Insulin resistance and the endothelium

There is increasing evidence of a parallel progression between insulin resistance and endothelial dysfunction, suggesting a close association between insulin action and the endothelium. Numerous studies have demonstrated that endothelial dysfunction occurs early in the insulin-resistant state and is predictive of future cardiovascular events. Similarly, insulin resistance has been associated with the metabolic syndrome, which also increases the risk of adverse cardiovascular outcomes. Approaches that improve endothelial dysfunction, such as treatment with statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or peroxisome proliferator-activated receptor gamma ligands, have been shown to prevent both diabetes and cardiovascular disease. This article reviews the relation between endothelial dysfunction and cardiovascular disease, assesses the endothelium in the spectrum of insulin resistance, and examines the effect of the thiazolidinediones on endothelial function.     

Insulin resistance and the endothelium

Type 2 diabetes is a cardiovascular disease equivalent that is associated with accelerated atherosclerosis and significant mortality. However, the metabolic syndrome and prediabetes are associated with increased cardiovascular mortality, indicating that atherogenic vascular changes begin prior to the onset of overt diabetes. At the core of diabetes and the metabolic syndrome is insulin resistance (IR), which sets the stage for dyslipidemia, hypertension, and inflammation. Endothelial dysfunction is the first stage of the atherosclerosis process and results from exposure to cardiovascular risk factors, such as IR and diabetes. IR and atherosclerosis follow parallel paths as they progress in severity. Thiazolidinediones, angiotensin-converting enzyme inhibitors, angiotensin receptor-AT1 blockers, and statins are widely used in the treatment of diabetes. Emerging evidence indicates that these pharmacologic agents have added mechanisms of action, especially on the endothelium and in the prevention of diabetes.     

Antimicrobial resistance in the tropics

Bacterial resistance to antimicrobial agents is an increasing problem in many areas of the tropics. In most countries there is little information available to determine the patterns of resistance in different pathogens, nor are local data available to influence prescribing. This paper will review the development of antimicrobial resistance in the tropics, consider the current priority problems, and suggest strategies that may be taken to improve the surveillance of resistance.     

Antibiotic resistance of Escherichia coli. Importance of the resistance to trimethoprim-sulfamethoxazole

Antimicrobial sensitivities, especially trimethoprim-sulfamethoxazole, were studied in all clinical isolates of Escherichia coli in an intensive care unit for over 18 months. Twenty-four per cent of strains were resistant to trimethoprim-sulfamethoxazole. Combined resistance to ampicillin +/- chloramphenicol (+/- tetracycline) and streptomycin (+/- kanamycin) with resistance to trimethoprim-sulfamethoxazole was demonstrated. These data confirm the previously reported increasing trimethoprim-sulfamethoxazole resistance which is probably plasmid-mediated and specify the resistances associated with trimethoprim-sulfamethoxazole resistance. These findings suggest that widespread prophylaxis in granulocytopenic patients with lower urinary tract infection by the trimethoprim-sulfamethoxazole association should be re-examined.     

Antiretroviral drug resistance and resistance testing

Antiretroviral resistance testing should be performed in newly diagnosed patients with acute or recent HIV infection and at the time of treatment failure, and there is growing support for testing in newly diagnosed, treatment-naive patients with chronic infection as well. Genotypic testing is preferred for baseline screening, because it is more sensitive than phenotypic testing for the presence of mixed populations of drug-susceptible and -resistant virus and because it is less expensive. Phenotypic testing provides quantitative information on the degree of resistance and is also able to assess interactions among mutations. As a result, it can be particularly useful in determining treatment options for treatment-experienced patients with multi-drug resistant virus. In many cases, there may be advantages to the use of both tests.     

Mitomycin resistance in mammalian cells expressing the bacterial mitomycin C resistance protein MCRA

The mitomycin C-resistance gene, mcrA, of Streptomyces lavendulae produces MCRA, a protein that protects this microorganism from its own antibiotic, the antitumor drug mitomycin C. Expression of the bacterial mcrA gene in mammalian Chinese hamster ovary cells causes profound resistance to mitomycin C and to its structurally related analog porfiromycin under aerobic conditions but produces little change in drug sensitivity under hypoxia. The mitomycins are prodrugs that are enzymatically reduced and activated intracellularly, producing cytotoxic semiquinone anion radical and hydroquinone reduction intermediates. In vitro, MCRA protects DNA from cross-linking by the hydroquinone reduction intermediate of these mitomycins by oxidizing the hydroquinone back to the parent molecule; thus, MCRA acts as a hydroquinone oxidase. These findings suggest potential therapeutic applications for MCRA in the treatment of cancer with the mitomycins and imply that intrinsic or selected mitomycin C resistance in mammalian cells may not be due solely to decreased bioactivation, as has been hypothesized previously, but instead could involve an MCRA-like mechanism.     

The nematode resistance gene Mi of tomato confers resistance against the potato aphid

Resistance against the aphid Macrosiphum euphorbiae previously was observed in tomato and attributed to a novel gene, designated Meu-1, tightly linked to the nematode resistance gene, Mi. Recent cloning of Mi allowed us to determine whether Meu-1 and Mi are the same gene. We show that Mi is expressed in leaves, that aphid resistance is isolate-specific, and that susceptible tomato transformed with Mi is resistant to the same aphid isolates as the original resistant lines. We conclude that Mi and Meu-1 are the same gene and that Mi mediates resistance against both aphids and nematodes, organisms belonging to different phyla. Mi is the first example of a plant resistance gene active against two such distantly related organisms. Furthermore, it is the first isolate-specific insect resistance gene to be cloned and belongs to the nucleotide-binding, leucine-rich repeat family of resistance genes.     

金黄色葡萄球菌的耐药性及其耐氟喹诺酮机制的研究

目的了解金黄色葡萄球菌(金葡菌)的耐药性及其耐氟喹诺酮的机制。方法用纸片扩散法测定200株金葡菌对12种抗生素的耐药性,琼脂稀释法测定52株耐环丙沙星金葡菌对3种氟喹诺酮的最低抑菌浓度（MIC）。聚合酶链反应-限制性长度多态性分析及利血平逆转实验分别检测耐环丙沙星金葡菌gyrA和grlA基因突变及norA基因表达。结果耐甲氧西林金葡菌（MRSA）占34%,并对多种抗菌药物耐药,但对万古霉素均敏感。MRSA对环丙沙星的耐药率高达79.4%,且对其他氟喹诺酮交叉耐药。52株耐环丙沙星金葡菌中42株（80.8%）检出gyrA基因84位点突变,grlA基因80位点和84位点突变分别有10株（19.2%）和14株（26.9%）,gyrA或双基因突变株对环丙沙星的MIC显著高于单独grlA突变株或不存在gyrA84位点突变株(P<0.01)。利血平逆转后52株耐药菌对3种氟喹诺酮的MIC显著降低(P<0.01)。结论金葡菌的耐药性日趋严重,特别是MRSA仅对万古霉素等少数抗菌药物敏感,目前氟喹诺酮不适宜治疗MRSA;临床分离金葡菌耐氟喹诺酮的机制大多涉及药物作用靶位gyrA和grlA的基因突变以及主动外排泵增强,耐药菌株grlA突变位点可能有地区差异。