Synthesis and antimicrobial activity of new 7 beta-(benzo[a]dihydrocarbazolyloxyacetyl)-substituted cephalosporins

Selected 7beta-(benzo[a]dihydrocarbazolyloxyacetyl)-substituted cephalosporins (1a-e) were synthesised and tested for their antimicrobial activity against Gram-positive and Gram-negative clinical pathogens. All compounds synthesised (1a-e) showed an in vitro antimicrobial activity similar to that of ceftriaxone and cefpirome against the Gram-positive bacteria, and superior to that of penicillin and cefaclor against pen-R Staphylococcus aureus species. Like all beta-lactam agents, compounds 1a-e were in an inactive Minimum Inhibitory Concentration (MIC > 32 microg/ml) against methicillin-resistant S. aureus species. Furthermore, as expected, no cross-resistance was observed against the erythromycin-resistant Staphylococcus pyogenes strain. Finally, it is worth underlining that compounds 1a and 1e showed a similar activity to that of ceftriaxone and superior to cefaclor against penicillin-resistant Streptococcus pneumoniae isolates, a key respiratory tract infection (RTI) causing pathogen difficult to treat with currently marketed antibiotics.     

Rolling of human bone-metastatic prostate tumor cells on human bone marrow endothelium under shear flow is mediated by E-selectin

Prostate tumor cells preferentially adhere to bone marrow endothelial cells (BMECs) compared with endothelial linings from other tissue microvessels, implicating the importance of BMEC adhesion in the predilection of prostate tumor metastasis to bone. E (endothelial)-selectin, which functions as an initiator of leukocyte adhesion to target tissue endothelium, is constitutively expressed on BMECs, suggesting that prostate tumor cells could use this adhesive mechanism to initiate their migration into bone. In this report, we demonstrate for the first time that human bone-metastatic prostate tumor cells roll on human BMECs under physiological flow conditions. We show that these dynamic adhesive interactions are dependent on the expression of BMEC E-selectin and sialylated glycoconjugates on bone-metastatic prostate tumor cells. We also establish the importance of both glycoprotein(s) and glycosphingolipid structures displaying sialyl Lewis X epitopes as potential E-selectin ligands on bone-metastatic prostate tumor cells. Coexpression of sialylated glycoproteins and glycolipids on bone-metastatic prostate tumor cells triggers robust E-selectin binding activity, which is identical to that observed on human hematopoietic progenitor cells. By Western blot analysis, we identify candidate E-selectin glycoprotein ligand(s); distinct sialyl Lewis X (or HECA-452 antigen)-bearing membrane proteins were resolved at M(r) 130,000 and M(r) 220,000 as well as others ranging from M(r) 100,000 to M(r) 220,000. Immunohistochemical analysis of HECA-452 antigen expression on normal prostate tissue and on low- and high-grade prostate adenocarcinoma shows that HECA-452 antigen expression is directly associated with prostate tumor progression and may indicate acquisition of E-selectin ligand expression. These findings provide novel insight into potential adhesive mechanisms promoting hematogenous dissemination of prostate tumor cells into bone.     

Lethal injuries among the members of the 4th Guardian Brigade of Croatian Army during the 1991-1995 war

OBJECTIVE: We analyzed the causes of deaths among the members of the 4th Guardian Brigade (GB) of the Croatian Army during the war in Croatia from 1991 to 1995: the site of the lethal injuries, the type of wounds, and estimated the severity of injuries with lethal outcome according to the Abbreviated Injury Scale. METHODS: This was a retrospective study using the files and data obtained from 4th GB, Croatian Ministry of Defense, and Croatian Ministry of War Veterans. RESULTS: During the War in Croatia from 1991 to 1995, 182 members of 4th GB were killed. One hundred fifteen (63.2%) suffered lethal injuries caused by shell fragments, 47 (25.8%) soldiers had gunshot wounds, and 20 ( 11.0%) died in traffic accidents. Mean Abbreviated Injury Scale for killed soldiers was 7.61 +/- 1.27. CONCLUSION: During the war in Croatia, the leading causes of death were mines and explosions, and, in a minor proportion, gunshot wounds.     

Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5

BACKGROUND: The short arm of chromosome 3 is thought to include one or more tumour suppressor genes (TSGs), since carcinoma of various tissues display deletions in this region. Many genes mapping to this region have recently been identified, including the LUCA-15/RBM5 gene. RESULTS: In this study we report the cloning from human bone marrow library of a splice variant of LUCA-15 which lacks exon 6, resulting in a frameshift and producing a truncated protein of 150 amino acids instead of 815 amino acids. This variant is widely expressed at a low level in normal tissues and is expressed at increased levels in T-leukaemic cell lines. Over-expression of this splice variant after electroporation both shortened the cell cycle and inhibited CD95-mediated apoptosis in CEM-C7 T-cells. In marked contrast, over-expression of the full length LUCA-15/RBM5 suppressed cell proliferation both by inducing apoptosis and by extending the G1 phase of the cell cycle. CONCLUSION: These results, taken together with previous observations from ourselves and others, suggest that LUCA-15 is involved in the control of both apoptosis and the cell cycle. Since oncogenesis often relies on separate changes in molecules regulating apoptosis on the one hand, and proliferation, on the other, the discovery of a candidate tumour suppressor gene which affects both processes simultaneously is likely to be of major significance.     

Intravenous lidocaine as adjuvant to sevoflurane anesthesia for endotracheal intubation in children

IMPLICATIONS: Supplementing a sevoflurane induction of anesthesia in children with IV lidocaine 2 mg/kg can suppress cough after tracheal intubation and thus improve intubating conditions. In addition, lidocaine minimizes blood pressure fluctuations after tracheal intubation.     

In vitro activity of dimethylarsinic acid against human leukemia and multiple myeloma cell lines

PURPOSE: Arsenic trioxide (As(2)O(3)), an inorganic arsenic compound, has recently been approved for the treatment of relapsed or refractory acute promyelocytic leukemia. However, systemic toxicity associated with As(2)O(3) treatment remains a problem. Inorganic arsenic is detoxified in vivo by methylation reactions into organic arsenic compounds that are less toxic. METHODS AND RESULTS: We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As(2)O(3), against a panel of eight leukemia and multiple myeloma cell lines. As(2)O(3) was tested in comparison. In clonogenic assay, the average concentration of DMAA that suppressed cell colony growth by 50% was 0.5-1 m M, while for As(2)O(3) it was on average 1-2 microM. At those concentrations DMAA and As(2)O(3) had significantly less effect on colony growth of normal progenitor cells. Cytotoxic doses of DMAA and As(2)O(3) in 3-day trypan blue dye exclusion assay experiments were similar to doses effective in clonogenic assay. Assessment of apoptosis by annexin V assay revealed a high rate of apoptosis in all cell lines treated with DMAA and As(2)O(3), but significantly less effect on normal progenitor cells. DMAA, unlike As(2)O(3), had no effect on the maturation of leukemic cells. CONCLUSIONS: DMAA exerts differential antiproliferative and cytotoxic activity against leukemia and multiple myeloma cells, with no significant effect on normal progenitor cells. However, concentrations of DMAA needed to achieve such efficacy are up to 1000 times those of As(2)O(3). Evaluation of novel organic arsenic that would combine the high efficacy of As(2)O(3) and the low toxicity of DMAA is warranted.     

Synthesis and prostaglandin synthase inhibitory activity of new aromatic O-alkyloxime ethers substituted with methylsulfonamido or methylsulfonyl groups on their aliphatic portion

Some aromatic O-alkyloxime ethers substituted with methylsulfonamido (7) or methylsulfonyl (8) groups on their aliphatic portions were prepared as analogues of structurally related cyclooxygenase (COX) inhibitors (6) bearing a carboxylic group typical of the classic non-steroidal anti-inflammatory drugs (NSAIDs) in the place of the sulfurated moiety. In addition, also analogues of compounds 8 in which the aliphatic chain is further lengthened by 1 (9), 2 (10), or 3 (11) carbon atoms were synthesized. All compounds (7-11) were tested in vitro towards COX2, and compounds 7-9 towards COX1, by measuring prostaglandin E2 (PGE(2)) production in activated J774.2 macrophages and U937 cell lines, respectively. While all new compounds were found to possess little or no activity on the COX2 isoenzyme, some of these (7a-7d, 8a, 8d, 9e and 9f) appeared to possess an appreciable activity on COX1, with % inhibition values at a concentration of 1 microM ranging from 30% of 8a to 76% of 9e. The COX1 selectivity of the new compounds was tentatively explained by means of a docking study of one of the more active compounds tested on both COX isoenzymes (7d), which indicated a different number of hydrogen bonding interactions with the Arg120 of the active sites of the two enzymes, and therefore, an energetically favored interaction (3.5 kcal/mol) with COX1, compared with COX2.     

Evidence for hair cell regeneration in the crista ampullaris of the lizard Podarcis sicula

We studied hair cell regeneration in the crista ampullaris of the lizard Podarcis sicula both in untreated animals and at early and late time intervals following a single high dose of gentamicin. The study was carried out using the S-phase marker 5-bromo-2'-deoxyuridine. Our ultrastructural and immunofluorescence studies showed that both apoptosis and hair cell regeneration happen in the lizard crista ampullaris in untreated animals, and that regenerative processes are greatly accelerated after treatment with the aminoglycoside antibiotic gentamicin. Our observations indicate that hair cell regeneration is strongly implicated in the repair of damaged sensory epithelium, and that new hair cells appear likely to arise from supporting cells.     

A molecular basis for hereditary motor and sensory neuropathy disorders

Charcot-Marie-Tooth disease (CMT), or inherited peripheral neuropathies, is one of the most frequent genetically inherited neurologic disorders, with a prevalence of approximately one in 2500 people. CMT is usually inherited in an autosomal dominant fashion, although X-linked and recessive forms of CMT also exist. Over the past several years, considerable progress has been made toward understanding the genetic causes of many of the most frequent forms of CMT, particularly those caused by mutations in Schwann cell genes inducing the demyelinating forms of CMT, also known as CMT1. Because the genetic cause of these disorders is known, it is now possible to study how mutations in genes encoding myelin proteins cause neuropathy. Identifying these mechanisms will be important both for understanding demyelination and for developing future treatments for CMT.