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.

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.

Methylprednisolone reverses vasopressin hyporesponsiveness in ovine endotoxemia.

Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U x min(-1)) decreases over time in ovine endotoxemia. An additional objective was to determine whether the anticipated hyporesponsiveness can be counteracted by corticosteroids. Fourteen adult ewes (37 +/- 1 kg) were instrumented for chronic hemodynamic monitoring. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation. After 16 h of endotoxemia, the sheep were randomized to receive either AVP (0.04 U x min(-1)) or the vehicle (normal saline; n = 7 each). After 6 h of AVP or placebo infusion, respectively, methylprednisolone (30 mg x kg(-1)) was injected. Arginine vasopressin infusion increased mean arterial pressure and systemic vascular resistance index at the expense of a reduced cardiac index (P < 0.05 each). Supraphysiologic AVP plasma levels in the treatment group (298 +/- 15 pg x mL(-1)) were associated with increased surrogate parameters of liver, mesenterial, and myocardial dysfunction. After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg x kg(-1)) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.

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.

Endogenous progesterone and the exogenous progestin norethisterone enanthate are associated with a proinflammatory profile in healthy men.

CONTEXT: Inflammatory processes are related to atherosclerosis. Identification of inflammation triggers may furnish new therapeutic pathways. In women, progestins can have a marked inflammatory capacity. OBJECTIVE AND DESIGN: We investigated the effects of progesterone in men within the setting of two independent trials. First, the relation of endogenous progesterone levels to inflammation markers was assessed in 67 healthy nonsmoking Caucasian men (age, 20-50 yr) on a cross-sectional basis. Second, in a longitudinal controlled trial (52 wk) involving 28 healthy men receiving i.m. medication, we determined the effects of an exogenous progestin (norethisterone enanthate 200 mg) in combination with a long-acting testosterone preparation (testosterone undecanoate 1000 mg) administered to avoid androgen deficiency caused by pituitary-hypothalamic feedback. Controls received testosterone plus placebo. RESULTS: In the cross-sectional study, progesterone levels were positively related to concentrations of IL-6 (r = 0.41; P < 0.001), C-reactive protein (r = 0.37; P = 0.007), soluble vascular cell adhesion molecule 1 (r = 0.28; P = 0.02), E-selectin (r = 0.45; P < 0.001), leptin (r = 0.42; P < 0.001), neutrophils (r = 0.62; P < 0.001), and serum protein fractions alpha-1 (r = 0.44; P < 0.001) and alpha-2 (r = 0.36; P = 0.002). During the pharmacological trial, the testosterone/progestin group exhibited a marked increase of IL-6 concentrations (P < 0.001), whereas these decreased in the testosterone/placebo group (P = 0.03). Antiinflammatory IL-10 levels decreased in the group receiving testosterone/progestin (P = 0.01) but did not change in the testosterone/placebo group. CONCLUSION: Progesterone concentrations correspond to an inflammatory profile in healthy men, and external progestins elicit a similar effect. Men receiving regimens for hormonal male contraception involving progestins should be monitored for inflammatory effects. Speculatively, testosterone treatment decreasing endogenous progesterone production may facilitate beneficial effects on inflammation profiles even in eugonadal men.

The interleukin-6/interleukin-6-receptor system is activated in donor hearts.

OBJECTIVES: To assess the potential of the donor heart to respond to interleukin-6 (IL6), the present study investigated the expression of IL6 receptor components in the myocardium of donor hearts before transplantation. BACKGROUND: Donor heart dysfunction early after transplantation has been associated with the cytokine storm after donor brain death. Proinflammatory cytokines are thought to play a central role in this process. Interleukin-6 is of specific interest because it has been associated with cardiac allograft dysfunction and is related to an impaired prognosis. Its action requires expression of the specific IL6 receptor (IL6R), and the common signal transducer of the IL6 family glycoprotein 130 (gp130) in the donor heart. METHODS: The activation of IL6, IL6R and gp130 messenger ribonucleic acid (mRNA) and protein was studied via reverse transcription-polymerase chain reaction (RT-PCR) and immunohistology in donor hearts (n = 6) and compared with patients undergoing evaluation of ventricular arrhythmias (control, n = 9) or with advanced heart failure (n = 20). RESULTS: Messenger RNA of IL6, IL6R and gp130 was strongly expressed in all chambers of donor hearts, whereas right ventricles of control patients did not show any expression (donor vs. control: p < 0.005). Right ventricles of failing hearts showed IL6, IL6R and gp130 mRNA levels comparable with those found in donor hearts. Immunohistochemistry paralleled the RT-PCR data on the protein level. While IL6 was mainly expressed by myocytes, both receptor components were preferentially found mainly on interstitial cells. CONCLUSIONS: The expression of the IL6 receptor components in the donor heart before transplantation establishes the condition sine qua non for the response of the donor heart to circulating IL6. This mechanism may explain the close association of elevated IL6 serum levels to acute cardiac allograft dysfunction in the early perioperative period.

Cerebral vascular and metabolic response to sustained systemic inflammation in ovine traumatic brain injury.

Traumatic brain injury (TBI) is frequently accompanied by a systemic inflammatory response secondary to multiple trauma, shock, or infections. This study investigated the impact of sustained systemic inflammation on cerebral hemodynamics and metabolism in ovine traumatic brain injury. Fifteen sheep were investigated for 14 hours. Head injury was induced with a nonpenetrating stunner in anesthetized, ventilated animals. One group (TBI/Endo, n = 6) subsequently received a continuous endotoxin infusion for 12 hours, whereas a second group (TBI, n = 6) received the carrier. Three instrumented animals served as sham controls. Head impact significantly increased intracranial pressure from 9 +/- 4 mm Hg to 21 +/- 15 mm Hg (TBI/Endo) and from 10 +/- 3 mm Hg to 24 +/- 19 mm Hg (TBI) (means +/- SD). Internal carotid blood flow increased and cerebral vascular resistance decreased (P < 0.05) during the hyperdynamic inflammatory response between 10 and 14 hours in the TBI/Endo group, whereas these parameters were at baseline level in the TBI group. Intracranial pressure remained unchanged during this period, but increased during hypercapnia. The CMRO2, PaCO2, and arterial hematocrit values were identical among the groups between 10 and 14 hours. It is concluded that chronic endotoxemia in ovine traumatic brain injury was associated with cerebral vasodilation uncoupled from global brain metabolism. Different mechanisms appear to induce cerebral vasodilation in response to inflammation and hypercapnia.

Silver-coated megaendoprostheses in a rabbit model--an analysis of the infection rate and toxicological side effects.

Deep infection of megaprostheses remains a serious complication in orthopedic tumor surgery. Despite the use of systemic and local antibiotic prophylaxis the reported infection rate is between 5% and 35%. Silver-coated medical devices proved their effectiveness in reducing infections. The objective of this study was to examine in vivo the antimicrobial efficacy and possible side-effects of a silver-coated megaprosthesis. In a first study, 30 rabbits (15 titanium versus 15 silver-coated Mutars-endoprostheses) were infected with Staphylococcus aureus. In a second study, toxicological side effects were analyzed in 10 rabbits with a silver-coated megaprosthesis. The silver group showed significantly (p<0.05) lower infection rates (7% versus 47%) in comparison with the titanium group. Measurements of the C-reactive-protein, neutrophilic leukocytes, rectal temperature and body weight showed significant (p<0.05) lower signs of inflammation in the silver group. The analysis of the silver concentration in blood (median 1.883ppb) and in organs (0.798-86.002ppb) showed elevated silver concentrations without pathologic changes in laboratory parameters and without histological changes of organs. In conclusion, the new silver-coated Mutars-megaprosthesis resulted in reduced infection rates without toxicological side effects, suggesting that this prosthesis might be a promising device in tumor surgery exhibiting antimicrobial activity.

The mutagenically separated polymerase chain reaction is a rapid and reliable method for genotyping of the tumour necrosis factor-alpha promoter polymorphism (-308 G/A).

BACKGROUND: The tumour necrosis factor-alpha (TNF alpha) promoter polymorphism (-308 G/A) has been shown to be associated with the susceptibility to and/or the severity of diverse diseases such as infections, autoimmunity, and malignancies. We developed a genotyping technique based on the mutagenically separated polymerase chain reaction (MS-PCR) which may be useful in the clinical risk assessment. METHODS: Different length allele-specific primers and an unspecific complementary strand primer were used in a one-tube assay. At least one PCR product was generated in a single reaction obviating the need for an internal control amplification. Introduction of additional base substitutions into the allele-specific primers led to a clear-cut separation between the alleles through the reduction of cross-reactions during amplification. The only post-PCR step required was the separation of allelic PCR products by size upon agarose gel electrophoresis. RESULTS: The allele frequencies in 300 German healthy Caucasians were 0.84 for TNF1 (-308 G) and 0.16 for TNF2 (-308 A) in accordance with published data obtained with the conventional RFLP method. No significant deviation from Hardy-Weinberg equilibrium was observed. The specificity of MS-PCR was confirmed by sequence-based typing. CONCLUSIONS: MS-PCR is a rapid, reliable, and cost-effective technique for genotyping of the TNF alpha promoter polymorphism (-308 G/A).

Arteriovenous carboxyhemoglobin difference is not correlated to TNF-alpha, IL-6, PCT, CRP and leukocytes in critically ill patients.

BACKGROUND: It is still unclear as to whether the paradoxical arteriovenous carboxyhemoglobin (COHb) difference found in critical illness may represent a novel marker of the acute inflammatory response. We determined whether the arterial and central venous COHb concentration or their difference may be correlated to classical pro-inflammatory markers. METHODS: Arterial and matched central venous blood gases were obtained from non-smoking intensive care patients undergoing gastrointestinal surgery, and were correlated with plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP) and leukocytes. RESULTS: No correlation was found between arteriovenous COHb difference and the investigated pro-inflammatory mediators. While arterial and central venous COHb concentrations were positively correlated to plasma concentrations of TNF-alpha (P< or =0.01), IL-6 (P<0.05) and PCT (P< or =0.01), they were neither interrelated with PCT nor with leukocytes. CONCLUSIONS: Arteriovenous COHb difference does not appear to be a marker of the acute inflammatory response. Future studies are needed to investigate whether arterial and central venous COHb concentrations by themselves may serve as indicators of systemic inflammation.

The chronosense -- what light tells man about biological time.

In the past 10 years, experimental studies have provided further evidence for the suggestion that the eye serves man as a dual sense organ, viz as a sense organ for sight but also for time and the regulation of biological rhythms. A small group of scientists interested in the adjustment of biological rhythms to the key Zeitgeber light wanted to answer the question whether rods and/or cones and/or other uncharacterized retinal photoreceptors contribute to this function in mammals. Intriguingly, in the course of elegant research, a number of laboratories around the world have been zeroing in on a novel non-rod, non-cone ocular photopigment which serves a number of responses to non-image-forming (NIF) photoreception in mammals. This paper intends to draw attention to possible implications of photoreception and phototransduction research for other scientific disciplines which study health and diesase effects in man. We therefore review the pivotal role of the photoreceptors -- old and new -- for the light-related timing and coordination of the interplay of otherwise less efficient biological rhythms. To distinguish our focus on time- and timing-related effects from classic image-forming (IF) and other NIF responses to ambient light, we refer informatively to chronoreceptors which mediate the sense of time, or chronosense. We conclude that syndisciplinary research into the physiology and pathophysiological implications of the chronosense is warranted and summarize a series of research questions.

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.