Comparison of patient-reported need of psycho-oncologic support and the doctor's perspective: how do they relate to disease severity in melanoma patients?

OBJECTIVE: Psycho-neuro-immune research suggests an association between cancer outcomes and psychosocial distress. Objective criteria to determine patients' levels of distress are important to establish potential links to disease outcomes. METHODS: We compared three patient-reported with one doctor-reported measures of psycho-oncologic distress frequently used in routine cancer care and investigated associations with standard disease severity parameters in melanoma patients. We enrolled n = 361 patients, successively seen at two outpatient university clinics in Germany. In the naturalistic study, n = 222 patients had been diagnosed <180 days and were seen for the first time (Group I); n = 139 had been diagnosed >180 days and were in after-care (Group II). RESULTS: Across groups, only moderate associations were seen between patient- reported and doctor-reported measures. Regarding clinical variables, disease severity and perceived need of psycho-oncologic support reported by patients or doctors showed hardly any association. After subgroup stratification, in patients of Group II, patient-reported and doctor-reported instruments showed some small associations with disease parameters commonly linked to more rapid cancer progression in patients who are in cancer after-care. CONCLUSIONS: Overall, the few and low associations suggest that need of psycho-oncologic support and clinical variables were largely independent of each other and doctors' perception may not reflect the patient's view. Therefore, the assessment of the patient perspective is indispensable to ensure that melanoma patients receive appropriate support, as such need cannot be derived from other disease parameters or proxy report. More research is needed applying psychometrically robust instruments that are ideally combined with sensitive biomarkers to disentangle psycho-neuro-immune implications in melanoma patients. Copyright © 2015 John Wiley & Sons, Ltd.

Abnormal thymic microenvironment in insulin-like growth factor-II transgenic mice.

OBJECTIVES: Intrathymic T cell differentiation is driven by the thymic microenvironment, a tridimensional network of cells and extracellular matrix (ECM). Previous data showed that lymphoid and microenvironmental compartments are under the control of hormones and growth factors. We then attempted to define if insulin-like growth factor-II (IGF-II) was also involved in such a control. METHODS: We used IGF-II transgenic (Tg) mice and studied their thymic microenvironment by immunohistochemistry. Moreover, we evaluated thymocytes in terms of their ability to adhere to thymic epithelial cells and to migrate through epithelial cells and ECM. RESULTS: Transgenic IGF-II expression results in abnormalities of the thymic epithelium. Terminal differentiation of thymic epithelial cells (TEC) is modified, with the appearance of large clusters of cells immunoreactive to the monoclonal antibody KL1, which specifically recognizes highly differentiated TEC. Accordingly, treatment of cultured TEC with exogenous IGF-II induces the appearance of KL1+ cells and increases TEC proliferation. IGF-II Tg animals exhibit increased serum levels of the TEC-derived hormone thymulin. These effects were seen even when the IGF-II transgene was inserted in dwarf mice. Moreover, deposition of fibronectin and laminin is also enhanced in IGF-II Tg mouse thymus and in IGF-II-treated TEC cultures. Furthermore, ECM-mediated interactions between thymocytes and TEC are affected by exogenous IGF-II, as exemplified by the enhancement of thymocyte adhesion to TEC monolayers and thymocyte migration in thymic nurse cell complexes. CONCLUSIONS: Our data indicate that IGF-II pleiotropically affects the thymic epithelium, both in vivo and in vitro, and that some of these changes may have consequences on thymocyte/TEC interactions.

Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia.

The hypothesis was tested that treatment with allopurinol, a xanthine oxidase inhibitor, or deferoxamine, a chelator of nonprotein-bound iron, preserved cerebral energy metabolism, attenuated development of edema, and improved histologic outcome in the newborn piglet at 24 h after hypoxia-ischemia. Thirty-two newborn piglets were subjected to 1 h of hypoxia-ischemia by occluding both carotid arteries and reducing the fraction of inspired oxygen; five newborn piglets served as sham-operated controls. The depth of hypoxia-ischemia was controlled by phosphorous magnetic resonance spectroscopy. Upon reperfusion and reoxygenation, piglets received vehicle (n= 12), allopurinol (30 mg/kg/d, n = 10), or deferoxamine (12.5 mg/kg/d, n = 10). The cerebral energy status was determined with phosphorous magnetic resonance spectroscopy. The presence of vasogenic edema was assessed by T2-weighted magnetic resonance imaging. Brain cell injury was assessed with caspase-3 activity, histology, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end (TUNEL)-labeling. At 24 h after hypoxia-ischemia, the phosphocreatine/inorganic phosphate ratios were significantly decreased in vehicle-treated, but not in allopurinol- or deferoxamine-treated piglets. Water T2 values were significantly increased at 24 h after hypoxia-ischemia in cerebral cortex, thalamus, and striatum of vehicle-treated piglets, but not in allopurinol- and deferoxamine-treated piglets. No differences in caspase-3 activity, histologic outcome, or TUNEL-labeling were demonstrated between the three treatment groups. We suggest that allopurinol and deferoxamine may have an additional value in the treatment of perinatal hypoxia-ischemia with other neuroprotective agents or in combination with hypothermia.

Dexamethasone differentially inhibits thyroxine- or growth hormone-induced body and organ growth of Snell dwarf mice.

Supraphysiological doses of glucocorticoids cause growth retardation in both animals and humans. Many studies have addressed the interaction of glucocorticoids with the GH/IGF system, but little is known about the effect of glucocorticoids on T(4)-stimulated growth. The Snell dwarf mouse is deficient in GH, thyroid-stimulating hormone, and prolactin and therefore allows the study of the effect of glucocorticoids on the growth induced by GH and T(4) without their mutual interaction. Four weeks of treatment with T(4) (1 micro g/d) or human GH (50 mU/d) equally increased nose-tail length (3.1 +/- 0.1 cm and 3.0 +/- 0.2 cm, respectively). Dexamethasone (DXM) had much less impact on T(4)-stimulated growth than on GH-induced growth (T(4) + DXM: 2.4 +/- 0.1 cm vs. GH+ DXM: 1.4 +/- 0.1 cm). Similar data were obtained for body weight gain. T4 and GH had a different effect on the weight of various organs: GH caused a higher increase in liver and lumbar vertebrae weight, and T(4) was a better stimulator for kidney (P < 0.05), thymus, and spleen growth. Remarkably, T(4)-stimulated growth of the organs was less affected by DXM than GH-induced organ growth. GH even potentiated the growth inhibition by DXM in the thymus and tibia. In conclusion, T(4)-stimulated growth in Snell dwarf mice is less affected by DXM than growth stimulated by GH

A turbo engine with automatic transmission? How to marry chemicomotion to the subtleties and robustness of life.

Most genomes are much more complex than required for the minimum chemistry of life. Evolution has selected sophistication more than life itself. Could this also apply to bioenergetics? We first examine mechanisms through which bioenergetics could deliver sophistication. We illustrate possible benefits of the turbo-charging of catabolic pathways, of loose coupling, low-gear catabolism, automatic transmission in energy coupling, and of homeostasis. Mechanisms for such phenomena may reside at the level of individual proton pumps, or consist of rerouting of electrons over parallel pathways. The mechanisms may be confined to preexisting components, or involve the plasticity of gene expression that is so characteristic of most living organisms. These possible benefits lead us to the conjecture that also bioenergetics has evolved more for sophistication than for necessity. We next discuss a hitherto unresolved enigma, i.e. that bioenergetics does not seem to be critical for the physiological state. To decide on how critical bioenergetics is, we quantified the control exerted by catabolism on important physiological functions such as growth rate and growth yield. We also determined whether a growth inhibition mostly affected bioenergetics (catabolism) or anabolism; if ATP increases with growth rate, then growth should be considered energy (catabolism) limited. The experimental results for Escherichia coli pinpoint the enigma: its energy metabolism (catabolism) is not critical for growth rate. These results might suggest that because it has no direct control over cell function, bioenergetics is unimportant. Paradoxically however, in biology, highly important mechanisms tend to have little control on cell function, precisely because of that importance. Sophistication in terms of homeostatic mechanisms has evolved to guarantee robustness of the most important functions: The most important mechanisms are redundant in biology. Bioenergetics may be an excellent example of this paradox, in line with the above conjecture. It may be highly important and sophisticated. We then discuss work that has begun to focus on the sophistication of bioenergetics. Homeostasis of the energetics of DNA structure in E. coli is extensive. It relies both on preexisting components and on responsive gene expression. The vastly parallel electron-transfer network of Paracoccus denitrificans engages in sophisticated dynamic and hierarchical regulation. The growth yield of the organism can depend on which terminal oxidases are active. Effective proton translocation may vary due to rerouting of electrons. We conclude that much sophistication of bioenergetics will be discovered in this era of functional genomics.

Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia.

BACKGROUND AND PURPOSE: Perinatal hypoxia-ischemia is a major cause of neonatal morbidity and mortality. Until now no established neuroprotective intervention after perinatal hypoxia-ischemia has been available. The delay in cell death after perinatal hypoxia-ischemia creates possibilities for therapeutic intervention after the initial insult. Excessive nitric oxide and reactive oxygen species generated on hypoxia-ischemia and reperfusion play a key role in the neurotoxic cascade. The present study examines the neuroprotective properties of neuronal and inducible but not endothelial nitric oxide synthase inhibition by 2-iminobiotin in a piglet model of perinatal hypoxia-ischemia. METHODS: Twenty-three newborn piglets were subjected to 60 minutes of hypoxia-ischemia, followed by 24 hours of reperfusion and reoxygenation. Five additional piglets served as sham-operated controls. On reperfusion, piglets were randomly treated with either vehicle (n=12) or 2-iminobiotin (n=11). At 24 hours after hypoxia-ischemia, the cerebral energy state, presence of vasogenic edema, amount of apparently normal neuronal cells, caspase-3 activity, amount of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL)-positive cells, and degree of tyrosine nitration were assessed. RESULTS: A 90% improvement in cerebral energy state, 90% reduction in vasogenic edema, and 60% to 80% reduction in apoptosis-related neuronal cell death were demonstrated in 2-iminobiotin-treated piglets at 24 hours after hypoxia- ischemia. A significant reduction in tyrosine nitration in the cerebral cortex was observed in 2-iminobiotin-treated piglets, indicating decreased formation of reactive nitrogen species. CONCLUSIONS: Simultaneous and selective inhibition of neuronal and inducible nitric oxide synthase by 2-iminobiotin is a promising strategy for neuroprotection after perinatal hypoxia-ischemia.

Antibodies directed against the E region of pro-insulin-like growth factor-II used to evaluate non-islet cell tumor-induced hypoglycemia.

BACKGROUND: Detection of incompletely processed precursor forms of insulin-like growth factor-II ("big" IGF-II) in plasma is essential for both the diagnosis and follow-up of non-islet cell tumor-induced hypoglycemia (NICTH) and may be relevant to other diseases as well. RIA using an antibody raised against a synthetic peptide consisting of the first 21 amino acids of the E domain [E(68-88)] of human pro-IGF-II cannot distinguish between E-peptide-containing big IGF-II and cleaved E domain or fragments. We therefore developed and validated an ELISA that specifically detects big IGF-II in plasma. METHODS: The ELISA used a solid-phase antibody to E(68-88) and a liquid-phase monoclonal hIGF-II antibody. Pro-IGF-II purified from normal human plasma was used as a calibrator. Acid Sep-Pak C(18) extracts of plasma from NICTH patients were analyzed, and the results were compared with those obtained for plasma samples from healthy individuals. In addition, blood specimens derived from dialyzed patients with chronic renal failure, which contained relatively high concentrations of cleaved E domain or fragments, were studied. The results were validated by acid Sephadex G-50 gel filtration. RESULTS: Results from this ELISA indicated that the concentration of big IGF-II in NICTH plasma was higher (mean +/- SD, 22.6 +/- 9.4 nmol/L) than in normal plasma (3.8 nmol/L). Conversely, the concentrations in pooled CRF plasma (2.0 +/- 0.8 nmol/L) were low. Antibodies directed against either E(68-88) or E(13-134) of pro-IGF-II could be used to detect these peptides in tumor tissue by immunohistochemistry. CONCLUSIONS: The possibility of quantifying pro-IGF-II by ELISA in plasma represents a potentially useful tool for the diagnosis and follow-up of NICTH and should facilitate further in vitro and in vivo studies on its regulation and function in humans.

Effects of selective nitric oxide synthase inhibition on IGF-1, caspases and cytokines in a newborn piglet model of perinatal hypoxia-ischaemia.

Selective inhibition of neuronal and inducible nitric oxide synthase (NOS) with 2-iminobiotin previously showed a reduction in brain cell injury. In the present study, we investigated the effects of 2-iminobiotin treatment on insulin-like growth factor-1 (IGF-1) expression, caspase activity and cytokine expression in a newborn piglet model of perinatal hypoxia-ischaemia. Newborn piglets were subjected to 1 h of hypoxia-ischaemia and were treated intravenously with vehicle or 2-iminobiotin. Vehicle-treated piglets showed reduced IGF-1 mRNA expression and increased caspase-3 activity and DNA fragmentation. 2-Iminobiotin treatment, administered immediately upon reperfusion, prevented these observations. No differences in caspase-8 and -9 activity and cytokine [interleukin (IL)-1alpha/beta, IL-6, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta] mRNA expression were demonstrated between vehicle- and 2-iminobiotin-treated piglets at 24 h following hypoxia-ischaemia. IGF-1 mRNA correlated inversely with caspase-3 and transferase-mediated dUTP-biotin in situ nick end labelling score in the cortex, but positively with caspase-8. Cytokine mRNA did not correlate with IGF-1 mRNA, caspase-3 activity or DNA fragmentation. The present results indicate that the previously demonstrated neuroprotective effect of 2-iminobiotin treatment after perinatal hypoxia-ischaemia coincided with a preservation of the endogenous IGF-1 production and reduced caspase-3 activity, but not with a significant decrease in cytokine production.