bluuebunny/crossref_metadata_2025 huggingface dataset:
Difficulties and pitfalls in the laboratory diagnosis of bleeding disorders
Authors: BOLTON‐MAGGS P. H. B. , FAVALORO E. J. , HILLARP A. , JENNINGS I. , KOHLER H. P.
Published: June 2012

Summary.  von Willebrand disease (VWD) is the most common inherited bleeding disorder, but variable severity and several classification types mean that diagnosis is often not straightforward. In many countries, the assays are not readily available and/or are not well standardized. The latest methods and the basis of VWD are discussed here, together with information from the international quality assessment programme (IEQAS). Factor XIII deficiency is a rare, but important bleeding disorder, which may be missed or diagnosed late. A discussion and update on this diagnosis is considered in the final section of our review.
Management of the elbow joint
Authors: HEIM M , BEETON K , BLAMEY G , GODDARD N
Published: June 2012

Summary.  The elbow is a complex joint that is prone to bleeding episodes. These features as well as the close proximity of the ulnar nerve and the need to use the elbow in many activities of daily living can lead to a range of symptoms including recurrent bleeds, pain, instability or loss of range of movement and nerve compression. Conservative management includes splinting and proprioceptive retraining monitored by a physiotherapist who is a musculoskeletal expert in hemophilia care. In the event that conservative measures are not successful a range of surgical options may be indicated including elbow replacement. These approaches continue to be evaluated in both the short and long term in order to determine the most effective treatment for the symptomatic elbow.
Knee arthropathy: when things go wrong
Authors: SOLIMENO L. , LUCK J. , FONDANESCHE C. , MCLAUGHLIN P. , NARAYAN P. , SABBOUR A. , SOHAIL T. , PASTA G.
Published: June 2012

Summary.  Joint bleeding, or haemarthrosis, is the most common type of bleeding episode experienced by individuals with haemophilia A and B. This leads to changes within the joints, including synovial proliferation, which results in further bleeding and chronic synovitis. Blood in the joint can also directly damage the cartilage, and with repeated bleeding, there is progressive destruction of both cartilage and bone. The end result is known as haemophilic arthropathy which is characterized by pain, stiffness and deformity. The joint most commonly affected is the knee. Haemophilic arthropathy can be prevented through regular prophylaxis and physiotherapy. However, when necessary, there are multiple surgical and non‐surgical options available. These procedures are indicated to improve the joint function and quality of life for haemophilic patients worldwide. In this review, the role of surgical and non‐surgical treatment of advanced knee arthropathy and its complications will be described.
Consequences of intra‐articular bleeding in haemophilia: science to clinical practice and beyond
Authors: FORSYTH A. L. , RIVARD G.‐É. , VALENTINO L. A. , ZOURIKIAN N. , HOFFMAN M. , MONAHAN P. E. , VAN MEEGEREN M. E. R. , FORRIOL F.
Published: June 2012

Summary.  Blood in the joint causes a number of physiological and pathological events that eventually lead to haemophilic arthropathy. Animal models show that blood in the joint induces inflammation that continues long after blood has been cleared [1]. TNF‐alpha, IL‐1beta and IL‐6 are inflammatory mediators that increase following haemarthrosis in haemophilic mice [2]. Conventional anti‐inflammatory drugs have failed to demonstrate a lasting effect in preventing haemophilic arthropathy. A new TNF‐alpha antagonist has shown promising results in haemophilic mice [3]. Similarly, the use of cyclo‐oxygenase‐2 inhibitors may reduce angiogenesis associated with the healing process following bleeding and the associated tissue damage [4]. Animal models are useful for studying the pathophysiology of haemarthropathy, however, when applying results from animals to humans, the differences in matrix turnover rate, thickness of cartilage and joint biomechanics must be kept in mind [5]. In people with haemophilia, there is a variable response to haemarthrosis as demonstrated by magnetic resonance imaging (MRI). Up to 30% of subjects have normal MRI despite having three or more haemarthroses into the same joint [6]. Once bone damage is present, little can be done to restore anatomic integrity. Several molecules, including members of the bone morphogenic protein subfamily, have been injected into bone defects in non‐haemophilic subjects with some evidence of benefit [7]. To achieve the primary goal of reducing blood in the joint and the negative sequelae, it is questionable to use ice to treat haemarthrosis. Indeed low temperature is associated with impairment of coagulation enzyme activity and platelet function [8].
Implementing musculoskeletal outcome assessments in clinical practice
Authors: FELDMAN B. M.
Published: June 2012

Summary.  Standardized outcome measures allow us to be more objective when measuring the impact of therapy on persons with haemophilia. Many excellent measures have been developed for haemophilia – especially in the health domains of structure and function, and activities; excellent health status/health‐related quality‐of‐life tools have also been developed for haemophilia. Studies from other disciplines suggest that the use of standardized outcome measures in daily practice leads to improvement in quality of care. Because of their potential complexity, measures must be chosen that are practical for use in clinic. Future research should be focussed on the best ways to implement the use of standardized outcome measures in haemophilia practice.
Models of prophylaxis
Authors: BERNTORP ERIK , FISCHER KATHELIJN , MINERS ALEC
Published: June 2012

Summary. Long‐term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well‐designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high‐dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long‐term consequences of the different prophylactic treatment strategies.

The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon.
Treatment of inherited platelet disorders
Authors: SELIGSOHN U.
Published: June 2012

Summary.  For patients affected by severe inherited platelet dysfunctions, e.g. Glanzmann thrombasthenia (GT) or Bernard‐Soulier syndrome (BSS), platelet transfusion is frequently needed for controlling spontaneous bleeding, and is always needed when trauma occurs or surgery is performed. For the mild‐to‐moderate bleeding entities, e.g. storage pool disease, thrombaxane A2 receptor defect, platelet transfusion is usually unnecessary. Transfusion of platelets should be used selectively and sparingly because of the substantial risk of alloimmunization against HLA antigens and/or platelet glycoproteins (GP) αIIb, β3, or αIIbβ3 in GT, and GPI‐IX‐V in BSS, which may lead to refractoriness to therapy. To reduce the risk, HLA‐matched single donors of platelets should be used. If such donors are unavailable, leucocyte‐depleted blood components should be used. Therapy other than platelet transfusion includes: (i) Prevention (vaccination against hepatitis B, avoidance of non‐steroidal anti‐inflammatory drugs, preservation of dental hygiene, correction of iron deficiency and prenatal diagnosis). (ii) Topical measures (compression with gauze soaked with tranexamic acid, fibrin sealants, splints for dental extractions and packing for nose bleeds). (iii) Antifibrinolytic agents that are useful for minor surgery and as adjuncts for other treatment modalities. (iv) Desmopressin that increases plasma levels of von Willebrand factor and factor VIII giving rise to increased platelet adhesiveness and aggregation associated with shortened bleeding time. (v) Recombinant factor VIIa (rFVIIa). GT patients have been treated for bleeding episodes by rFVIIa with partial success. The mechanism by which rFVIIa arrests bleeding is probably related to increased thrombin generation by a tissue factor‐independent process, enhanced platelet adhesion and restoration of platelet aggregation. (vi) Female hormones. Excessive bleeding during menarche in patients with GT or BSS can be controlled by high doses of oestrogen followed by high doses of oral oestrogen–progestin. Menorrhagia later in life can be managed by continuous oral contraceptives. Depo‐medroxyprogesterone acetate administered every 3 months is an alternative when combined oral contraceptives are contraindicated.
New approaches to the management of hepatitis C in haemophilia in 2012
Authors: ZOULIM F. , BAILLY F.
Published: June 2012

Summary.  Hepatitis C virus (HCV) infection is common in patients with Haemophilia. As in other patients, its natural history is characterized by disease progression towards cirrhosis and hepatocellular carcinoma. Many patients with hereditary bleeding disorders infected with HCV are also infected with HIV which is a factor of faster liver disease progression. In the past years, major progress has been made in the management of hepatitis C with the development of non invasive tools to assess liver fibrosis stage, i.e. fibroscan and biomarkers. With these tools, it is now possible to predict with good accuracy the liver disease stage and to take treatment decision. The landscape of antiviral therapy has evolved rapidly, especially for patients infected with HCV genotype 1. Triple therapy with interferon, ribavirin and protease inhibitors has been approved recently, the results of clinical trials showing a clear added benefit in terms of sustained virologic response in naive patients compared to interferon ‐ ribavirin combination therapy. However, results are less promising in cirrhotic patients who failed a previous line of therapy, with a higher rate of side effects and a lower rate of virologic response in patients who qualified as null responders to IFN based therapy. Clinical trials with triple therapy are ongoing in HCV‐HIV coinfected patients. Furthermore, new IFN free regimen relying on the combination of direct acting antivirals are currently being evaluated in HCV genotype 1 and non‐1 infected patients. These advances provide new hope in the management of chronic hepatitis C, including patients with hereditary bleeding disorders.
Inherited platelet disorders
Authors: NURDEN A. T. , FRESON K. , SELIGSOHN U.
Published: June 2012

Summary. Inherited diseases of the megakaryocyte lineage give rise to bleeding when platelets fail to fulfill their hemostatic function upon vessel injury. Platelet defects extend from the absence or malfunctioning of adhesion (GPIb‐IX‐V, Bernard–Soulier syndrome) or aggregation receptors (integrin αIIbβ3, Glanzmann thrombasthenia) to defects of primary receptors for soluble agonists, secretion from storage organelles, activation pathways and the generation of procoagulant activity. In disorders such as the Chediak–Higashi, Hermansky–Pudlak, Wiskott–Aldrich and Scott syndromes the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure hemostasis. Some FT affect platelet morphology and give rise to the ‘giant platelet’ syndromes (e.g.MYH9‐related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may also affect other cells and in some cases interfere with development and/or functioning of major organs. Diagnosis of platelet disorders requires platelet function testing, studies often aided by the quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. New generation DNA‐based procedures including whole exome sequencing offer an exciting new perspective. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is often used for mild disorders. Substitute therapies are available including rFVIIa and the potential use of thrombopoietin analogues for FT. Stem cell or bone marrow transplanation has been successful for several diseases while gene therapy shows promise in the Wiskott–Aldrich syndrome.
Musculoskeletal problems in persons with inhibitors: How do we treat?
Authors: CAVIGLIA H. , NARAYAN P. , FORSYTH A. , GIANGRANDE P. , GILBERT M. , GODDARD N. , MULDER K. , RAHIM S.
Published: June 2012

Summary.  Inhibitors are a serious complication, considerably increasing the morbidity, mortality and cost of treatment in this patient group [1]. The challenge of treating people with haemophilia (PWH) with inhibitors can be met by a well‐coordinated multidisciplinary team specialized in haemophilia. Each treatment centre must run a screening programme to detect inhibitors within their population and develop protocols to treat these patients. The treatment centre in Buenos Aires developed a screening programme that tests all our patients twice a year, ensuring early detection of inhibitors and early treatment of complications. In 2006, we analysed the quality of life (QOL) of non‐inhibitor patients and compared it with inhibitor patients detected by this programme and found no differences in QOL measured by the SF36 questionnaire and no differences in school absenteeism [2]. When diagnosis of the inhibitor does not come from a screening programme, its presence is suspected upon a lack of response to conventional replacement therapy for musculoskeletal bleeding, losing the ‘golden moment’ of treatment. This complication is much more serious when facing a traumatic bleed. In this situation, the lack of early diagnosis can lead to permanent damage or even death. Due to the cost of bypassing factors and the lack of experience of the medical team in the treatment of patients with inhibitors, many treatments that would improve the QOL of patients are instituted in an insufficient manner. Therefore, patients with haemophilia and inhibitors are often untreated or undertreated in their community. Orthopaedic surgeons and physiotherapists play a key role in the treatment of these patients and should be included in therapeutic decision making and most specifically in the postoperative treatment of patients with haemophilia and inhibitors. It is important that these patients have quick access to a trained therapeutic team in order to obtain an early diagnosis and treatment plan to prevent the evolution of the pathological process. Early treatment is cost‐effective in maintaining and improving the QOL of patients. Experience in patients with haemophilia and inhibitors is not very extensive. Today, this situation is changing, with several treatment centres beginning to perform surgeries in these most complex patients, giving them a chance to improve their QOL. This article presents the experience of experts from various fields involved in treating patients with inhibitors from a developed and developing world perspective.
Differences between developed and developing countries in paediatric care in haemophilia
Authors: DE KLEIJN P. , ODENT T. , BERNTORP E. , HILLIARD P. , PASTA G. , SRIVASTAVA A. , ILIESCU A. , MOHANTY S.
Published: June 2012

Summary. The aim of this article is to provide an up‐to‐date overview on paediatric haemophilia care in the world, with emphasis on medical treatment, rehabilitation, and orthopaedic surgery. The reason these specific professions caregivers are included is that over 90% of bleeding episodes in people with haemophilia (PWH) occur within the musculoskeletal system; and of these 80% of bleedings occur in joints.
Assessing acute coronary syndrome patients' cardiac‐related beliefs, motivation and mood over time to predict non‐attendance at cardiac rehabilitation
Authors: Herber Oliver R. , Jones Martyn C. , Smith Karen , Johnston Derek W.
Published: June 2012

Aim

This research protocol describes and justifies a study to assess patients' cardiac‐related beliefs (i.e. illness representations, knowledge/misconceptions, cardiac treatment beliefs), motivation and mood over time to predict non‐attendance at a cardiac rehabilitation programme by measuring weekly/monthly changes in these key variables.

Background

Heart disease is the UK's leading cause of death. Evidence from meta‐analyses suggests that cardiac rehabilitation facilitates recovery following acute cardiac events. However, 30–60% of patients do not attend cardiac rehabilitation. There is some evidence from questionnaire studies that a range of potentially modifiable psychological variables including patients' cardiac‐related beliefs, motivation and mood may influence attendance.

Design

Mixed‐methods.

Methods

In this study, during 2012–2013, electronic diary data will be gathered weekly/monthly from 240 patients with acute coronary syndrome from discharge from hospital until completion of the cardiac rehabilitation programme. This will identify changes and interactions between key variables over time and their power to predict non‐attendance at cardiac rehabilitation. Data will be analysed to examine the relationship between patients' illness perceptions, cardiac treatment beliefs, knowledge/misconceptions, mood and non‐attendance of the cardiac rehabilitation programme. The qualitative component (face‐to‐face interviews) seeks to explore why patients decide not to attend, not complete or complete the cardiac rehabilitation programme.

Discussion

The identification of robust predictors of (non‐)attendance is important for the design and delivery of interventions aimed at optimizing cardiac rehabilitation uptake. Funding for the study was granted in February 2011 by the Scottish Government Chief Scientist Office (CZH/4/650).
Genetically diverse but with surprisingly little geographical structure: the complex history of the widespread herb Carex nigra (Cyperaceae)
Authors: Jiménez‐Mejías Pedro , Luceño Modesto , Lye Kåre Arnstein , Brochmann Christian , Gussarova Galina
Published: June 2012

Aim  Based on extensive range‐wide sampling, we address the phylogeographical history of one of the most widespread and taxonomically complex sedges in Europe, Carex nigra s. lat. We compare the genetic structure of the recently colonized northern areas (front edge) and the long‐standing southern areas (rear edge), and assess the potential genetic basis of suggested taxonomic divisions at the rank of species and below.

Location  Amphi‐Atlantic, central and northern Europe, circum‐Mediterranean mountain ranges, central Siberia, Himalayas.

Methods  A total of 469 individuals sampled from 83 populations, covering most of the species’ range, were analysed with amplified fragment length polymorphism (AFLP) and chloroplast DNA (cpDNA) markers. Bayesian clustering, principal coordinates analysis, and estimates of diversity and differentiation were used for the analysis of AFLP data. CpDNA data were analysed with statistical parsimony networks and maximum parsimony and Bayesian inference of phylogenetic trees.

Results  Overall genetic diversity was high, but differentiation among populations was limited. Major glacial refugia were inferred in the Mediterranean Basin and in western Russia; in addition, there may have been minor refugia in the North Atlantic region. In the southern part of the range, we found high levels, but geographically quite poorly structured genetic diversity, whereas the levels of genetic diversity varied among different areas in the north. North American populations were genetically very similar to the European populations.

Main conclusions  The data are consistent with extensive gene flow, which has obscured the recent history of the taxon. The limited differentiation in the south probably results from the mixing of lineages expanding from several local refugia. Northward post‐glacial colonization resulted in a leading‐edge pattern of low diversity in the Netherlands, Belgium, Scotland and Iceland, whereas the observed high diversity levels in Fennoscandia suggest broad‐fronted colonization from the south as well as from the east. The patterns found in the American populations are consistent with post‐glacial colonization, possibly even with anthropogenic introduction from Europe. Our data also suggest that the tussock‐forming populations of C. nigra, often referred to as a distinct species (Carex juncella), represent an ecotype that has originated repeatedly from different populations with creeping rhizomes.
Effects of flunixin meglumine and ketoprofen on mediator production inex vivoandin vitromodels of inflammation in healthy dairy cows
Authors: DONALISIO C. , BARBERO R. , CUNIBERTI B. , VERCELLI C. , CASALONE M. , RE G
Published: June 2012

Donalisio, C., Barbero, R., Cuniberti, B., Vercelli, C., Casalone, M., Re, G. Effects of flunixin meglumine and ketoprofen on mediator production inex vivoandin vitromodels of inflammation in healthy dairy cows.J. vet. Pharmacol. Therap. 36, 130–139.

In this study,ex vivoassays were carried out in dairy cows to evaluate the anti‐inflammatory effects of two nonsteroidal anti‐inflammatory drugs: ketoprofen (KETO) and flunixin meglumine (FM). Twelve healthy Holstein dairy cattle were randomly allocated to two groups (n=6): group 1 received FM and group 2 received KETO at recommended therapeutic dosages. The anti‐inflammatory effects of both drugs were determined by measuring the production of coagulation‐induced thromboxane B2(TXB2), lipopolysaccharides (LPS) (10 μg/mL)‐induced prostaglandin E2(PGE2), and calcium ionophore (60 μm)‐induced leukotrien B4(LTB4). Cytokine production was assessed by measuring tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and interleukin‐8 (CXCL8) concentrations after incubation in the presence of 10 μg/mL LPS. The IC50of FM and KETO was determinedin vitroby determining the concentration of TXB2and PGE2in the presence of scalar drug concentrations (10−9–10−3 m). Both FM and KETO inhibited the two COX isoforms in vitro, but showed a preference for COX‐1. FM and KETO showed similar anti‐inflammatory effects in the cow.
Pharmacokinetics and dose selection of a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles
Authors: FREISE K. J. , SAVIDES M. C. , RIGGS K. L. , OWENS J. G. , NEWBOUND G. C. , CLARK T. P.
Published: June 2012

Freise, K.J., Savides, M.C., Riggs, K.L., Owens, J.G., Newbound, G.C., Clark, T.P. Pharmacokinetics and dose selection of a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles.J. vet. Pharmacol. Therap.35(Suppl. 2), 21–26.

A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg/kg (100 μL/kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1‐mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (tlag) of 0.333 h in the 1.3 mg/kg group and 0 in the other two groups. The mean Cmaxincreased with dose and were 2.28, 2.67, and 4.71 ng/mL in the 1.3, 2.6 and 5.2 mg/kg dose groups, respectively. Mean terminal half‐lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg/kg dose groups, respectively. The mean AUC0‐LLOQfrom lowest to highest dose groups were 157, 268, and 645 ng·h/mL and were dose proportional with aR2value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg/kg (50 μL/kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg/kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg/kg group.
The effectiveness of a long‐acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study
Authors: LINTON D. D. , WILSON M. G. , NEWBOUND G. C. , FREISE K. J. , CLARK T. P.
Published: June 2012

Linton, D. D., Wilson, M. G., Newbound, G. C., Freise, K. J., Clark, T. P. The effectiveness of a long‐acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study. J. vet. Pharmacol. Therap.35 (Suppl. 2), 53–64.

A prospective, double‐blinded, positive‐controlled, multicenter, noninferiority clinical study was conducted to evaluate the safety and effectiveness of a long‐acting transdermal fentanyl solution (TFS) for the control of postoperative pain. Four hundred forty‐five client‐owned dogs of various breeds were randomly assigned to receive a single dose of TFS (2.6 mg/kg [∼50 μL/kg]) (N = 223) applied 2–4 h prior to surgery or buprenorphine (20 μg/kg) (N = 222) administered intramuscularly 2–4 h prior to surgery and every 6 h through 90 h. There were 159 (35.7%) males and 286 (64.3%) females ranging from 0.5 to 16 years of age and 3 to 98.5 kg enrolled. Pain was scored using the modified Glasgow Composite Pain Scale with an a priori dropout criteria of ≥8 (20 maximum score). The one‐sided upper 95% confidence interval of the mean difference between fentanyl and buprenorphine treatment failures was 5.6%, which was not greater than the a priori selected margin difference of 15%. Adverse events attributed to either treatment were minimal in impact and were approximately equal between groups. Sustained plasma fentanyl concentrations provided by a single pre‐emptive dose of TFS are safe and effective and are noninferior to repeated injections of buprenorphine in controlling postoperative pain over 4 days. This long‐acting fentanyl formulation provides veterinarians with a novel, registered option for the control of postoperative pain in dogs that improves dosing compliance and potentially mitigates the disadvantages of oral, parenteral, and patch delivered opioids.
Naloxone reversal of an overdose of a novel, long‐acting transdermal fentanyl solution in laboratory Beagles
Authors: FREISE K. J. , NEWBOUND G. C. , TUDAN C. , CLARK T. P.
Published: June 2012

Freise, K. J., Newbound, G. C., Tudan, C., Clark, T. P. Naloxone reversal of an overdose of a novel, long‐acting transdermal fentanyl solution in laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 45–51.

Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid‐induced effects of a fivefold overdose of long‐acting transdermal fentanyl solution was evaluated in dogs. Twenty‐four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 μg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 μg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 μg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 μg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1–3 h following termination of the naloxone dosage regimens. The opioid‐induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 μg/kg i.m. naloxone administered at hourly intervals.
The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs
Authors: SAVIDES M. C. , POHLAND R. C. , WILKIE D. A. , ABBOTT J. A. , NEWBOUND G. C. , FREISE K. J. , CLARK T. P.
Published: June 2012

Savides, M. C., Pohland, R. C., Wilkie, D. A., Abbott, J. A., Newbound, G. C., Freise, K. J., Clark, T. P. The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs.J. vet. Pharmacol. Therap.35(Suppl. 2), 35–43.

Previous studies have demonstrated that a single, topical application of a novel, long‐acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty‐four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 μL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose‐limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher‐dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.
Pharmacokinetics and the effect of application site on a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles
Authors: FREISE K. J. , NEWBOUND G. C. , TUDAN C. , CLARK T. P.
Published: June 2012

Freise, K. J., Newbound, G. C., Tudan, C., Clark, T. P. Pharmacokinetics and the effect of application site on a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles.J. vet. Pharmacol. Therap.35(Suppl. 2), 27–33.

Application of transdermal drugs to different anatomical sites can result in different absorption characteristics. The pharmacokinetics (PKs) and bioequivalence of a single 2.6 mg/kg (50 μL/kg) dose of a novel, long‐acting transdermal fentanyl solution were determined when applied topically to the ventral abdominal or dorsal interscapular skin of 40 healthy laboratory Beagles. The PKs were differentiated by a more rapid initial absorption of fentanyl from the dorsal application site. Mean plasma fentanyl concentrations remained above 0.6 ng/mL from 4 to 96 h in the dorsal application group and from 8 to 144 h in the ventral application group. Bioequivalence analysis demonstrated that the sites were not equivalent; the 90% confidence intervals of the ratio of the geometric means for both the maximum concentration (Cmax) and the area under the curve (AUC) were not contained within the 80–125% interval. TheCmaxwas 2.34 ± 1.29 (mean ± standard deviation) and 2.02 ± 0.84 ng/mL for the ventral and dorsal application groups, respectively. The terminal elimination half‐lives (t1/2) for both groups were similar with values of 137 ± 58.9 and 117 ± 59.6 h for the ventral and dorsal application site groups, respectively. A mean absorption rate of ≥2 μg · kg/h was maintained from 2 to 144 h following dorsal application and from 2 to 264 h following ventral application. These results suggest that transdermal fentanyl solution could be applied as a single dose to the dorsal scapular area 2–4 h prior to surgery with analgesia lasting a minimum of 4 days.
The history and pharmacology of fentanyl: relevance to a novel, long‐acting transdermal fentanyl solution newly approved for use in dogs
Authors: KUKANICH B. , CLARK T. P.
Published: June 2012

KuKanich, B., Clark, T. P. The history and pharmacology of fentanyl: relevance to a novel, long‐acting transdermal fentanyl solution newly approved for use in dogs.J. vet. Pharmacol. Therap.35(Suppl. 2), 3–19.

Fentanyl is a potent mu opioid receptor agonist that was discovered to identify an improved human health analgesic over morphine, an opioid frequently associated with histamine‐release, bradycardia, hyper‐ or hypotension, and prolonged postoperative respiratory depression. Historically, the pharmacological features of fentanyl have been described primarily through the study of the human approved fentanyl citrate formulation. In conscious dogs, fentanyl has a wide margin of safety, possesses minimum effects on the cardiovascular and respiratory systems, and is readily reversible. Other pharmacological features include sedation, mild reductions in body temperature, and dose‐dependent reduction in food intake. The short duration of effect of available fentanyl citrate solutions has limited its clinical use to perioperative injections or constant rate infusions (CRIs). To extend the analgesic effect, additional fentanyl delivery technologies have been developed for human health including the fentanyl patch that has been used in an extra‐label manner in dogs. Beyond the slow onset and variability in fentanyl delivery, several additional disadvantages have precluded common use of patches in dogs. The recent approval of long‐acting transdermal fentanyl solution for dogs provides a new approach for sustained delivery of fentanyl for the control of postoperative pain in dogs. It has a rapid onset of action, prolonged duration, and mitigates the disadvantages of oral, parenteral, and patch‐delivered opioids. The availability of a safe and effective approved opioid in dogs may allow further optimization of postoperative analgesia in this species. The objective of this review is to summarize the history and pharmacology of fentanyl and to integrate information about the newly approved long‐acting transdermal fentanyl solution.
Genetic basis of local adaptation and flowering time variation in Arabidopsis lyrata
Authors: LEINONEN PÄIVI H. , REMINGTON DAVID L. , LEPPÄLÄ JOHANNA , SAVOLAINEN OUTI
Published: June 2012

Understanding how genetic variation at individual loci contributes to adaptation of populations to different local environments is an important topic in modern evolutionary biology. To date, most evidence has pointed to conditionally neutral quantitative trait loci (QTL) showing fitness effects only in some environments, while there has been less evidence for single‐locus fitness trade‐offs. At QTL underlying local adaptation, alleles from the local population are expected to show a fitness advantage. Cytoplasmic genomes also can have a role in local adaptation, but the role of cytonuclear interactions in adaptive differentiation has remained largely unknown. We mapped genomic regions underlying adaptive differentiation in multiple fitness components and flowering time in diverged populations of a perennial plant Arabidopsis lyrata. Experimental hybrids for this purpose were grown in natural field conditions of the parental populations in Norway and North Carolina (NC), USA, and in the greenhouse. We found QTL where high fitness and early flowering were associated with local alleles, indicating a role of different selection pressures in phenotypic differentiation. At two QTL regions, a fitness component showing local adaptation between the parental populations also showed signs of putative fitness trade‐offs. Beneficial dominance effects of conditionally neutral QTL for different fitness components resulted in hybrid vigour at the Norwegian site in the F2 hybrids. We also found that cytoplasmic genomes contributed to local adaptation and hybrid vigour by interacting with nuclear QTL, but these interactions did not show evidence for cytonuclear coadaptation (high fitness of local alleles combined with the local cytoplasm).
Parallelism in the oxygen transport system of the lake whitefish: the role of physiological divergence in ecological speciation
Authors: EVANS MELISSA L. , PRÆBEL KIM , PERUZZI STEFANO , BERNATCHEZ LOUIS
Published: June 2012

In North America, populations of lake whitefish (Coregonus clupeaformis) have evolved sympatric ‘dwarf’ and ‘normal’ ecotypes that are associated with distinct trophic niches within lakes. Trophic specialization should place diverging physiological demands on individuals, and thus, genes and phenotypes associated with energy production represent ideal candidates for studies of adaptation. Here, we test for the parallel divergence of traits involved in oxygen transport in dwarf and normal lake whitefish from Québec, Canada and Maine, USA. We observed significant differences in red blood cell morphology between the ecotypes. Specifically, dwarfs exhibited larger nuclei and a higher nucleus area/total cell area than normal whitefish in all of the lakes examined. In addition, isoelectric focusing gels revealed variation in the haemoglobin protein components found in whitefish. Dwarf and normal whitefish exhibited a similar number of protein components, but the composition of these components differed, with dwarf whitefish bearing a greater proportion of cathodic components compared to the normals. Furthermore, dwarf whitefish showed significant haemoglobin gene upregulation in the brain compared with the levels shown in normals. Together, our results indicate that metabolic traits involved in oxygen transport differ between the whitefish ecotypes and the strong parallel patterns of divergence observed across lakes implicates ecologically driven selection pressures. We discuss the function of these traits in relation to the differing trophic niches occupied by the whitefish and the potential contributions of trait plasticity and genetic divergence to energetic adaptation.
Mitochondrial barcodes are diagnostic of shared refugia but not species in hybridizing oak gallwasps
Authors: NICHOLLS JAMES A. , CHALLIS RICHARD J. , MUTUN SERAP , STONE GRAHAM N.
Published: June 2012

Mitochondrial DNA barcodes provide a simple taxonomic tool for systematic and ecological research, with particular benefit for poorly studied or species‐rich taxa. Barcoding assumes genetic diversity follows species boundaries; however, many processes disrupt species‐level monophyly of barcodes leading to incorrect classifications. Spatial population structure, particularly when shared across closely related and potentially hybridizing taxa, can invalidate barcoding approaches yet few data exist to examine its impacts. We test how shared population structure across hybridizing species impacts upon mitochondrial barcodes by sequencing the cytochrome b gene for 518 individuals of four well‐delimited Western Palaearctic gallwasp species within the Andricus quercuscalicis species group. Mitochondrial barcodes clustered individuals into mixed‐species clades corresponding to refugia, with no difference in within‐ and between‐species divergence. Four nuclear genes were also sequenced from 4 to 11 individuals per refugial population of each species. Multi‐locus analyses of these data supported established species, with no support for the refugial clustering across species seen in mitochondrial barcodes. This pattern is consistent with mitochondrial introgression among populations of species sharing the same glacial refugium, such that mitochondrial barcodes identify a shared history of population structure rather than species. Many taxa show phylogeographic structure across glacial refugia, suggesting that mitochondrial barcoding may fail when applied to other sets of co‐distributed, closely related species. Robust barcoding approaches must sample extensively across population structure to disentangle spatial from species‐level variation. Methods incorporating multiple unlinked loci are also essential to accommodate coalescent variation among genes and provide power to resolve recently diverged species.
Ionic conductances regulating the excitability of colonic smooth muscles
Authors: Koh S. D. , Ward S. M. , Sanders K. M.
Published: June 2012

The tunica muscularis of the gastrointestinal (GI) tract contains two layers of smooth muscle cells (SMC) oriented perpendicular to each other. SMC express a variety of voltage‐dependent and voltage‐independent ionic conductance(s) that develop membrane potential and control excitability. Resting membrane potentials (RMP) vary through the GI tract but generally are within the range of −80 to −40 mV. RMP sets the ‘gain’ of smooth muscle and regulates openings of voltage‐dependent Ca2+channels. A variety of K+channels contribute to setting RMP of SMC. In most regions, RMP is considerably less negative than the K+equilibrium potential, due to a finely tuned balance between background K+channels and non‐selective cation channels (NSCC). Variations in expression patterns and openings of K+channels and NSCC account for differences of the RMP in different regions of the GI tract. Smooth muscle excitability is also regulated by interstitial cells (interstitial cells of Cajal (ICC) and PDGFRα+cells) that express additional conductances and are electrically coupled to SMC. Thus, ‘myogenic’ activity results from the integrated behavior of the SMC/ICC/PDGFRα+cell (SIP) syncytium. Inputs from excitatory and inhibitory motor neurons are required to produce the complex motor patterns of the gut. Motor neurons innervate three cell types in the SIP, and receptors, second messenger pathways, and ion channels in these cells mediate postjunctional responses. Studies of isolated SIP cells have begun to unravel the mechanisms responsible for neural responses. This review discusses ion channels that set and regulate RMP of SIP cells and how neurotransmitters regulate membrane potential.
Ulcerative colitis patients in remission have an altered secretory capacity in the proximal colon despite macroscopically normal mucosa
Authors: Gustafsson J. K. , Hansson G. C. , Sjövall H.
Published: June 2012

Background  One of the hallmarks of acute colitis is loss of epithelial transport. For unknown reasons, many patients still suffer from GI symptoms during remission, indicating a sustained imbalance between absorption and secretion. We hypothesize that the colonic epithelium becomes more reactive to secretagogues to compensate for a failing barrier.

Methods  Biopsies from ascending colon and sigmoid colon of UC patients in remission and controls were mounted in Ussing chambers. Membrane current (Im) and epithelial capacitance (Cp) were used as markers for anion secretion and mucus exocytosis. Carbachol (1 mmol L−1) and forskolin (10 μmol L−1) were used to study Ca2+ and cAMP‐mediated secretion.

Key Results  Baseline values showed segmental patterns with higher Im in ascending colon and higher Cp in sigmoid colon of both UC patients and controls, but the patterns did not differ between the groups. The Im response to forskolin was increased (+35%) in the ascending colon of UC patients and the Im response to carbachol was decreased (−40%) in the same segment. No group differences were seen in the distal colon for either the forskolin or carbachol‐induced Im responses. The Cp response to carbachol was instead up‐regulated in the distal colon of UC patients, but remained unaffected in the proximal colon.

Conclusions & Inferences  The proximal colonic mucosa of UC patients in remission seems to shift its reactivity to secretagogues, becoming more sensitive to cAMP‐dependent secretion and less sensitive to Ca2+‐dependent secretion. This phenomenon may contribute to residual diarrhea in this patient group, despite resolution of inflammation.
Beetles with ‘trochantelli’: phylogeny of Cephenniini (Coleoptera: Staphylinidae: Scydmaeninae) focussing on Neotropical genera
Authors: JAŁOSZYŃSKI PAWEŁ
Published: June 2012

Neotropical genera of Cephenniini characterized by an additional leg ‘segment’ (‘trochantellus’) are revised, and the following new taxa are described:Shyrigen.n.,Shyri pichinchasp.n.(type species ofShyri) (Ecuador),Shyri perversussp.n.(Ecuador),Shyri quitusp.n.(Ecuador),Shyri microphthalmussp.n.(Ecuador),Monstrophenniumgen.n.(type species:Cephennium spinicolleSchaufuss),Furcodesgen.n.,Furcodes apicalissp.n.(type species ofFurcodes) (Mexico),Furcodes tutulesp.n.(Honduras),Paracephennium pumiliosp.n.(Costa Rica),Pseudocephennium iwokramanumsp.n.(Guyana),Pseudocephennium trilineatumsp.n.(Guyana),Pseudocephennium araguanumsp.n.(Venezuela),Pseudocephennium maximumsp.n.(Venezuela),Pseudocephennium peruvianumsp.n.(Peru),Pseudocephennium cochabambanumsp.n.(Bolivia),Pseudocephennium saramaccanumsp.n.(Suriname) andPseudocephennium brokopondonumsp.n.(Suriname).Pseudocephennium spinicolle(Schaufuss) is transferred toMonstrophennium. Cladistic analysis of characters from adult morphology of all genera of Cephenniini and a large outgroup sample from Cyrtoscydmini, Eutheiini, Scydmaenini, Clidicini and Mastigini strongly supported the monophyly of Cephenniini. However, only theCephennomicrusgroup comprising nine genera was strongly supported as a monophyletic clade, while only weak support was found for the previously suggestedCephennodesgroup andCephenniumgroup. Two alternative hypotheses concerning the phylogeny of Cephenniini are put forward and discussed: (i) theCephenniumgroup is sister to all remaining Cephenniini; or (ii) theCephennomicrusgroup is sister to all remaining Cephenniini. The Neotropical genera with ‘trochantellus’ form a well‐supported clade derived from the ancestral lineage of theCephennodesgroup.