Necrotizing fasciitis caused by the treatment of chronic non-specific back pain.

BACKGROUND: Chronic back pain is a multifactorial disease that occurs particularly in adults and has many negative effects on the quality of daily life. Therapeutic strategies are often multimodal and designed for a long-term therapy period. In some cases, one option is joint infiltration or intrathecal injection with local anaesthetics. An adverse effect of this intervention may be necrotic fasciitis, a disease with high mortality and few therapeutic options. CASE PRESENTATION: This case shows a 53-year-old female patient who developed necrotic fasciitis after infiltrations of the sacroiliac joint and after epidural-sacral and intrathecal injections. CONCLUSION: Thanks to early and aggressive surgical intervention, antibiotic treatment and hyperbaric oxygenation, she survived this serious complication and was able to return to life.

Precursor-Directed Biosynthesis and Fluorescence Labeling of Clickable Microcystins.

Microcystins, cyclic nonribosomal heptapeptides, are the most well-known cyanobacterial toxins. They are exceptionally well studied, but open questions remain concerning their physiological role for the producing microorganism or their suitability as lead compounds for anticancer drug development. One means to study specialized metabolites in more detail is the introduction of functional groups that make a compound amenable for bioorthogonal, so-called click reactions. Although it was reported that microcystins cannot be derivatized by precursor-directed biosynthesis, we successfully used this approach to prepare clickable microcystins. Supplementing different azide- or terminal alkyne containing amino acid analogues into the cultivation medium of microcystin-producing cyanobacteria strains, we found that these strains differ strongly in their substrate acceptance. Exploiting this flexibility, we generated more than 40 different clickable microcystins. We conjugated one of these derivatives with a fluorogenic dye and showed that neither incorporation of the unnatural amino acid analogue nor attachment of the fluorescent label significantly affects the cytotoxicity against cell lines expressing the human organic anion transporting polypeptides 1B1 or 1B3. Using time-lapse microscopy, we observed that the fluorescent microcystin is rapidly taken up into eukaryotic cells expressing these transporters.

Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.

BACKGROUND: Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. METHODS AND RESULTS: Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls. CONCLUSIONS: Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.

Isoprostanes and neuroprostanes: total synthesis, biological activity and biomarkers of oxidative stress in humans.

Isoprostanes (IsoPs) and neuroprostanes (NeuroPs) are formed in vivo by a free radical non-enzymatic mechanism involving peroxidation of arachidonic acid (AA, C20:4 n-6) and docosahexaenoic acid (DHA, C22:6 n-3) respectively. This review summarises our research in the total synthesis of these lipid metabolites, as well as their biological activities and their utility as biomarkers of oxidative stress in humans.

L-Arginine enhances the triglyceride-lowering effect of simvastatin in patients with elevated plasma triglycerides.

We recently noticed a possible triglyceride-lowering effect during dietary supplementation with L-arginine. The major limitation of prior studies on L-arginine, however, was that triglyceride levels were not the primary end point, and patients were not necessarily hypertriglyceridemic. Therefore, we conducted a 2-arm, randomized, double-blind study in 33 hypertriglyceridemic patients to investigate the hypothesis that oral L-arginine may lower serum triglyceride levels in hypertriglyceridemic patients on and off statins. The study consisted of a 6-week run-in phase, 6 weeks of treatment with L-arginine (n = 22, 1.5 g bid) or placebo (n = 11), and a 6-week extension period where simvastatin (20 mg qd) was added. All patients received dietary advice during each study visit. Routine and lipid laboratory parameters were determined in the local routine clinical laboratory. Treatment with L-arginine alone had no effects on serum lipids compared to placebo. The combination of L-arginine with simvastatin led to a significantly stronger reduction in triglycerides compared to placebo plus simvastatin (-140.5 +/- 149.2 mg/dL vs -56.1 +/- 85.0 mg/dL; P = .048). In addition, we found simvastatin-induced increases in aspartate transaminase and fibrinogen to be attenuated by L-arginine as compared to placebo. We conclude from our data that L-arginine enhances the effects of simvastatin on lipid metabolism, but it has no triglyceride-lowering effects when given alone.

Telmisartan improves endothelial function in patients with essential hypertension.

BACKGROUND: : Hypertension is a cardiovascular risk factor commonly associated with endothelial dysfunction and increased renal vascular resistance. Angiotensin receptor blockers (ARBs) may beneficially affect these parameters via antagonism of angiotensin type 1 (AT1) receptor-mediated vasoconstriction and vascular superoxide production. We therefore investigated whether the new ARB telmisartan improves endothelial function and renal vascular resistance in patients with essential hypertension. METHODS: : Thirty-seven patients with essential hypertension were randomized to receive telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks in a prospective, parallel group study. Brachial artery flow-mediated (endothelium-dependent) dilation (FMD) and renal vascular resistance index (RVRI) were evaluated using high-resolution ultrasound before, at 3 weeks (low dose), and at 6 weeks (high dose) after initiation of treatment. RESULTS: : At baseline, FMD and RVRI did not significantly differ between treatment groups. After 3 weeks of treatment neither treatment significantly changed FMD or RVRI. After 6 weeks of treatment, patients randomized to receive telmisartan alone or the combination, but not those treated with nisoldipine alone, displayed a significantly improved FMD, whereas RVRI values again were not significantly different as compared to those at baseline. CONCLUSION: : In our study cohort of patients with essential hypertension, treatment with telmisartan improved FMD but did not change RVRI. Future studies will demonstrate whether this telmisartan-induced effect may contribute to a blood pressure-independent reduction in cardiovascular morbidity.

Mobilization of putative high-proliferative-potential endothelial colony-forming cells during antihypertensive treatment in patients with essential hypertension.

Recent studies have shown that in response to vascular damage or ischemia, bone marrow-derived endothelial progenitor cells (EPCs) are recruited into the circulation. To investigate whether antihypertensive treatment has an influence on the number of circulating EPCs, patients with essential hypertension were treated either with the angiotensin receptor antagonist telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks. At baseline and after 3 and 6 weeks of treatment, EPCs were identified and quantified by fluorescence-activated cell sorting (FACS) analysis and by their capacity to generate colony-forming units of the endothelial lineage (CFU-EC) in a methylcellulose-based assay. During treatment, patients in the nisoldipine groups, but not in the telmisartan group, showed a significant mobilization of EPCs, which in part had the capacity to generate large-sized colonies comprising more than 1,000 cells. Moreover, a remarkable correlation between the number of CFU-EC and the number of circulating CD133(+)/CD34(+)/CD146(+) cells was observed, thereby providing strong evidence that cells with this phenotype represent functional EPCs. No correlation was found between the numbers of CFU-EC and the blood pressure levels at any time point during the treatment. Hence, nisoldipine-induced mobilization of EPCs might represent a novel mechanism by which this antihypertensive compound independently of its blood pressure-lowering effect contributes to vasoprotection in patients with essential hypertension.

Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension.

Hypertension is a cardiovascular risk factor commonly associated with insulin resistance, the metabolic syndrome, and type 2 diabetes mellitus. Recent in vitro data indicate that certain angiotensin receptor antagonists, for example, telmisartan, activate peroxisome proliferator-activated receptor gamma (PPAR-gamma) and increase adiponectin protein content in adipocytes. By this means, they may improve insulin sensitivity in vivo. To investigate the effect of antihypertensive treatment on insulin sensitivity and fasting adiponectin serum levels, 37 nondiabetic patients with essential hypertension were randomized to receive telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks in a prospective, parallel group study. Fasting serum glucose, insulin, and adiponectin were evaluated before, 3 weeks (low dose), and 6 weeks (high dose) after initiation of treatment. Furthermore, the effect of telmisartan on PPAR-gamma receptor activity was investigated in vitro using a PPAR-gamma reporter gene assay. As reported previously, telmisartan significantly enhanced PPAR-gamma receptor activity in vitro. At baseline, a positive correlation between insulin serum levels and body mass index of investigated subjects was observed, whereas body mass index and serum adiponectin levels were negatively associated. High-dose treatment with telmisartan but not with nisoldipine reduced serum insulin levels as well as the homeostasis model assessment of insulin resistance, but did not affect serum adiponectin levels. In conclusion, in our study cohort of nondiabetic patients with essential hypertension, telmisartan improved insulin sensitivity by mechanisms apparently not involving adiponectin induction. Future studies will demonstrate whether these telmisartan-induced effects may contribute to a blood pressure-independent reduction in cardiovascular morbidity.