occurring enantiomer, plays a major role in the anti-inflammatory activity displayed by different essential oils, suggesting that linalool-producing species are potentially anti-inflammatory agents. In this study, the antinociceptive activity of (-)-linalool was examined in two different pain models in mice: the acetic acid-induced writhing response, a model of inflammatory pain, and the hot plate test, a model of supraspinal analgesia. Moreover, the effect of (-)-linalool on spontaneous locomotor activity (25, 50, 75 and 100 mg/kg) was evaluated. The results show that this compound induced a significant reduction of the acid-induced writhing at doses ranging from 25 to 75 mg/kg. Such effect was completely reversed both by the opioid receptor antagonist naloxone and by the unselective muscarinic receptor antagonist atropine. In the hot plate test, only the dose of 100 mg/kg of (-)-linalool resulted in a significant effect. (-)-Linalool induced a dose dependent increase of motility effects, thus ruling out the confounding influence of a possible sedative effect. The more pronounced effect of (-)-linalool on the writhing test with respect to the hot plate test is consistent with the observation that (-)-linalool possesses anti-inflammatory activity. Finally, the activation of opioidergic and cholinergic systems appears to play a crucial role in (-)-linalool-induced antinociception.     

A novel atypical retinoid endowed with proapoptotic and antitumor activity

The novel atypical retinoid E-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid (ST1926, 4) exhibited a potent antiproliferative activity on a large panel of human tumor cells. Despite almost complete loss of ability to activate RARs, the compound was an effective apoptosis inducer and surprisingly produced DNA damage, that likely contributes to the proapoptotic activity. Following oral administration, 4 was well tolerated and caused tumor growth inhibition in the ovarian carcinoma, A2780/DX, and in the human melanoma, MeWo, growing in nude mice, thus supporting the therapeutic interest of the novel agent.     

Antimicrobial prophylaxis in laparoscopic gynecologic surgery: a prospective randomized study comparing amoxicillin-clavulanic acid with cefazolin

Numerous studies have been published in recent years about antimicrobial prophylaxis in gynecologic surgery, but the optimal drug and schedule for the different surgical procedures is still a matter of debate. The aim of the present study was to compare two ultra-short term antimicrobial prophylaxis regimens (amoxicillin-clavulanic acid and cefazolin) in preventing infections following laparoscopic gynecologic operations. Three hundred sixty women hospitalized for a laparoscopic gynecologic surgery procedure were included in the study between January 1999, and December 2001. Patients were randomly allocated to receive amoxicillin-clavulanic acid (2.2 g) [Group A] or cefazolin (2 g) [Group B] as a single dose 30 minutes before surgery. Each patient was assessed daily until discharge to evidence febrile status and the presence of infections at the operative site, urinary tract and respiratory tract. In the amoxicillin-clavulanic acid (Group A) and cefazolin (Group B) groups, overall 164 and 172 patients, respectively, were evaluable for prophylactic efficacy at hospital discharge. Infectious complications were infrequent in both groups with febrile morbidity occurring in only one patient (0.6%) in the amoxicillin-clavulanic group. No sign of infections at the surgical site, urinary tract and respiratory tract was observed in either group. No death due to sepsis was recorded. It is concluded that ultra-short term prophylaxis with both amoxicillin-clavulanic acid and cefazolin is safe and effective in elective laparoscopic gynecologic surgery.     

Presence of detectable levels of soluble HLA-G molecules in CSF of relapsing-remitting multiple sclerosis: relationship with CSF soluble HLA-I and IL-10 concentrations and MRI findings

We have investigated the presence of non-classical soluble HLA-G molecules (sHLA-G) in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients and the possible relationships between CSF levels of sHLA-G, classical soluble HLA-I (sHLA-I) molecules, IL-10 amounts and Magnetic Resonance Imaging (MRI) findings were evaluated. We studied by ELISA technique the sHLA-I, sHLA-G and IL-10 levels in CSF of 50 relapsing-remitting (RR) MS patients stratified according to clinical and MRI evidence of disease activity. Thirty-six patients with other inflammatory neurological disorders (OIND) and 41 with non-inflammatory neurological disorders (NIND) were used as controls. CSF mean levels were significantly higher in MS and OIND than in NIND for sHLA-I (p<0.001) and in MS than in controls for sHLA-G (p<0.001), with no differences among the various groups for IL-10 mean concentrations. An increase in CSF sHLA-I was found in MS patients with Gd-enhancing lesions (p<0.01), while sHLA-G and IL-10 were more represented in MS patients without lesional activity on MRI scans (p<0.02). In MRI-inactive MS, CSF IL-10 mean concentrations were significantly greater in patients with CSF-detectable levels of sHLA-G than in those without any evidence of CSF sHLA-G expression (p<0.05). Our findings suggest that CSF classical sHLA-I and non-classical sHLA-G levels may modulate MS activity as assessed by MRI acting in opposite directions. The association observed between sHLA-G and IL-10 when Gd-enhancing lesion resolved indicates a potential immunoregulatory role for IL-10 in the control of MS disease activity by shifting the sHLA-I/sHLA-G balance towards sHLA-G response.     

The psychosocial approach to the planning and implementation of vaccine trials for HIV infection

The production of an effective vaccine for HIV infection is one of the major challenges for the third millennium public health. Here we review published studies addressing the issue of incentives and barriers influencing the choice to participate in a vaccine trial. Currently available literature clearly indicates the need to include psychosocial dimensions in the preparation and implementation of vaccine trials. The underestimation of participants' satisfaction about information communication may lead to non-adherence and to drop-out from the trials. Proper attention to communication skills of professionals involved in participants' enrollment and follow-up is essential to ensure trial success.     

CDKN2A/p16 in ependymomas

Sixteen cases of ependymoma were studied for CDKN2A/p16 inactivation by immunohistochemistry using a p16 monoclonal antibody, by homozygous deletion (HD) assay and 5CpG promoter methylation assay (methylation-specific PCR). Three out of 16 cases were p16 immuno-negative: two corresponded to grade II ependymomas and one to grade III. The latter ependymoma, characterized by a high Ki-67/MIB-1 LI, was the only one of the whole series to show CDKN2A HD. No promoter methylation was found in the two immuno-negative cases without CDKN2A HD. Alternative mechanisms, such as point mutations or alterations in p16 post-translational regulation, may be responsible for p16 inactivation. Since in our series just one out of eight anaplastic cases showed negative immunostaining and CDKN2A HD, p16/CDKN2A inactivation may not play an important role in the malignant transformation of ependymomas.Amplification of CCND1 and CDK4, p27/Kip1 degradation and TP53 mutations were previously studied by other authors and were demonstrated not to correlate with anaplasia. Up to date, molecular genetic studies have not been useful in recognizing the anaplastic variant in ependymomas.