Network topology of stable isotope interactions in a sub-arctic raptor guild.

Predation is an ecologically important process, and intra-guild interactions may substantially influence the ecological effects of predator species. Despite a rapid expansion in the use of mathematical graph theory to describe trophic relations, network approaches have rarely been used to study interactions within predator assemblages. Assemblages of diurnal raptors are subject to substantial intra- and interspecific competition. Here we used the novel approach of applying analyzes based on network topology to species-specific data on the stable isotopes (13)C and (15)N in feathers to evaluate patterns of relative resource utilization within a guild of diurnal raptors in northern Sweden. Our guild consisted of the golden eagle (Aquila chrysaetos), the gyrfalcon (Falco rusticolus), the peregrine falcon (Falco peregrinus) and the rough-legged buzzard (Buteo lagopus). We found a modular trophic interaction structure within the guild, but the interactions were less nested than expected by chance. These results suggest low redundancy and hence a strong ecological importance of individual species. Our data also suggested that species were less connected through intra-guild interactions than expected by chance. We interpret our results as a convergence on specific isotope niches, and that body size and different hunting behaviour may mediate competition within these niches. We finally highlight that generalist predators could be ecologically important by linking specialist predator species with disparate dietary niches.

Electrolyte ion adsorption and charge blocking effect at the hematite/aqueous solution interface: an electrochemical impedance study using multivariate data analysis.

A model-free multivariate analysis using singular value decomposition is employed to refine an equivalent electrical circuit model in order to probe the electrochemical properties of the hematite/water interface in dilute NaCl and NH4Cl solutions using electrochemical impedance spectroscopy. The result shows that the surface protonation is directly related to the mobility and trapping of charge carriers at the mineral surface. Moreover, the point of zero charge can be found at pH where the charge transfer resistance is the highest, in addition to the minimum double layer capacitance. The inner-sphere interaction of the NH4(+) ion with the surface is indicated by an increase of capacitance for charge carrier trapping from the protonated surface as well as lower double layer capacitance and open circuit potential. It is clear that the intrinsic electrochemical activity of hematite depends on the degree of surface (de)protonation and other inner-sphere adsorption, as these processes affect the charge carrier density in the surface state. This work also highlights an important synergistic effect of the two spectral analyses that enables EIS to be utilized in an in-depth investigation of mineral/water interfaces.

Functional responses of the rough-legged buzzard in a multi-prey system.

The functional response is a key element of predator-prey interactions. Basic functional response theory explains foraging behavior of individual predators, but many empirical studies of free-ranging predators have estimated functional responses by using population-averaged data. We used a novel approach to investigate functional responses of an avian predator (the rough legged-buzzard Buteo lagopus Pontoppidan, 1763) to intra-annual spatial variation in rodent density in subarctic Sweden, using breeding pairs as the sampling unit. The rough-legged buzzards responded functionally to Norwegian lemmings (Lemmus lemmus L. 1758), grey-sided voles (Myodes rufocanus Sundevall, 1846) and field voles (Microtus agrestis L. 1761), but different rodent prey were not utilised according to relative abundance. The functional response to Norwegian lemmings was a steep type II curve and a more shallow type III response to grey-sided voles. The different shapes of these two functional responses were likely due to combined effects of differences between lemmings and grey-sided voles in habitat utilisation, anti-predator behaviour and size-dependent vulnerability to predation. Diet composition changed less than changes in relative prey abundance, indicating negative switching, with high disproportional use of especially lemmings at low relative densities. Our results suggest that lemmings and voles should be treated separately in future empirical and theoretical studies in order to better understand the role of predation in this study system.

Evolution of fibrosis during HCV recurrence after liver transplantation--influence of IL-28B SNP and response to peg-IFN and ribavirin treatment.

The IL-28 gene is associated with sustained viral response (SVR) after treatment with peg-IFN and ribavirin in liver transplant recipients with chronic hepatitis C genotype 1 infection. We analysed the importance of recipient and donor IL-28B genotype for response to treatment and fibrosis progression in 54 liver transplant recipients. Fibrosis stage (F) was defined as mild when F≤2 and severe when F≥3 in a liver biopsy or according to liver elasticity analysis. We found a significantly lower prevalence of IL-28B SNP CC in the recipients (22%) than in the donors (67%), P<0.0001. SVR was seen in 61% of the recipients with mild and 27% with severe fibrosis pretreatment, P=0.01. Recipients with IL-28 CC and non-CC had mild fibrosis in 64% and 38% prior to treatment, P=0.13. At follow-up, after treatment, significantly more recipients with CC had mild fibrosis than non-CC recipients (75% versus 32%, P=0.0072), and all with CC and SVR had mild fibrosis. The strongest baseline factor predicting SVR was genotype. Hence, 13/19 (68%) genotype non-1 patients reached SVR versus only 9/35 (26%) genotype 1 patients, P=0.0022. In summary, we found that liver transplant recipients with IL-28B CC tended to have less advanced fibrosis prior to and significantly less after SOC treatment and that all recipients with IL-28B CC who achieved SVR had mild fibrosis at follow-up. A significantly higher SVR rate was achieved in recipients with mild than severe fibrosis pretreatment and with genotype non-1 than 1 infection. Our findings indicate that treatment for post-transplant HCV recurrence should be offered before advanced fibrosis is seen in the recipient.

Indoleamine 2,3-dioxygenase expression and functional activity in dendritic cells exposed to cholera toxin.

Indoleamine 2,3-dioxygenase (IDO), a tryptophan-metabolizing enzyme expressed by dendritic cells (DC), has the potential to inhibit T cell responses and to promote tolerance. In contrast, cholera toxin (CT), the enterotoxin produced by Vibrio cholerae, promotes T cell responses, partly through its ability to induce DC maturation and promote antigen presentation. We hypothesized that the adjuvant activity of CT is associated with a lack of induction of IDO in DC. To test this hypothesis, monocyte-derived DC were pulsed with CT, and the IDO mRNA expression, IDO functional activity and cytokine production were measured as well as the ability of DC to induce T cell responses in vitro. Cholera toxin exposure induced enhanced levels of IDO mRNA in DC but no functional IDO protein activity. Cholera toxin pulsing however primed DC for CD40L-induced IDO protein activity. CD40L stimulation of CT-pulsed DC induced a modest IL-12p40 production, but not IL-12p70 or IL-23 secretion. Furthermore, CT-pulsed DC induced strong allogeneic and autologous T cell responses in vitro, which were not affected by the IDO-specific inhibitor 1-methyl tryptophan. Our results show that CT per se does not induce the expression of functional IDO protein, although it primes DC for CD40L-mediated IDO production and IL-12p40 secretion. Furthermore, CT-treated DC were equally powerful in their T cell stimulatory capacity as cytokine-matured DC.

Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells.

Sphingosine kinase 1 (SK1) converts sphingosine to the bioactive lipid sphingosine 1-phosphate (S1P). S1P binds to G-protein-coupled receptors (S1PR1-5) to regulate cellular events, including Ca2+ signaling. The SK1/S1P axis and Ca2+ signaling both play important roles in health and disease. In this respect, Ca2+ microdomains at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are of importance in oncogenesis. Mitofusin 2 (MFN2) modulates ER-mitochondria contacts, and dysregulation of MFN2 is associated with malignancies. We show that overexpression of SK1 augments agonist-induced Ca2+ release from the ER resulting in increased mitochondrial matrix Ca2+. Also, overexpression of SK1 induces MFN2 fragmentation, likely through increased calpain activity. Further, expressing putative calpain-cleaved MFN2 N- and C-terminal fragments increases mitochondrial matrix Ca2+ during agonist stimulation, mimicking the SK1 overexpression in cells. Moreover, SK1 overexpression enhances cellular respiration and cell migration. Thus, SK1 regulates MFN2 fragmentation resulting in increased mitochondrial Ca2+ and downstream cellular effects.

Physician dispensing: an old idea is new again.

Faced with declining reimbursement for infusional therapies, an oncology practice turned to physician dispensing to offset the loss. Its leaders quickly discovered that the dispensing-vendor landscape was limited, and few guidelines existed for product line development. Yet the approach offers a competitive response to the changing health care landscape. With physician-dispensing prescription costs 50 percent below the national average and generic substitution 50 percent higher than the national average, the potential cost savings for payers and consumers is staggering.

Carcinoembryonic antigen titers on effusion fluid. A diagnostic tool?

Carcinoembryonic antigen (CEA) has been demonstrated in tumors and body fluids, suggesting that effusion fluid (EF) CEA titer might separate benign and malignant EF. Plasma and EF CEA titers were determined on 141 patients with either benign (86) or malignant (55) EF. Although plasma CEA titers separated patients with either a benign or malignant EF 56% of the time, this separation was better accomplished (90% of the time) using EF CEA (P less than .0001). A malignant EF was associated with an EF CEA titer greater than or equal to ng/ ml or when, in the range 5.0 to 9.9 ng/ml, the EF CEA titer was greater than twice the plasma CEA. Paired plasma and EF CEA titers may aid in determining the benign or malignant origin of an EF.

Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial-host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls. METHODS: We analyzed serum obtained from 88 patients (74 females) aged 19(43)-73 years and 106 healthy volunteers (77 females) aged 19(38)-62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and 33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires. KEY RESULTS: We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients (ρ = 0.38; p = 0.0045). CONCLUSIONS & INFERENCES: Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients' self-reported anxiety score.

Bestrophin-3 is differently expressed in normal and injured mouse glomerular podocytes.

AIM: Bestrophins are putative calcium-activated chloride channels. Recently, cell-protective functions for Bestrophin-3 (Best3) were proposed. Best3 exists in different splice variants. We have here examined expression, alternative splicing and localization of Best3 in mouse podocytes under normal conditions and during endoplasmic reticulum (ER) stress. METHODS: Best3 expression was determined on the mRNA level using quantitative PCR and on the protein level by immunohistochemistry and Western blotting. RESULTS: Staining for Best3 was pronounced in glomeruli and was detected in cultured mouse podocytes. Best3 did not co-localize with markers for endothelial cells (CD31), podocyte foot processes (synaptopodin) or microtubules (actin). However, immunogold-based electron microscopy and co-localization with nestin showed Best3 presence in podocyte primary processes and cell bodies. Only two splice variants of Best3 mRNA (both lacking exons 2 and 3, and one also lacking exon 6), but no full-length variant, were detected. ER stress induced by lipopolysaccharides in vivo transiently elevated mRNA levels of total Best3 and its two splice variants with different time courses. In cultured podocytes under ER stress induced by thapsigargin, the expression of total Best3, its splice variants and nestin transiently increased with similar time courses. The ER stress marker C/EBP homologous protein (CHOP) and nestin mRNA increased during ER stress in vivo and in vitro. CONCLUSIONS: Best3 is localized intracellularly in cell bodies and primary processes of mouse podocytes and is co-localized with nestin. Two splice variants of Best3 are expressed in glomeruli and in cultured podocytes, and their expression is differentially regulated in ER stress.

Metastatic and histologic presentations in unknown primary cancer.

The patient with metastatic adeno- or undifferentiated carcinoma who presents with a cryptic primary is subjected to an extensive diagnostic search. These efforts apparently stem from the following assumptions: 1). The ultimately proven primary sites in such patients will occur with the same frequency as the most commonly occurring carcinomas (i.e., lung, breast, colon, prostate, etc.); and 2). Metastatic patterns and histologies seen at diagnosis are the same as for patients presenting with these more common tumors. Our data contradict these assumptions. For example, the most commonly occurring unknown primary was pancreas. Rarely occurring primaries included breast and prostate. Lung cancer was observed frequently, but the presentation was atypical because of the large proportion of female patients. In addition, the metastatic patterns at diagnosis were unusual for many of the ultimately proven primary sites. In an attempt to deal with these contradictions, a method to search for new relationships between primary site and metastatic-histologic presentations was employed. This method succeeded in placing the location of the primary cancer to above or below the diaphragm in 80% of the patients studied retrospectively. Tested prospectively in a small group of patients, the method appears to be clincally useful. Finally, in this study we have made the diagnosis, antemortem, of the primary cancer site (PCS) in only 30 of 264 patients. The failure to find the primary site, dispite extensive radiologic work-up, was disappointing to the authors, and emphasizes the difficulty of finding PCS antemortem. In our study pancreas and lung appear to be most common cryptic primary sites.

New proline mimetics: synthesis of thrombin inhibitors incorporating cyclopentane- and cyclopentenedicarboxylic acid templates in the P2 position. Binding conformation investigated by X-ray crystallography.

With the aim to prepare nonpeptidic thrombin inhibitors, the amino acids of the thrombin-inhibiting tripeptide chain D-Phe-Pro-Arg were replaced with isosteres. Arg was replaced with the more rigid P1 truncated p-amidinobenzylamine (Pab), Pro with either cyclopentane-1, 2-dicarboxylic acid or cyclopentene-1,5-dicarboxylic acid, and D-Phe with a series of readily available lipophilic amines. One of the most potent compounds (25, pIC(50) = 6.01) in these series was cocrystallized with thrombin where the X-ray crystal structure provide insight to the structure-activity relationship (SAR).

Tactile/kinesthetic stimulation effects on preterm neonates.

Tactile/kinesthetic stimulation was given to 20 preterm neonates (mean gestational age, 31 weeks; mean birth weight, 1,280 g; mean time in neonatal intensive care unit, 20 days) during transitional ("grower") nursery care, and their growth, sleep-wake behavior, and Brazelton scale performance was compared with a group of 20 control neonates. The tactile/kinesthetic stimulation consisted of body stroking and passive movements of the limbs for three, 15-minute periods per day for a 10 days. The stimulated neonates averaged a 47% greater weight gain per day (mean 25 g v 17 g), were more active and alert during sleep/wake behavior observations, and showed more mature habituation, orientation, motor, and range of state behavior on the Brazelton scale than control infants. Finally, their hospital stay was 6 days shorter, yielding a cost savings of approximately $3,000 per infant. These data suggest that tactile/kinesthetic stimulation may be a cost effective way of facilitating growth and behavioral organization even in very small preterm neonates.

Effect of long-term anemia and retransfusion on central circulation during exercise.

The purpose of this study was to evaluate the effect of long-term anemia and subsequent retransfusion of erythrocytes on various circulatory parameters. Anemia was induced in nine healthy male subjects by repeated venesections. The stored blood was retransfused after 9 wk (range 8-11 wk). Exercise tests were performed before venesection in the control state (C), in the anemic state (A), and 48 h after retransfusion (R). Hemoglobin concentration levels were 146 +/- 10 g/l in C, 110 +/- 7 g/l in A, and 145 +/- 9 g/l in R. Maximal O2 uptake was 4.55 +/- 0.6, 3.74 +/- 0.7, and 4.45 +/- 0.6 l/min in C, A, and R, respectively. A decrease in heart rate of 7 beats/min (P less than 0.01) and in cardiac output of 2 l/min (P less than 0.05) at maximal exercise occurred in the anemic state compared with control values. These decreases were not reversed but, rather, were further accentuated after retransfusion. The adaptive response to submaximal exercise (cycling at 150-175 W) in anemia was mediated to the amount of 50% by an increase in cardiac output (mainly an increase in heart rate) and 50% was due to increased O2 extraction in the peripheral tissue. In conclusion, long-term anemia was found to decrease the heart rate and cardiac output at maximal exercise. Furthermore the close correlation between hemoglobin concentration and maximal O2 uptake in humans is confirmed.

The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.

UNLABELLED: Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7-5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human alpha-thrombin compared with melagatran [inhibition constant (K(i)) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis. CONCLUSION: By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

Lung function and bronchial reactivity in aluminum potroom workers.

Lung function and bronchial reactivity were measured in 38 aluminum potroom workers with no airway symptoms and in 20 healthy referents (office workers). All of the participants were non-smokers. The magnitude of exposure to airborne dust (alumina) and fluorides was determined. The aluminum potroom workers had obstructive lung function impairment with a significant decrease in expiratory flow and an increase in residual volume. Diffusing capacity was found to be lower than in the referents. No bronchial hyperreactivity was found in the aluminum potroom workers. The exposure to inhaled alumina and particulate and gaseous fluorides in the plant was low, 15-20% of the Swedish exposure limits. The finding of only modest lung function alterations with no bronchial hyperreactivity in the aluminum potroom workers is not consistent with the results of other authors. This discrepancy can probably be explained by the fact that the exposure to inhaled contaminants in the investigated aluminum plant was low.

Combined near-infrared spectroscopy and multifrequency bio-impedance investigation of skin alterations in diabetes patients based on multivariate analyses.

A group of 34 diabetic men, with different degrees of diabetes complications, including skin changes, were studied by near-infrared (NIR) spectroscopy and total body multi-frequency bio-impedance analyses (MFBIA-body). Skin reflectance spectra were measured with a fibre-optic probe in four locations (sites): hand, arm, leg and foot. As control subjects, a group of 23 healthy males were also measured. A combined multivariate analysis of the two types of spectrum was performed. It was concluded that the NIR method has the potential to detect diabetes-related skin conditions and also that the combination of the two techniques provides a higher potential for classification and discrimination of the skin conditions, with correct classification increasing from 63% to 85%.

[Disaster management lessons can be learned from the Gothenburg fire]. / Katastrofmedicinska lärdomar kan dras av Göteborgsbranden.

On the night of October 29, 1998, a fire broke out in an old warehouse in Gothenburg, where nearly 400 teenagers had gathered for a disco party. More than 200 patients were brought to four different hospitals in the region. Sixty-one people died at the scene due to inhalation of toxic fumes caused by the fire. Another two died later in the hospital due to severe burns. Disaster management in Sweden is based on mobile medical teams consisting of hospital staff supporting ambulance crews in the event of major incidents. Only one team together with a GP was able to be mobilized during this incident. Thus, medical care at the scene was limited. The principle of OEload and go pi was used, placing the major burden of triage on the hospitals. The limited numbers of medical personnel and available supplies caused major stress for the physicians involved at the scene.

Potential clinical utility of gene-expression profiling in identifying tumors of uncertain origin.

AIM: To evaluate the potential impact of a gene-expression-based test on the diagnosis of primary tumors in difficult-to-diagnose cases. MATERIALS & METHODS: The Tissue of Origin Test uses 2000 gene measurements to classify the most likely primary tumor. We categorized 284 consecutive samples by pretest diagnosis, then recategorized the samples using test results to identify cases with changes in diagnosis. RESULTS: A total of 64% of incoming diagnoses were nonspecific. A leading diagnosis for the primary site was provided for remaining cases, indicating an unresolved differential. Overall, the test predicted a change in the most likely primary site, either a change from nonspecific to specific site or a change from one specific primary site to another in 81% of the cases and confirmed the suspected primary site for 15% of cases. CONCLUSION: A new molecular diagnostic has the potential to change both primary site identification and therapy selection for the majority of patients tested.