Evidence for enemy release in invasive common dace Leuciscus leuciscus in Ireland: a helminth community survey and systematic review.

Invasive species lose parasites in the process of invasion and tend to be less parasitized than conspecifics in the native range and sympatric native species in the invasive range (enemy release). We evaluated enemy release in an invasive freshwater fish in Ireland, common dace Leuciscus leuciscus, using helminth parasite community surveys at the core and front of the invasive range of common dace. Furthermore, we undertook a systematic literature review of helminth infection in common dace across its native range in Great Britain and Europe and invasive range in Ireland. The helminth parasite community survey revealed that invasive common dace were infected with fewer helminth species at the invasion front than at the core. Four helminth taxa - Acanthocephala, Monogenea, Digenea and Nematoda - were present in dace at the invasion core compared to only a single helminth species (Pomphorhynchus tereticollis) at the front. The systematic review revealed that invasive common dace in Ireland hosted fewer species of helminths than common dace in the native range. We report a total of three helminth species in common dace in Ireland compared to 24 in Great Britain and 84 in Continental Europe. Our results support the hypotheses that invasive populations are less parasitized than native populations and that more recently established populations host fewer parasites. However, we demonstrate that invasive species may continue to experience release from parasites long after initial invasion.

Lessons learned from the development of a hidradenitis suppurativa xenograft mouse model.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease originating from the pilosebaceous unit, in which patients develop painful abscesses, sinus tracts, nodules and scarring, typically in intertriginous areas. Major gaps in our understanding of HS exist, and these may be partially due to the lack of an animal model for experimental studies. We developed an HS xenograft mouse model using human HS lesions grafted onto immunocompromised mice. Although the model had its limitations, several informative lessons were learned, which may contribute to future attempts at an HS animal model.

Specimen Collection for Translational Studies in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053-4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is  retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

Association between thyroid dysfunction and dysglycaemia: a prospective cohort study.

AIMS: To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia. METHODS: In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted. RESULTS: During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.15, 95% CI 1.04-1.26), but were not at greater risk of diabetes (adjusted hazard ratio 0.96, 95% CI 0.64-1.44). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia. CONCLUSIONS: People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify.

Patient-specific 3D models aid planning for triplane proximal femoral osteotomy in slipped capital femoral epiphysis.

PURPOSE: Slipped capital femoral epiphysis (SCFE) can result in a complex three-dimensional (3D) deformity of the proximal femur. A three-plane proximal femoral osteotomy (TPFO) has been described to improve hip mechanics. The purpose of this study was to evaluate the benefits of using 3D print technology to aid in surgical planning. PATIENTS AND METHODS: Fifteen children treated with TPFO for symptomatic proximal femoral deformity due to SCFE were included in this study. Ten patients were treated by a single surgeon with (model group, n = 5) or without (no-model group, n = 5) a 3D model for pre-operative planning, and compared with patients treated by two senior partners without the use of a model (senior group, n = 5) to evaluate for a learning curve. Peri-operative data including patient body mass index (BMI), surgical time and fluoroscopy time were recorded. RESULTS: Children in all three groups had similar BMIs at the time of the TPFO. Post-operative radiographic parameters were equally improved in all three groups. On average, surgical time decreased by 45 minutes and 38 minutes, and fluoroscopy time decreased by 50% and 25%, in the model group compared with the no-model and senior groups, respectively. CONCLUSIONS: Patient-specific 3D models aid in surgical planning for complex 3D orthopaedic deformities by enabling practice of osteotomies. Results suggest that 3D models may decrease surgical time and fluoroscopy time while allowing for similar deformity correction. These models may be especially useful to overcome steep learning curves for complex procedures or in trainee education through mock surgical procedures.

Trophic flexibility and opportunism in pike Esox lucius.

The first comprehensive investigation of pike Esox lucius trophic ecology in a region (Ireland) where they have long been thought to be a non-native species is presented. Diet was investigated across habitat types (lake, river and canal) through the combined methods of stable-isotope and stomach content analyses. Variations in niche size, specialization and the timing of the ontogenetic dietary switch were examined, revealing pronounced opportunism and feeding plasticity in E. lucius, along with a high occurrence of invertivory (up to 60 cm fork length, LF ) and a concomitant delayed switch to piscivory. Furthermore, E. lucius were found to primarily prey upon the highly available non-native roach Rutilus rutilus, which may alleviate predation pressure on brown trout Salmo trutta, highlighting the complexity of dynamic systems and the essential role of research in informing effective management.

Trophic flexibility by roach Rutilus rutilus in novel habitats facilitates rapid growth and invasion success.

Stable isotope and gut content analyses, in conjunction with backcalculated length-at-age estimates of growth, were employed to examine the relationship between trophic ecology and growth rate of a successful invader, Rutilus rutilus, in eight lakes in Ireland. The data revealed that R. rutilus was a trophic generalist in Irish lakes. It utilized a greater proportion of pelagic resources in mesotrophic lakes than in eutrophic lakes, potentially due to a greater density of benthic macroinvertebrates in eutrophic systems. The species was characterized by a large dietary and isotopic niche width and high temporal and spatial variations in diet. Growth rates were typical of those found in the native range of the species and were unrelated to either lake productivity or fish's diet. A generalist trophic ecology confers significant advantages on an invasive species, allowing it to exploit a variety of novel resources and fluctuations in prey availability.

The new VARSKIN 4 photon skin dosimetry model.

A new photon skin dosimetry model, described here, was developed as the basis for the enhanced VARSKIN 4 thin tissue dosimetry code. The model employs a point-kernel method that accounts for charged particle build-up, photon attenuation and off-axis scatter. Early comparisons of the new model against Monte Carlo particle transport simulations show that VARSKIN 4 is highly accurate for very small sources on the skin surface, although accuracy at shallow depths is compromised for radiation sources that are on clothing or otherwise elevated from the skin surface. Comparison results are provided for a one-dimensional point source, a two-dimensional disc source and three-dimensional sphere, cylinder and slab sources. For very small source dimensions and sources in contact with the skin, comparisons reveal that the model is highly predictive. With larger source dimensions, air gaps or the addition of clothing between the source and skin; however, VARSKIN 4 yields over-predictions of dose by as much as a factor of 2 to 3. These cursory Monte Carlo comparisons confirm that significant accuracy improvements beyond the previous version were achieved for all geometries. Improvements were obtained while retaining the VARSKIN characteristic user convenience and rapid performance.

Development and deployment of an underway radioactive cesium monitor off the Japanese coast near Fukushima Dai-ichi.

A custom radiation monitoring system was developed by Oregon State University at the request of the Woods Hole Oceanographic Institute to measure radioactive cesium contaminants in the ocean waters near Fukushima Dai-ichi Nuclear Power Plant. The system was to be used on board the R/V Ka'imikai-O-Kanaloa during a 15 d research cruise to provide real-time approximations of radionuclide concentration and alert researchers to the possible occurrence of highly elevated radionuclide concentrations. A NaI(Tl) scintillation detector was coupled to a custom-built compact digital spectroscopy system and suspended within a sealed tank of continuously flowing seawater. A series of counts were acquired within an energy region corresponding to the main photopeak of (137)Cs. The system was calibrated using known quantities of radioactive (134)Cs and (137)Cs in a ratio equating to that present at the reactors' ocean outlet. The response between net count rate and concentration of (137)Cs was then used to generate temporal and geographic plots of (137)Cs concentration throughout the research cruise in Japanese coastal waters. The concentration of (137)Cs was low but detectable, reaching a peak of 3.8 ± 0.2 Bq/L.

Repeated delta1-opioid receptor stimulation reduces delta2-opioid receptor responses in the SA node.

Ultra-low-dose methionine-enkephalin-arginine-phenylalanine improves vagal transmission (vagotonic) and decreases heart rate via delta(1)-opioid receptors within the sinoatrial (SA) node. Higher doses activate delta(2)-opioid receptors, interrupt vagal transmission (vagolytic), and reduce the bradycardia. Preconditioning-like occlusion of the nodal artery produced a vagotonic response that was reversed by the delta(1)-antagonist 7-benzylidenaltrexone (BNTX). The following study tested the hypothesis that extended delta(1)-opioid receptor stimulation reduces subsequent delta(2)-receptor responses. The delta(2)-agonist deltorphin II was introduced in the SA node by microdialysis to evaluate delta(2) responses before and after infusion of the delta(1)-agonist TAN-67. TAN-67 reduced the vagolytic effect of deltorphin by two-thirds. When the delta(1)-antagonist BNTX was combined with TAN-67, the deltorphin response was preserved, suggesting that attrition of the prior response was mediated by delta(1) activity. When TAN-67 was omitted in time control studies, some loss of delta(2) responses was apparent in the absence of the delta(1) treatment. This loss was also eliminated by BNTX, suggesting that the attenuation of the response after deltorphin alone was also the result of delta(1) activity. Additional studies tested TAN-67 alone in the absence of prior deltorphin. When time controls were conducted without the initial deltorphin treatment, a robust vagolytic response was observed. When TAN-67 preceded the delayed deltorphin, the vagolytic response was eroded, indicating an independent effect of TAN-67. BNTX infused afterward was unable to restore the delta(2) response. These data support the conclusion that the loss of the delta(2) response resulted from reduced delta(2) activity mediated by continued delta(1)-receptor stimulation and not the arithmetic consequence of increased competition from that same delta(1) receptor.

Bimodal delta-opioid receptors regulate vagal bradycardia in canine sinoatrial node.

Methionine-enkephalin-arginine-phenylalanine (MEAP) introduced into the interstitium of the canine sinoatrial (SA) node by microdialysis interrupts vagal bradycardia. In contrast, raising endogenous MEAP by occluding the SA node artery improves vagal bradycardia. Both are blocked by the same delta-selective antagonist, naltrindole. We tested the hypothesis that vagal responses to intranodal enkephalin are bimodal and that the polarity of the response is both dose- and opioid receptor subtype dependent. Ultralow doses of MEAP were introduced into the canine SA node by microdialysis. Heart rate frequency responses were constructed by stimulating the right vagus nerve at 1, 2, and 3 Hz. Ultralow MEAP infusions produced a 50-100% increase in bradycardia during vagal stimulation. Maximal improvement was observed at a dose rate of 500 fmol/min with an ED50 near 50 fmol/min. Vagal improvement was returned to control when MEAP was combined with the delta-antagonist naltrindole. The dose of naltrindole (500 fmol/min) was previously determined as ineffective vs. the vagolytic effect of higher dose MEAP. When MEAP was later reintroduced in the same animals at nanomoles per minute, a clear vagolytic response was observed. The delta1-selective antagonist 7-benzylidenenaltrexone (BNTX) reversed the vagal improvement with an ED50 near 1 x 10-21 mol/min, whereas the delta2-antagonist naltriben had no effect through 10-9 mol/min. Finally, the improved vagal bradycardia previously associated with nodal artery occlusion and endogenous MEAP was blocked by the selective delta1-antagonist BNTX. These data support the hypothesis that opioid effects within the SA node are bimodal in character, that low doses are vagotonic, acting on delta1-receptors, and that higher doses are vagolytic, acting on delta2-receptors.

Copper and lead concentrations in salt marsh plants on the Suir Estuary, Ireland.

Concentrations of Cu and Pb were determined in the roots and shoots of six salt marsh plant species, and in sediment taken from between the roots of the plants, sampled from the lower salt marsh zone at four sites along the Suir Estuary in autumn 1997. Cu was mainly accumulated in the roots of monocotyledonous and dicotyledonous species. Pb was mainly accumulated in the roots of monocotyledons, while dicotyledons tended to accumulate Pb in the shoots. In the case of Aster tripolium there was a clear differentiation in the partitioning of Pb within the plant, between low and high salinity sites. At the low salinity sites, Pb accumulated only in the roots while at the high salinity sites there was a marked translocation to the shoots. The increase in Pb concentrations in roots and shoots of A. tripolium was accompanied by a concomitant decrease in sediment concentrations of Pb. This inverse correlation between sediment and plant concentrations of Pb was also recorded for Spartina spp. and Schoenoplectus tabernaemontani but in the case of these species the roots contained higher concentrations of Pb regardless of salinity levels. These differences in accumulation of Cu and Pb in various salt marsh species, and the influence of salinity on the translocation of Pb in A. tripolium in particular, should be taken into account when using these plants for biomonitoring purposes.

Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity.

PTEN, a tumor suppressor among the most commonly mutated proteins in human cancer, is recognized to be both a protein phosphatase and a phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) 3-phosphatase. Previous work [Maehama and Dixon, J. Biol. Chem. 273 (1998) 13375-13378] has led to a consensus that inositol phosphates are not physiologically relevant substrates for PTEN. In contrast, we demonstrate that PTEN is an active inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P(5)) 3-phosphatase when expressed and purified from bacteria or HEK cells. Kinetic data indicate Ins(1,3,4,5,6)P(5) (K(m)=7.1 microM) and PtdIns(3,4,5)P(3) (K(m)=26 microM) compete for PTEN in vivo. Transient transfection of HEK cells with PTEN decreased Ins(1,3,4,5,6)P(5) levels. We discuss the physiological significance of these studies in relation to recent work showing that dephosphorylation of Ins(1,3,4,5,6)P(5) to inositol 1,4,5,6-tetrakisphosphate is a cell signaling event.

Ca 125 as a marker of tumor activity in advanced urothelial malignancy.

PURPOSE: The discovery of increased CA 125 in a patient with metastatic bladder carcinoma prompted a prospective study to screen those referred for consideration of adjuvant or palliative chemotherapy of advanced urothelial malignancy for high serum CA 125. Although CA 125 is a useful marker of ovarian cancer and, reportedly, is expressed by a few other tumors, to our knowledge no association with transitional cell malignancy of the urothelium has been previously described. MATERIALS AND METHODS: A group of 68 patients with nodal or metastatic disease was examined. A total of 60 patients had lower urinary tract tumors, 6 had renal or ureteral transitional cell carcinoma and 2 had both lesions. Of these patients 21 underwent surgery alone, 40 underwent both surgery and chemotherapy, and 5 were treated by chemotherapy only. There were 2 patients who received no treatment. Periodic serum CA 125 was obtained in cases found to be initially marker positive and with a change in clinical status. RESULTS: Of the 68 patients 48 (71%) had increased CA 125. Variation in the serum level with change in disease status was often dramatic (mean 516.3 units per dl.). Of 30 radiologically measurable disease progressions 16 were accompanied by increasing CA 125. Increases were seen in 80% of patients who had increased baseline levels. In 5 cases marker increases were seen in the absence of measurable progression but the clinical course indicated therapeutic failure. Decreasing CA 125 reflected 3 of 5 imaged regressions. Overall, a 42% decrease in median levels was seen after chemotherapy. Significantly more cases of metastatic or residual disease were marker positive. CONCLUSIONS: CA 125 appears to be a marker of disease activity in a patient subset with advanced urothelial malignancy. The clinical use of CA 125 in this population is worthy of further study.

Genetic rationale for microheterogeneity of human diphosphoinositol polyphosphate phosphohydrolase type 2.

Selective expression of enzymes that adjust the intensity of turnover of diphosphoinositolpolyphosphates may regulate vesicle trafficking and DNA repair. For example, the type 2 human diphosphoinositolpolyphosphate phosphohydrolases (hDIPP2alpha and 2beta) are distinguished by a solitary amino-acid residue; the type 2beta isoform contains Gln86 whereas the type 2alpha isoform does not, yet the latter has 2-5 fold more catalytic activity than its beta counterpart (J. Biol.Chem. (2000) 12730). We discovered that both alpha and beta-type mRNAs were co-expressed in clonal cell-lines. We sought a genetic explanation for this microheterogeneity. Two BACs containing distinct, but intronless, hDIPP2beta genes were cloned. Only one of these genes could potentially give rise to our previously characterized hDIPP2beta mRNA; the other gene has several sequence differences and, in any case, is likely a processed pseudogene. These BACS were mapped to 1q12-q21 and 1p12-p13 by FISH. No analogous intronless hDIPP2alpha gene was detected by analysis of 21 individual genomic DNAs. However, sequence analysis of a third hDIPP2 gene (at 12q21) places the Gln86 CAG codon within an AGCAG pentamer, offering adjacent, alternate intronic 3'-boundaries. Thus, 'intron boundary skidding' by spliceosomes provides a mechanism for yielding both hDIPP2alpha and hDIPP2beta mRNAs. Our studies expand the repertoire of molecular mechanisms regulating diphosphoinositolpolyphosphate metabolism and function.

The transcriptional regulator, Arg82, is a hybrid kinase with both monophosphoinositol and diphosphoinositol polyphosphate synthase activity.

The Arg82 gene of Saccharomyces cerevisiae encodes a transcriptional regulator that phosphorylates inositol 1,4,5-trisphosphate [Saiardi et al. (1999) Curr. Biol. 9, 1323-1326]. However, some controversy has surrounded the nature of the reaction products. We now show that Arg82 phosphorylates inositol 1,3,4,5-tetrakisphosphate to inositol pentakisphosphate, which is itself converted to two isomers of diphosphoinositol tetrakisphosphate, one of which has never previously been identified. One of the diphosphoinositol phosphates was further phosphorylated by a yeast cell lysate. We propose that Arg82 is an ancestral precursor of two distinct and specific enzyme families: inositol 1,4,5-trisphosphate kinases and diphosphoinositol polyphosphate synthases.

Local opiate receptors in the sinoatrial node moderate vagal bradycardia.

Met-enkephalin-arg-phe (MEAP) interrupts vagal bradycardia when infused into the systemic circulation. This study was designed to locate the opiate receptors functionally responsible for this inhibition. Previous observations suggested that the receptors were most likely located in either intracardiac parasympathetic ganglia or the pre-junctional nerve terminals innervating the sinoatrial node. In this study 10 dogs were instrumented with a microdialysis probe inserted into the sinoatrial node. The functional position of the probe was tested by briefly introducing norepinephrine into the probe producing an increase in heart rate of more than 30 beats/min. Vagal stimulations were conducted at 0.5, 1.2 and 4 Hz during vehicle infusion (saline ascorbate). Cardiovascular responses during vagal stimulation were recorded on-line. MEAP was infused directly into the sinoatrial node via the microdialysis probe. The evaluation of vagal bradycardia was repeated during the nodal application of MEAP, diprenorphine (opiate antagonist), and diprenorphine co-infused with MEAP. MEAP introduced into the sinoatrial node via the microdialysis probe reduced vagal bradycardia by more than half. Simultaneous local nodal blockade of these receptors with the opiate antagonist, diprenorphine, eliminated the effect of MEAP demonstrating the participation by opiate receptors. Systemic infusions of MEAP produced a reduction in vagal bradycardia nearly identical to that observed during nodal administration. When local nodal opiate receptors were blocked with diprenorphine, the systemic effect of MEAP was eliminated. These data lead us to suggest that the opiate receptors responsible for the inhibition of vagal bradycardia are located within the sinoatrial node with few, if any, participating extra-nodal or ganglionic receptors.

Transient arterial occlusion raises enkephalin in the canine sinoatrial node and improves vagal bradycardia.

The C-terminal proenkephalin sequence, Methionine-enkephalin-arginine-phenylalanine (MEAP), is abundant in the myocardium and when delivered into the sinoatrial (SA) node by microdialysis, the peptide had significant vagolytic activity. The study that follows was conducted to determine if an increase in endogenous nodal MEAP could be demonstrated during reduced nodal blood flow and was endogenous MEAP similarly vagolytic. Microdialysis probes were placed in the canine SA node and perfused at 5 microl per min. The SA node artery was occluded and released four times at 10-min intervals. The intermittent occlusions were followed by one or two prolonged occlusions (30 min). Vagally mediated bradycardia was compared before, during, and after occlusion of the artery. An increase in recovered MEAP (70-220 fmol) was recorded during each of the initial 10-min occlusions. MEAP returned to baseline during each subsequent 10-min reperfusion. There was a sustained increase in MEAP (110-150 fmol) during longer occlusions. Contrary to the hypothesis, the increased MEAP during arterial occlusion was coincident with improved vagal bradycardia. The improvement in vagally mediated bradycardia was highly reproducible and was observed again during a second 30-min occlusion. The improved vagal function was reversed or reduced, respectively, when naltrindole or glibenclamide was included in the microdialysis inflow during arterial occlusion. Although these observations suggested that opioid receptors and ATP-sensitive K+ channels might have been involved, only a single dose of each agent was practical. Therefore, the specificity of these two responses remains to be confirmed. In summary, the recovery of endogenous opioids from the sinoatrial node increased during reduced arterial perfusion of the node. Contrary to expectations, the increase in recovered endogenous opioids was accompanied byimproved rather than impaired vagal bradycardia.