An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro

BACKGROUND: Unstable atherosclerotic plaques that cause acute coronary events usually contain abundant macrophages expressing matrix metalloproteinases (MMPs) and tissue factor (TF), molecules that probably contribute to plaque rupture and subsequent thrombus formation. Lipid lowering with HMG-CoA reductase inhibitors reduces acute coronary events. METHODS AND RESULTS: To test whether lipid lowering with an HMG-CoA reductase inhibitor retards macrophage accumulation in rabbit atheroma, we administered cerivastatin to immature Watanabe heritable hyperlipidemic rabbits (cerivastatin group, n=10, cerivastatin 0.6 mg x kg(-1) x d(-1); control group, n=9, saline 0.6 mL x kg(-1) x d(-1)) for 32 weeks and measured macrophage accumulation and expression of MMPs and TF. Serum cholesterol levels after 32 weeks were 809+/-40 mg/dL (control group) and 481+/-24 mg/dL (treated group). Cerivastatin diminished accumulation of macrophages in aortic atheroma. Macrophage expression of MMP-1, MMP-3, MMP-9, and TF also decreased with cerivastatin treatment. Cerivastatin reduced the number of macrophages expressing histone mRNA (a sensitive marker of cell proliferation) detected by in situ hybridization but did not alter macrophages bearing a marker of death (TUNEL staining). Cerivastatin treatment (>or=0.01 micromol/L) also reduced growth, proteolytic activity due to MMP-9, and TF expression in cultured human monocyte/macrophages. CONCLUSIONS: These results suggest that lipid lowering with HMG-CoA reductase inhibitors alters plaque biology by reducing proliferation and activation of macrophages, prominent sources of molecules responsible for plaque instability and thrombogenicity.     

Verhandlungen ärztlicher Gesellschaften

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Verhandlungen Ärztlicher Gesellschaften

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Prosthodontic rehabilitation of oral function in head-neck cancer patients with dental implants placed simultaneously during ablative tumour surgery: an assessment of treatment outcomes and quality of life

The aim of this prospective study was to assess treatment outcome and impact on quality of life of prosthodontic rehabilitation with implant-retained prostheses in head-neck cancer patients. Fifty patients were evaluated by standardized questionnaires and clinical assessment. All received the implants during ablative tumour surgery in native bone in the interforaminal area. About two-thirds of the patients (n=31) needed radiotherapy post-surgery. Both in irradiated and non-irradiated bone two implants were lost 18-24 months after installation. Peri-implant tissues had a healthy appearance. No cases of osteoradionecrosis occurred. In 15 patients no functional implant-retained lower dentures could be made for various reasons. The other 35 patients all functioned well, with an improvement in quality of life. Major improvement was observed in the non-irradiated patients. In the irradiated patients, less improvement in many functional items was observed, while items related to the oral sequelae of radiotherapy did not improve. Similar to the quality-of-life assessments, denture satisfaction was improved and tended to be higher in non-irradiated than irradiated patients. Implant-retained lower dentures can substantially improve the quality of life related to oral functioning and denture satisfaction in head-neck cancer patients. This effect is greater in non-irradiated than irradiated cancer patients.     

Preliminary functional results of endoscope-assisted transoral treatment of displaced bilateral condylar mandible fractures

Temporomandibular joint (TMJ) function was evaluated following endoscope-assisted transoral open reduction and miniplate fixation of displaced bilateral condylar mandibular fractures. The transoral treatment of bilateral condylar fractures was performed in 13 patients from May 2000 to December 2004. Eleven of the 13 patients had additional mandibular fractures. Out of 26 fractures of the condylar process, 11 were located at the condylar neck and 15 were subcondylar. One, 6 and 12 months after surgery TMJ function was evaluated. Anatomic reduction was achieved using an endoscope-assisted transoral approach even when the condylar fragment was displaced medially and in fractures with comminution. Good TMJ function was noted 6 and 12 months after surgery. Mouth opening was measured to be more than 40 mm without deviation. Postoperative range of motion with a satisfying lateral excursion was found. Early rehabilitation and pre-injury TMJ function was achieved following minimally invasive anatomic fracture reduction.     

First Survey of Metallo-β-Lactamases in Clinical Isolates of Pseudomonas aeruginosa in a German University Hospital

A total of 489 clinical isolates of Pseudomonas aeruginosa was investigated for metallo-β-lactamase (MBL) production. Molecular analysis detected a bla_VIM-1 gene in the chromosome of one isolate and a bla_VIM-2 gene carried on the plasmid in seven isolates. Moreover, we showed that an initial screening by combined susceptibility testing of imipenem and ceftazidime followed by a confirmatory EDTA combination disk test represents a valid alternative to the molecular investigation of MBL genes, making MBL detection possible in routine diagnostic laboratories.Metallo-β-lactamase (MBL)-producing Gram-negative bacteria are an increasing public health problem worldwide because of their resistance to all β-lactams except aztreonam (3). MBL genes are typically part of an integron and are either carried on transferable plasmids or are part of the bacterial chromosome (28). The most common transferable MBL families include the VIM-, IMP-, GIM-, SPM-, and SIM-type enzymes which have been detected primarily in Pseudomonas aeruginosa but were also found in other Gram-negative bacteria, including nonfermenters and members of the family Enterobacteriaceae (22). Recently, two new subgroups of MBLs, designated NDM-1 and DIM-1, were identified in a clinical isolate of Klebsiella pneumoniae in India and in a clinical isolate of Pseudomonas stutzeri in the Netherlands, respectively (21, 31).In most studies, reduced susceptibility to imipenem has been adopted as the sole criterion for further phenotypic or molecular investigations in order to detect MBLs (11, 19, 20, 23). However, this criterion seems to be suboptimal, as it does not allow exclusion of isolates characterized by the loss of the OprD porin, the most common mechanism of resistance to imipenem in P. aeruginosa (14, 22). Moreover, several phenotypic tests for detecting MBLs, such as the MBL Etest (20, 25), EDTA combination disk test (20, 25, 30), EDTA disk synergy test (10), and imipenem lysate MBL assay (27), have been developed and evaluated. However, the performance of each of these tests seems to be strongly affected by the local rate of MBL-producing isolates.In Germany, VIM-, and GIM-type enzymes in P. aeruginosa isolates have already been detected (1, 8, 26). Recently, Elias et al. described a nosocomial outbreak caused by a bla_VIM-2-positive P. aeruginosa in patients of the Department of Urology of the university hospital of the University of Würzburg, Würzburg, Germany, between November and December 2007 (4). However, to the best of our knowledge, no systematic surveys of the occurrence of MBLs in clinical isolates of P. aeruginosa have been conducted in Germany so far.Accordingly, this study was designed with the following aims: (i) to develop improved screening criteria for the detection of MBL-producing P. aeruginosa; (ii) to determine the proportion of MBL-producing isolates in clinical isolates of P. aeruginosa in the university hospital of the University of Würzburg in Germany; (iii) to assess the relatedness of MBL-producing isolates; (iv) to determine the locations of the MBL genes detected; and (v) to evaluate two phenotypic tests as confirmatory tests for the detection of MBL production.Since no standard imipenem MIC breakpoints for MBL producers are available, we first analyzed the MICs of imipenem in 10 well-characterized P. aeruginosa control strains shown previously to produce IMP-, VIM-, GIM-, SIM-, and SPM-type enzymes (Table ​(Table1).1). Identification to the species level was confirmed using Vitek 2 GN cards (bioMérieux, Nürtingen, Germany). Antimicrobial susceptibility testing was carried out with Vitek 2 AST-N021 and AST-N110 cards (bioMérieux). MICs were interpreted as recommended by the CLSI (2). All MBL-producing positive-control strains were intermediate sensitive or resistant to imipenem (MIC ≥ 8 μg/ml). Subsequently, we investigated 26 consecutive nonreplicate clinical isolates of P. aeruginosa with an imipenem MIC of ≥8 μg/ml for the presence of MBL genes by multiplex PCR as described by Ellington et al. (5). All clinical isolates were collected in our laboratory throughout 2007 before the outbreak at the university hospital of the University of Würzburg, Würzburg, Germany (4), and all isolates were shown by multiplex PCR to be negative for MBL genes. Since the loss of the OprD porin, the most common mechanism of resistance to imipenem in P. aeruginosa, does not confer ceftazidime resistance (15), we analyzed the ceftazidime MICs in the MBL-producing positive-control strains and in the 26 MBL-negative isolates. While all 10 MBL-producing positive-control strains were resistant to ceftazidime (MIC ≥ 32 μg/ml), only 6 of the 26 MBL-negative isolates were resistant to ceftazidime (P < 0.01) (Table ​(Table1).1). Consequently, we adopted MIC breakpoints for the initial screening of MBL producers of ≥8 μg/ml for imipenem and ≥32 μg/ml for ceftazidime.

TABLE 1.

Comparison of imipenem and ceftazidime MICs in well-characterized MBL-producing positive-control strains and in MBL-negative clinical isolates^a