Impact of copeptin on diagnosis, risk stratification, and intermediate-term prognosis of acute coronary syndromes.

BACKGROUND: The aim of the current study was to evaluate the diagnostic and intermediate-term prognostic impact of C-terminal portion of provasopressin (copeptin) in combination with troponin I. METHODS: In this prospective single-center study we recruited a total of 230 unselected patients with suspected recent acute coronary syndrome (ACS) presenting consecutively at our chest pain unit. Troponin I and copeptin levels were determined at presentation and after 3-6 h. Follow-up was performed after 180 days. RESULTS: Acute myocardial infarction (AMI) was the final diagnosis in 107 patients (STEMI: 24, NSTEMI: 83). The median copeptin level was significantly higher in patients having AMI than in those without (20.83 vs. 12.2 pmol/L, p < 0.0001). A troponin I level <0.04 ng/mL in combination with copeptin <14 pmol/L at admission ruled out AMI with an negative predictive value (NPV) of 97.3 %. p = 0.0045 for the added value of copeptin to troponin I. Kaplan-Meier analysis showed that copeptin levels above the diagnostic cut-off were associated with an elevated intermediate-term (180 days) mortality (p = 0.019), while no patient with copeptin values below the cut-off died. Univariate Cox regression analysis identified copeptin as strong predictor of intermediate-term mortality (HR 4.28, 95 % CI 1.58-11.6, p = 0.004). The predictive performance for prediction of 180-day mortality was significantly better if copeptin was included (C-index of 0.80) compared with that of troponin alone (C-index 0.78, p = 0.01 for the added value of copeptin to troponin I). CONCLUSIONS: Additional assessment of copeptin allows a rapid and reliable exclusion of AMI and improves diagnostic accuracy in myocardial ischemia. This study showed for the first time that copeptin provides valuable predictive information for risk stratification and intermediate-term outcome in ACS patients.

What do we know 40 years after Nixon declared the 'war on cancer'? On the origin, prevention and treatment of cancer.

Evolutionary principles suggested by Darwin and Wallace some 150 years ago can provide insights into the origins of cancer. Moreover, they can form a basis for answering the question implicitly posed when Nixon declared the war on cancer in 1971: Can we actually 'cure' cancer? As explained lucidly by Greaves in 2001, necessary keys to evolution and thus for the origin of species, including ours, are changes of genes or mutations; but changes of genes are also necessary links in the causal chains which lead to cancer. In effect, cancer is therefore, according to Greaves, an 'evolutionary legacy'. Intriguingly, the realization that cancer is a consequence of changes in genes which are conditiones sine qua non for evolution suggests a mutation paradox on an evolutionary scale: in individuals, mutations may have devastating adverse health effects, including cancer. Populations, however, as a whole can be expected to benefit ultimately from changes of genes to better adapt to environmental challenges. On the basis of premises from evolution theory, it remains for us to interweave growing insights into evolutionary principles with realistic objectives for the primary prevention of and, where the latter fails, coexistence with cancer so that what we do for patients can become more of an art rather than a war.

Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock.

OBJECTIVE: To compare the effects of a first-line therapy of combined arginine vasopressin, levosimendan, and norepinephrine with arginine vasopressin + norepinephrine or norepinephrine alone in ovine septic shock. DESIGN: Prospective, randomized, controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: Twenty-one chronically instrumented sheep. INTERVENTIONS: After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with arginine vasopressin (0.5 mU·kg·min), combined arginine vasopressin (0.5 mU·kg·min) and levosimendan (0.2 µg·kg·min), or normal saline (each n = 7) for 24 hrs. In all groups, open-label norepinephrine was additionally titrated to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary. MEASUREMENTS AND MAIN RESULTS: Arginine vasopressin + levosimendan + norepinephrine improved left ventricular contractility (higher stroke work indices at similar or lower preload) and pulmonary function (Pao2/Fio2 ratio) when compared with the other groups (p < .05 each). Both nonadrenergic treatment strategies reduced open-label norepinephrine doses. However, only arginine vasopressin + levosimendan + norepinephrine limited fluid requirements and positive fluid balance vs. both other groups (p < .05 each). In addition, arginine vasopressin + levosimendan + norepinephrine increased mixed venous oxygen saturation as compared with arginine vasopressin + norepinephrine. Histologic tissue analyses and pulmonary hemeoxygenase-1 activity revealed no differences among groups. Notably, arginine vasopressin + levosimendan + norepinephrine therapy reduced pulmonary 3-nitrotyrosine levels (p = .028 vs. control animals) as well as urinary protein/creatinine ratio (p < .05 each) and slightly prolonged survival when compared with both other groups (4 hrs vs. arginine vasopressin + norepinephrine: p = .013; 7 hrs vs. norepinephrine alone: p = .003). CONCLUSIONS: First-line cardiovascular support with combined arginine vasopressin and levosimendan supplemented with norepinephrine improves myocardial, vascular, pulmonary, and renal function as compared with arginine vasopressin + norepinephrine in septic shock.

Renal effects of saline-based 10% pentastarch versus 6% tetrastarch infusion in ovine endotoxemic shock.

BACKGROUND: Conflicting data exist on the renal effects of hydroxyethyl starch (HES) preparations. The current study evaluates the effects of saline-based 6% HES 130/0.4, 10% HES 200/0.5, and a balanced isotonic crystalloid on renal function and microscopic changes in ovine endotoxemic shock. METHODS: Thirty sheep were subjected to endotoxin infusion (Salmonella typhosa) at incremental doses until mean arterial pressure was less than 65 mmHg. Animals were randomized to receive fluid resuscitation with saline-based 6% HES 130/0.4, 10% HES 200/0.5, or a balanced isotonic crystalloid (n = 10 each). Animals surviving the 12-h intervention period were anesthetized and killed. Kidney samples were taken for microscopic analyses. RESULTS: Endotoxemia was associated with hemoconcentration, protein extravasation, and arterial hypotension. Fluid resuscitation established a hypotensive-hyperdynamic circulation with increased cardiac index and oxygen delivery and decreased afterload. Diuresis was lowest in animals treated with 10% HES 200/0.5. In addition, plasma creatinine and urea concentrations increased in sheep treated with 10% HES 200/0.5 (1.2 +/- 0.1 and 19 +/- 2 mg/dl) when compared with the other two groups (0.9 +/- 0.1 and 15 +/- 1 mg/dl, 6% HES 130/0.4; 0.9 +/- 0.1 and 15 +/- 1 mg/dl, crystalloids; each P < 0.05). Electron microscopic tubular injury score was highest in sheep treated with 10% HES 200/0.5 (P < 0.001 vs. 6% HES 130/0.4). CONCLUSIONS: In ovine endotoxemic shock, saline-based 10% HES 200/0.5 was linked to impaired renal function and more pronounced tubular epithelial injury when compared with 6% HES 130/0.4 and balanced crystalloids.

How to surf today's information tsunami: on the craft of effective reading.

In this editorial, we provide concise suggestions to help individuals decide what scientific papers to read and how to read them. We do so because--like others--we are frequently asked by people with interest in science as to how to effectively surf today's information tsunami. This is particularly important in, but not confined to, universities and other research institutions where reading scientific papers is a fundamental task that forms the basis for all other academic activities such as writing papers or grant applications, providing reviews for a journal, preparing for postdoctoral positions, qualifying for collaborations or making oral or poster presentations. Included in our Advices 1-8 are concise suggestions which range from the appropriate motivation for reading articles in books, journals or on the internet to the very craft of systematically reviewing and, indeed, constantly challenging what one reads. We close this editorial with reading Advice 9 "You should always identify the roots of thinking and research" and 10 "The Golden Rule: set aside reading time" which should be necessary conditions for everyone who works in science. Importantly, while maintaining focus on material immediately pertinent to one's primary research area, one should read about developments in other fields as well because this may be the key to original, and sometimes revolutionary, research.

Cytokine plasma levels: reliable predictors for radiation pneumonitis?

BACKGROUND: Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC. METHODOLOGY/PRINCIPAL FINDINGS: In 52 NSCLC patients (stage I-III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-beta1, and immunoreactivity was quantified (grade 1-4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-beta1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-beta1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients. CONCLUSIONS/SIGNIFICANCE: The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-beta1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.

Neanderthal, chimp and human genomes: hypotheses wanted for research into brain evolution.

The recent sequencing of Neanderthal DNA and the release of drafts of human and chimp genomes in 2001 and 2005, respectively, provide an opportunity to better understand why our brain is different from those of extinct and living relatives. However, it is not clear that hypothesis-free analysis of genetic differences alone will shed light on the complex "big bang" evolution of human brains that is thought to have taken place about 100,000 years ago. Rather than pursuing black box genomics, we suggest that genetic analyses should be guided by hypotheses. One plausible candidate in this regard is the"fat-utilization" hypothesis proposed by the late David Horrobin.

Lack of toxicological side-effects in silver-coated megaprostheses in humans.

Deep infection of megaprostheses remains a serious complication in orthopedic tumor surgery. Furthermore, reinfection gets a raising problem in revision surgery of patients suffering from infections associated with primary endoprosthetic replacement of the knee and hip joint. These patients will need many revision surgeries and in some cases even an amputation is inevitable. Silver-coated medical devices proved their effectiveness on reducing infections, but toxic side-effects concerning some silver applications have been described as well. Our study reports about a silver-coated megaprosthesis for the first time and can exclude side-effects of silver-coated orthopedic implants in humans. The silver-levels in the blood did not exceed 56.4 parts per billion (ppb) and can be considered as non-toxic. Additionally we could exclude significant changes in liver and kidney functions measured by laboratory values. Histopathologic examination of the periprosthetic environment in two patients showed no signs of foreign body granulomas or chronic inflammation, despite distant effective silver concentrations up to 1626 ppb directly related to the prosthetic surface. In conclusion the silver-coated megaprosthesis allowed a release of silver without showing any local or systemic side-effects.