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Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer‐induced metabolic dysfunction and cachexia. Adenosine monophosphate‐activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer‐associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer‐associated metabolic dysfunction, insulin resistance and cachexia. In vastus lateralis muscle biopsies from n= 26 patients with non‐small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant‐negative AMPKα2 (kinase‐dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n= 27, WT + LLC: n= 34, mAMPK‐KiDe: n= 23, mAMPK‐KiDe + LLC: n= 38). Moreover, male LLC‐tumour‐bearing mice were treated with (n= 10)/without (n= 9) 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue‐specific 2‐[3H]deoxy‐d‐glucose (2‐DG) uptake and immunoblotting. Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat‐free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour‐bearing mAMPK‐KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK‐KiDe mice displayed lower insulin‐stimulated 2‐DG uptake in skeletal muscle (quadriceps: −35%, soleus: −49%, extensor digitorum longus: −48%) and the heart (−29%) than that in non‐tumour‐bearing mice. In skeletal muscle, mAMPK‐KiDe abrogated the tumour‐induced increase in insulin‐stimulated TBC1D4thr642phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour‐bearing mice in an AMPK‐dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389(mTORC1 substrate) and ACCser212(AMPK substrate) and rescued cancer‐induced insulin intolerance. Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK‐deficient mice developing metabolic dysfunction in response to cancer, including AMPK‐dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer‐associated metabolic dysfunction and possibly cachexia.

ABSTRACTAdipose tissue mitochondrial function is gaining increasing interest since it is a good marker of overall health. Methodological challenges and variability in assessing mitochondrial respiration in fresh adipose tissue with high-resolution respirometry are unknown and should be explored. Mitochondrial respiratory capacity (MRC) in human adipose tissue declines in a gradual manner when analyses are postponed 3 h and 24 h, with a statistically significant decline 24 h after obtaining the biopsy. This decline in MRC is associated with a reduced integrity of the outer mitochondrial membrane at both time points. This study suggests that the optimal amount of tissue to be used is 20 mg and that different technicians handling the biopsy do not affect MRC.

Background: While preclinical studies suggest that mitochondria play a pivotal role in ischaemia–reperfusion injury, the knowledge of mitochondrial function in human out-of-hospital cardiac arrest remains scarce. The present study sought to compare oxidative phosphorylation capacity in skeletal muscle biopsies from out-of-hospital cardiac arrest patients to healthy controls.Methods: This was a substudy of a randomised trial comparing targeted temperature management at 33°C versus 36°C for out-of-hospital cardiac arrest patients. Skeletal muscle biopsies were obtained from adult resuscitated comatose out-of-hospital cardiac arrest patients 28 hours after initiation of targeted temperature management, i.e. at target temperature prior to rewarming, and from age-matched healthy controls. Mitochondrial function was analysed by high-resolution respirometry. Maximal sustained respiration through complex I, maximal coupled respiration through complex I and complex II and maximal electron transport system capacity was compared.Results: A total of 20 out-of-hospital cardiac arrest patients and 21 controls were included in the analysis. We found no difference in mitochondrial function between temperature allocations. We found no difference in complex I sustained respiration between out-of-hospital cardiac arrest and controls (23 (18–26) vs. 22 (19–26) pmol O2/mg/s, P=0.76), whereas coupled complex I and complex II respiration was significantly lower in out-of-hospital cardiac arrest patients versus controls (53 (42–59) vs. 64 (54–68) pmol O2/mg/s, P=0.01). Furthermore, electron transport system capacity was lower in out-of-hospital cardiac arrest versus controls (63 (51–69) vs. 73 (66–78) pmol O2/mg/s, P=0.005).Conclusions: Mitochondrial oxidative phosphorylation capacity in skeletal muscle biopsies was reduced in out-of-hospital cardiac arrest patients undergoing targeted temperature management compared to age-matched, healthy controls. The role of mitochondria as risk markers and potential targets for post-resuscitation care remains unknown.

Hepatic lipid metabolism is highly dynamic, and disruption of several circadian transcriptional regulators results in hepatic steatosis. This includes genetic disruption of the glucocorticoid receptor (GR) as the liver develops. To address the functional role of GR in the adult liver, we used an acute hepatocyte-specific GR knockout model to study temporal hepatic lipid metabolism governed by GR at several preprandial and postprandial circadian timepoints. Lipidomics analysis revealed significant temporal lipid metabolism, where GR disruption results in impaired regulation of specific triglycerides, nonesterified fatty acids, and sphingolipids. This correlates with increased number and size of lipid droplets and mildly reduced mitochondrial respiration, most noticeably in the postprandial phase. Proteomics and transcriptomics analyses suggest that dysregulated lipid metabolism originates from pronounced induced expression of enzymes involved in fatty acid synthesis, β-oxidation, and sphingolipid metabolism. Integration of GR cistromic data suggests that induced gene expression is a result of regulatory actions secondary to direct GR effects on gene transcription.

Myalgia is a common adverse effect of statin therapy, but the underlying mechanism is unknown. Statins may reduce levels of coenzyme Q10 (CoQ10), which is an essential electron carrier in the mitochondrial electron transport system, thereby impairing mitochondrial respiratory function, potentially leading to myalgia.

AbstractAccording to Michael Tomasello humans cannot help but be informative. Apes, like chimps, do not point at each other, only humans do so in order to attract attention, that is, to (get) help, play and share experiences. In shared cooperative activities, individual rationality is transformed into social rationality. A feeling of ‘we-ness’ is being born, a ‘we’ intentionality. It is Tomasello’s claim that in shared cooperative activities, the collaborators must first all be mutually responsive to each other’s intentional states. In The Cultural Origins ofHuman Cognitionhe states that human infants are very social from the moment they are born, if not before, and that intention reading and human beings’ inborn capability to identify with conspecifics are the clues to the unique human interaction and joint attention. The four theses of this article are: (1) the idea of the prosocial nature of the infant lacks convincing arguments; (2) Tomasello reflects and honours the zeitgeist(that is, the hope that we will see a scientific shift away from predominant methodological individualism towards more ‘social’ and ‘emphatic’- oriented approach); (3) his concepts of language as a tool and linguistic interaction as a derived form of pointing gestures are very limited; and (4) he underestimates the power and ‘nature’ of unforeseen events. Social synchronisation creates the possibility for joint attention and not intention reading. New forms of social interaction do notspring from cognitive intention reading processes insidethe brain. Humans have certain biological predispositions, but they cannot explain joint attention patterns.

Background/Aims:Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects postprandial GLP-2 responses and to correlate these with postprandial SMA blood flow. Methods:Responses of the GI hormone glucose-dependent insulinotropic polypeptide (GIP) and GLP-2 were measured following an 80-min liquid meal test in 8 patients (6 males) with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI) and 8 healthy control subjects (5 males). Postprandial GI hormone responses were correlated with change in SMA flow as assessed by the resistance index. Results:Patients with CP and PEI exhibited the greatest postprandial GLP-2 responses (1,870 8 249 vs. 1,199 ± 108 pM·80 min, p = 0.027). No difference was observed with regard to GIP. GLP-2, but not GIP, responses correlated significantly with postprandial SMA flow. Conclusion:These results suggest that delayed assimilation of nutrients in patients with CP and PEI increases the secretion of GLP-2 - possibly due to delivery of a larger nutrient load to the distal part of the small intestine, where GLP-2 secreting L-cells are abundant - and that this hypersecretion of GLP-2 is associated with a higher SMA flow.

AbstractBackground/Aims:Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects postprandial GLP-2 responses and to correlate these with postprandial SMA blood flow. Methods:Responses of the GI hormone glucose-dependent insulinotropic polypeptide (GIP) and GLP-2 were measured following an 80-min liquid meal test in 8 patients (6 males) with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI) and 8 healthy control subjects (5 males). Postprandial GI hormone responses were correlated with change in SMA flow as assessed by the resistance index. Results:Patients with CP and PEI exhibited the greatest postprandial GLP-2 responses (1,870 ± 249 vs. 1,199 ± 108 pM·80 min, p = 0.027). No difference was observed with regard to GIP. GLP-2, but not GIP, responses correlated significantly with postprandial SMA flow. Conclusion:These results suggest that delayed assimilation of nutrients in patients with CP and PEI increases the secretion of GLP-2 – possibly due to delivery of a larger nutrient load to the distal part of the small intestine, where GLP-2 secreting L-cells are abundant – and that this hypersecretion of GLP-2 is associated with a higher SMA flow.Copyright © 2010 S. Karger AG, Basel and IAP

Background/Aims:The diagnosis of chronic pancreatitis is often difficult in the early stages of the disease. Morphological tests may be normal, and reliable methods for the evaluation of the exocrine pancreatic function are time-consuming and troublesome. A new test for exocrine pancreatic function, using endoscopic aspiration of secretin-stimulated pancreatic juice, has been developed. We evaluated the test using the Lundh meal test as reference. Methods:The endoscopie secretin stimulation test (ESST) was performed in a consecutive row of 24 patients referred for pancreatic function testing because of clinical suspicion of chronic pancreatitis and in 23 healthy volunteers. The participants fasted overnight and secretin was given intravenously (1 CU/kg) as a bolus the following morning. Thirty minutes after administration of secretin, the tip of the duodenoscope was placed close to the ampulla of Vater and duodenal aspirate was drawn for 10 min. Intraduodenal concentrations of lipase, bicarbonate, elastase and zinc were measured. The concentration of lipase during the Lundh test (4 × 20 min aspiration) was used as reference test in the patients. Results:Judged from the Lundh test, the exocrine pancreatic function was nearly abolished in 5 patients (<10% of lower normal limit), reduced in 6 patients and normal in 13 patients. ESST failed in 1 patient (no aspirate). Lipase concentrations (KU/I) were significantly lower in the patients with nearly abolished function compared to patients with reduced or normal exocrine pancreatic function (NEPF; Mann-Whitney U test: p < 0.01), but an overlap was found between patients with reduced exocrine pancreatic function [100.1 (median); 60.0–225.0 (range)] patients with NEPF (145.7; 44.6–268.0) and healthy controls (175.0; 84.8–381.0). Bicarbonate concentrations (mEq/l) were significantly lower in patients with reduced exocrine pancreatic fuction (51.2; 32.5–69.6) compared to patients with NEPF (80.0; 48.1–101.8; Mann-Whitney U test: p < 0.05). Pancreatic elastase concentration was significantly lower in the group with nearly abolished exocrine function compared to patients with NEPF (Mann-Whitney U test: p < 0.05), but there was no difference between elastase concentrations among the other groups. We found significant correlation between lipase and bicarbonate concentrations during ESST and lipase concentrations during the Lundh test in all 23 patients (Spearman's Ranktest: p = 0.597 and 0.683, respectively, p < 0.01). By using receiver operating characteristic curves, best cut-off point for bicarbonate was estimated. Lipase and bicarbonate results in the healthy volunteers were not statistically different from results in patients with NEPF. No side effects were observed except for worsening of nausea and abdominal pain in 2 of the patients. Conclusion:The ESST is safe, and by combining the estimation of lipase and bicarbonate concentrations this test is a rapid, easy and useful diagnostic test for exocrine pancreatic function.

Background/Aims: The diagnosis of chronic pancreatitis is often difficult in the early stages of the disease. Morphological tests may be normal, and reliable methods for the evaluation of the exocrine pancreatic function are time-consuming and troublesome. A new test for exocrine pancreatic function, using endoscopic aspiration of secretin-stimulated pancreatic juice, has been developed. We evaluated the test using the Lundh meal test as reference. Methods: The endoscopic secretin stimulation test (ESST) was performed in a consecutive row of 24 patients referred for pancreatic function testing because of clinical suspicion of chronic pancreatitis and in 23 healthy volunteers. The participants fasted overnight and secretin was given intravenously (1 CU/kg) as a bolus the following morning. Thirty minutes after administration of secretin, the tip of the duodenoscope was placed close to the ampulla of Vater and duodenal aspirate was drawn for 10 min. Intraduodenal concentrations of lipase, bicarbonate, elastase and zinc were measured. The concentration of lipase during the Lundh test (4 × 20 min aspiration) was used as reference test in the patients. Results: Judged from the Lundh test, the exocrine pancreatic function was nearly abolished in 5 patients (<10 of lower normal limit), reduced in 6 patients and normal in 13 patients. ESST failed in 1 patient (no aspirate). Lipase concentrations (KU/l) were significantly lower in the patients with nearly abolished function compared to patients with reduced or normal exocrine pancreatic function (NEPF; Mann-Whitney U test: p < 0.01), but an overlap was found between patients with reduced exocrine pancreatic function [100.1 (median); 60.0–225.0 (range)] patients with NEPF (145.7; 44.6–268.0) and healthy controls (175.0; 84.8–381.0). Bicarbonate concentrations (mEq/l) were significantly lower in patients with reduced exocrine pancreatic function (51.2; 32.5–69.6) compared to patients with NEPF (80.0; 48.1–101.8; Mann-Whitney U test: p < 0.05). Pancreatic elastase concentration was significantly lower in the group with nearly abolished exocrine function compared to patients with NEPF (Mann-Whitney U test: p < 0.05), but there was no difference between elastase concentrations among the other groups. We found significant correlation between lipase and bicarbonate concentrations during ESST and lipase concentrations during the Lundh test in all 23 patients (Spearman’s Rank test: ρ = 0.597 and 0.683, respectively, p < 0.01). By using receiver operating characteristic curves, best cut-off point for bicarbonate was estimated. Lipase and bicarbonate results in the healthy volunteers were not statistically different from results in patients with NEPF. No side effects were observed except for worsening of nausea and abdominal pain in 2 of the patients. Conclusion: The ESST is safe, and by combining the estimation of lipase and bicarbonate concentrations this test is a rapid, easy and useful diagnostic test for exocrine pancreatic function. and IAP

Objectives To analyse which subgroups of perinatal deaths contribute most to the perinatal mortality rate in Lithuania compared with Denmar/Sweden.

The new technologies inherit powerful capacities for processing information. However, it must be realized that these new qualities should be integrated into the educational process without losing already existing qualities. Thus a too narrow-minded interest in processing public information can easily lead to neglect of the development of personal knowledge. An analysis of the differences between these two concepts is carried out. It is argued that knowledge cannot simply be transmitted but must be induced in the learner. Therefore, the pioneer era of the use of new information technology in education must now be transcended and attention directed towards how new information technology is interfaced with human activities like discussion, explanation and personal understanding. This is not just a question of good software or courseware but of realizing that education is a matter of human development that must never be reduced to mere

The responses of luteinizing hormone, follicle-stimulating hormone, and prolactin to prolonged administration of the dopamine receptor antagonist metoclopramide (5 mg twice daily) were investigated in six normal women and six women with low-weight amenorrhea (LWA). In contrast to the normal group, the LWA group showed no significant changes in the mean basal prolactin level or the mean prolactin response to stimulation with thyrotropin-releasing hormone, but there was a significant elevation of the mean net increase in luteinizing hormone after stimulation with gonadotropin-releasing hormone. On the basis of these data, the possibility of increased central dopaminergic activity in women with LWA is discussed.

In an attempt to determine whether prolactin influences estrogen biosynthesis in the ovary, the estrogenic responses of women with amenorrhea under treatment with human menopausal gonadotropin (hMG), with and without the simultaneous administration of the prolactin inhibitor bromocriptine, were investigated in a total of 20 treatment cycles.

Background. In 1991 the rate of intrapartum death of non-malformed fetuses was higher in Denmark than in Sweden (4.2 vs. 1.9 per 10,000, OR 2.24). However, it is not clear whether this difference reflects potentially avoidable cases and / or suboptimal care.Material and Methods. Short descriptions were made from medical records of all 50 intrapartum deaths in Denmark and Sweden in 1991. Ten obstetricians, two from each of the Nordic countries, reviewed the cases to determine whether (1) intra-uterine death might have occurred before admission, (2) surveillance and intervention were insufficient, (3) fetal death was potentially avoidable by improved obstetric care; and, if so, to suggest ways of improved health care.Results. There was a statistically higher rate of insufficient care (surveillance and intervention) (high or less degree) in the Danish cases (66% vs. 55%). The proportion of potentially avoidable fetal deaths was also higher in Denmark (59% vs. 52%) although the difference was not statistically significant.Conclusion. The significantly higher rate of intrapartum death of non-malformed infants in 1991 in Denmark compared to Sweden might be reduced by improved intrapartum surveillance and interventions.

Two subjects kept records of everyday events and thoughts over a 5 month period. Each day both true and false records were created. Seven months later, the subjects attempted to recognise each diary entry and to judge whether it referred to a true or false record. The subjects also dated each entry believed to be true and provided various ratings, including the nature of memory awareness associated with the recognition judgement. Those items remembered correctly as true were dated more accurately than items incorrectly remembered as true (false memories). However, even false memories that is, self-convincing lies were consistently dated better than chance. Furthermore, events were dated more accurately than thoughts, and items that were recollectively experienced were associated with enhanced dating accuracy. These findings are at odds with the notion of temporal traces or tags and instead support the reconstructive nature of temporal knowledge in autobiographical memory.

Important issues related to quality in the use of technology with children with learning disabilities are discussed. The need for basic pedagogical considerations is stressed, and the impact of the computer on the learning process is introduced relative to the factors of learner control, motivation, feedback types, graphics, and screen design. The use of computer-assisted programs with speech feedback is analyzed relative to children with reading disabilities. Finally, a scheme containing the main considerations related to what constitutes “quality” is presented.

Glucagon-like peptide-1 (GLP-1) may be one ofthe enterogastrone hormones of the ileal brakemechanism. We therefore studied its effects on gastriclipase secretion in healthy volunteers and vagotomized patients during infusion of pentagastrin. Theintestinal incretin hormone GLP-1 (glucagon-likepeptide-1, 7-36 amide) was investigated because of itsinhibitory effects on gastric acid secretion andmotility. GLP-1 infused intravenously in amountscorresponding to the postprandial release significantlyinhibited pentagastrinstimulated gastric lipasesecretion and lipolytic activity. The inhibitory effectof GLP-1 persisted in vagotomized patients,suggesting that fundic chief cells, from which gastriclipase is released, or neighboring inhibitory cellscould be equipped with GLP-1 receptors. Vagotomizedpatients had significantly higher plasma concentrationsof gastrin and secretin. No significant changes ofgastrin, secretin, and CCK secretion were seen duringGLP-1 infusion in the vagotomized patients, whereas secretin decreased significantly in the healthyvolunteers. GLP-1 seems to be a naturally occurringinhibitor of gastric lipase secretion acting via anonvagal mechanism. Our results indicate that gastric lipase secretion is subject to hormonalstimulatory as well as inhibitory mechanisms.

Background. Since 1950 the perinatal mortality has been significantly higher in Denmark than in Sweden. In 1991 the rate in Denmark was 8.0/1000 deliveries compared to 6.5/1000 in Sweden. An international audit was designed to investigate whether the perinatal death rates in the two countries to some extent could reflect differences in the quality of care, indicated by the numbers of perinatal deaths in categories of potentially avoidable deaths.Material and methods. Medical records of 97% of all perinatal deaths in 1991 in the two countries were analyzed. A new classification focusing on potential avoidability from a health services perspective was elaborated at a Nordic-Baltic workshop, using the variables: time of death in relation to admission and delivery, fetal malformation, gestational age, growth-retardation and Apgar score at 5 min.Results. Rates of perinatal deaths of malformed infants (0.00195 and 0.00145) and intrapartum deaths of non-malformed infants (0.00042 and 0.00019) was significantly higher in Denmark than in Sweden.Conclusion. Application of the Nordic-Baltic Perinatal Death Classification on perinatal deaths in Denmark and Sweden in 1991 raises the questions as to why the rate of perinatal death of malformed infants is higher in Denmark than in Sweden and whether intrapartum care in Denmark could be improved.

Insulin was withdrawn from 7 patients with Type I (insulin-dependent) diabetes and 4 patients with insulin-dependent diabetes secondary to chronic pancreatitis, both groups without residual beta-cell function. Median plasma glucagon concentrations rose slightly, but significantly after withdrawal of insulin in Type I diabetic patients (from 14 (range: 11-16) to 19 (14-25) pmol/l by 6 h), but not in the patients with secondary diabetes. This was accompanied by a significantly higher increase in blood glucose concentration from 5.1 (4.9-5.7) to 15.2 (12.9-18.1) mmol/1 by 6 h in Type I diabetic patients compared with patients with secondary diabetes (from 4.9 (4.3-6.7) to 13.1 (10.9-13.5) mmol/l) (p<0.01). Beta-hydroxybutyrate increased to a similar extent in the two groups, whereas no significant increases were found in glycerol and lactate in any of the groups. Increased secretion of glucagon is not essential for the development of hyperglycemia and ketonemia in patients with diabetes secondary to chronic pancreatitis, but may augment the degree of hyperglycemia in Type I diabetic patients compared with patients having secondary diabetes.

Pituitary adenoma was suspected in a woman of 74 with hypercorticism, hypokalaemic alkalosis and radiographically enlarged sella turcica. However, non-suppressibility of steroid excretion by high-dose dexamethasone and low plasma concentration of ACTH suggested adrenal tumour. Detailed analysis of urinary steroid excretions demonstrated unusually large amounts of corticosterone metabolites, 14.6 mg/24 h compared to a mean normal value of 0.5 mg. The basal levels of the remaining pituitary hormones were unremarkable.The patient died incidentally before a planned adrenalectomy. The autopsy disclosed an adrenal carcinoma and an empty sella turcica. The enlarged pituitary fossa was lined by a narrow rim of histological normal pituitary tissue.

Freud used archaeological excavation as a metaphor for the remembering of previous experiences in therapy. This metaphor for memory has recently come under attack on the grounds that modern psychology of memory has cast doubt on whether memories preserve "historical truths." In particular, it seems that information about later events-including verbalizations and narrativizations of the original event-are integrated with and thus change the memory. This contrasts with the solid, immutable objects that are supposedly uncovered by archaeologists. However, it is now recognized that the nature of archaeological evidence does not fit this naive view. Not only do objects change over time, but the process of excavation inevitably disturbs and destroys contextual evidence decisive for interpretation. It is argued here that with this richer contemporary understanding of archaeology, Freud's metaphor of memory is still quite appropriate. Some epistemological implications are discussed as examples of interesting issues suggested by the revised archaeology metaphor.

Fibronectin is a glycoprotein found in soluble form in plasma and in an insoluble form in connective tissue matrices. Fibronectin isolated from canine peritoneal effusions by affinity chromatography on gelatin-Sepharose was found to be immunologically indistinguishable from the plasma form, as shown by double immunodiffusion techniques. Utilizing an enzyme immunoassay technique, 7 patients with disseminated splenic hemangiosarcoma were found to have peritoneal fibronectin concentrations of 309 ± 133 (mean ± SD) µg/ml. In 8 patients with widespread lymphoma the peritoneal fibronectin concentrations were 323 ± 147 µg/ml. In 5 patients with hepatoma the peritoneal fibronectin concentrations were 361 ± 121 µg/ml. In 6 patients, 2 with mesothelioma, 2 with pancreatic adenocarcinomas, and 2 with prostatic adenocarcinoma, the peritoneal fibronectin concentrations were 315 ± 115 µg/ml. The lowest concentrations 117 ± 46 µg/ml, were found in patients with malignant disease and concurrent peritoneal thrombus formation. These data suggest that decreased fibronectin concentrations in peritoneal effusions are associated with, at least, a locally hypercoagulable state.

The present study investigated the influence of reader and text variables on personal resonance while reading literature. As the reader variable, the distance between readers' cultural background and the thematic content of the text was studied. A Hungarian short story dealing with themes that are central to the cultural and historical past of that country was presented to Hungarian (culturally proximate) and Danish (culturally distant) readers. As the text style variable, narrative point of view (POV) was manipulated by changing some inside POV passages to outside POV. The findings indicate that cultural proximity did result in the generation of a larger proportion of personally experienced, contextually rich, and vividly remembered events. The occasional use of inside, psychological POV in the story enhanced this effect in the Hungarian (culturally proximate) group, but not in the Danish group. However, the phenomenal quality of remindings elicited locally by reading the inside POV text passages differed from those of the same passages written from the outside POV, irrespective of readers' cultural background. This suggests that compositional text devices, as narrative POV, may have universal effects on literary reading.

Three cases of gastritis in sows due to the stomach worm Hyostrongylus rubidus are described. This disease has not previously been reported from the Scandinavian countries.

Biopsies from auricular hematomas in 36 dogs and the whole ears from 4 dogs with recent untreated or old healed unilateral hematomas were studied microscopically. A predominantly intrachondral location of the hematomas was demonstrated. They apparently arise as sequelae to primary, traumatically induced, intrachondral ruptures with subsequent cleavage of the cartilage plate. Occasionally, in some areas, separation occurs between the perichondrium and the corium. The hemorrhage presumably results from rupture of small blood vessels where these pass through the foramina in the cartilage. No difference in histological appearance was found between auricular cartilage from affected dogs and normal dogs in the same age range. No breed predisposition was demonstrable.

Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

ETNK1 kinase is responsible for the phosphorylation of ethanolamine to phosphoethanolamine (P-Et) (Kennedy, 1956, J Biol Chem). Recurrent somatic mutations occurring on ETNK1were identified in about 13% of patients affected by atypical chronic myeloid leukemia (aCML), in 3-14% of chronic myelomonocytic leukemia (CMML), and in 20% of systemic mastocytosis (SM) patients with eosinophilia (Gambacorti-Passerini, 2015, Blood; Lasho, 2015, Blood Cancer J). ETNK1 mutations, encoding for H243Y, N244S/T/K, and G245V/A amino acid substitutions, cluster in a very narrow region of the ETNK1 catalytic domain and cause an impairment of ETNK1 enzymatic activity leading to a significant decrease in the intracellular concentration of P-Et (Gambacorti-Passerini, 2015, Blood). Despite this evidence, however, their oncogenic role remained largely unexplained. Here, we investigated the specific role of these mutations by using cellular CRISPR/Cas9 and ETNK1 overexpression models as well as aCML patients’ samples. We showed that mutated ETNK1 causes a significant increase in mitochondrial activity (1.87 fold increase compared to WT; p=0.0002) and in ROS production (2.05 fold increase compared to WT; p<0.0001). Since ROS are responsible for DNA oxidative damage, we firstly generated ChIP-Seq data for ETNK1 mutated cells using an antibody raised against the oxoguanine (oxoG) and we compared oxoG signal against the wild-type cell line, to assess whether ETNK1 mutations could cause accumulation of DNA lesions. This analysis revealed a significant increase in oxoG in mutated cells, compared to WT (p=0.018). Then, we investigated if these lesions were driving the onset of a mutator phenotype by applying the 6-thioguanine (6-TG) resistance assays to our cell models, showing that in the mutated cells there was a 5.4 fold increase in colony number compared to the WT line (p<0.0001). Moreover, we investigated if the ROS-mediated genotoxic insult operating in ETNK1-mutated lines could be also associated with an increase in DNA double-strand breaks. Comparison of ETNK1-N244S and ETNK1-WT lines revealed a sharp increase in the number of γH2AX foci (2.52 fold increase; p=0.0002) in the former. At this point, we hypothesized that the decreased P-Et concentration in ETNK1-mutated cells could be responsible for the increased mitochondrial activity. ETNK1-N244S cells treated with P-Et showed a complete restoration of the normal mitochondrial membrane potential and generation of ROS. Moreover, the mutator phenotype was reverted by P-Et treatment, supporting the hypothesis of a direct involvement of P-Et in the induction of DNA damage. To dissect the mechanism by which P-Et intracellular levels were able to control mitochondria activity, we isolated the mitochondrial oxidative phosphorylation complexes I to IV and we measured the activity of each complex in absence/presence of increasing P-Et concentrations. This approach revealed a profound, dose-dependent decrease in redox activity for mitochondrial complex II (P-Et 10μM: 1.80 fold decrease; p=0.0012; P-Et 20μM: 7.40 fold decrease; p<0.0001; P-Et 50μM: 28.85 fold decrease; p<0.0001) and virtually no effect for the other three complexes, indicating that P-Et controls mitochondria potential through direct inhibition of complex II. To gain insight into the specific mechanism by which P-Et could repress complex II, we analyzed its activity in competition assays in presence of both P-Et and increasing concentration of succinate, the endogenous substrate of succinate dehydrogenase (SDH), showing that succinate supplementation was able to restore the normal SDH activity starting from 50µM. Taken globally, these data suggest that P-Et acts as a competitive inhibitor of succinate for SDH activity. In line with these data, automatic docking of P-Et inside the SDH catalytic domain confirmed that P-Et can occupy the succinate binding site in an energetically favorable conformation, mimicking succinate. In conclusion, the reduced activity of mutant ETNK1 leads to the accumulation of new mutations through the reduced competition of P-Et with succinate, increased mitochondrial activity and ROS production. This mechanism can be blocked, at least in vitro, by P-Et supplementation, suppressing the accumulation of new mutations mediated by the ETNK1-dependent mutator phenotype. In vivo studies will address the therapeutic potential of P-Et.

Summary and Conclusion: A rare case of severe rectal bleeding beginning in adult life is reported. A diffuse, cavernous hemangioma of the right transverse colon was visualized by superior mesenteric arteriography and the diagnosis was confirmed by peroperative colonoscopy carried out through a colotomy. The patient was treated by right hemicolectomy. the diagnostic value of selective abdominal arteriography in patients who have severe rectal bleeding is demonstrated.