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The cardiac conduction system in large carnivores, such as the African lion (Panthera leo), represents a significant knowledge gap in both veterinary science and in cardiac electrophysiology. Short QT intervals have been reported from zoo‐kept, anaesthetized lions, and our goal was to record the first ECGs from wild, conscious lions roaming freely, and compare them to zoo‐kept lions under the hypothesis that short QT is unique to zoo‐kept lions. Macroscopic and histological examinations were performed on heart tissue removed from nine healthy zoo lions. ECGs were recorded from the nine anaesthetized zoo‐kept lions, and from 15 anaesthetized and conscious wild lions in Africa. Our histological and topographical description of the lion's heart matched what has previously been published. In conscious lions, the ECG recordings revealed a mean heart rate of 70 ± 4 beats/min, with faster heart rates during the night. PQ and QT intervals were heart rate dependent in the conscious lions. Interestingly, QT intervals recorded in wild lions were markedly longer than QT intervals from zoo lions (398 ± 40 vs. 297 ± 9 ms, respectively; P < 0.0001). Anaesthesia or heart rate did not account for this difference. We provide a comprehensive description of the cardiac anatomy and electrophysiology of wild and zoo‐kept lions. QT intervals were significantly shorter in zoo lions, suggesting functional disparities in cardiac electrophysiology between wild and zoo‐kept lions, potentially related to physical fitness. These findings underscore the plasticity of cardiac electrophysiology and may be of value when reintroducing endangered species into the wild and when managing lions in human care. What is the central question of this study?How do electrocardiograms from zoo lions and free‐roaming wild lions compare?What is the main finding and its importance?QT intervals in zoo lions are shorter compared to wild lions, which may be relevant for our understanding of animals in human care and may influence conservation strategies. [ABSTRACT FROM AUTHOR]

The article discusses the debate among cardiologists and veterinarians regarding the susceptibility of kangaroos to fatal ventricular arrhythmias. While previous studies suggested kangaroos were prone to such arrhythmias, new research conducted on Eastern grey kangaroos found that despite their short QT intervals, they were resistant to pacing-induced ventricular fibrillation. The study concluded that the kangaroo heart does not possess a vulnerable substrate for ventricular arrhythmias, contrary to previous beliefs. [Extracted from the article]

Biocatalytic degradation of plastic waste is anticipated to play an important role in future recycling systems. However, enzymatic degradation of crystalline poly (ethylene terephthalate) (PET) remains consistently poor. Herein, we employed functional assays to elucidate the molecular underpinnings of this limitation. This included utilizing complementary activity assays to monitor the degradation of PET disks with varying crystallinity (XC), as well as determining enzymatic kinetic parameters for soluble PET fragments. The results indicate that an efficient PET‐hydrolase, LCCICCG, operates through an endolytic mode of action, and that its activity is limited by conformational constraints in the PET polymer. Such constraints become more pronounced at high XC values, and this limits the density of productive sites on the PET surface. Endolytic chain‐scissions are the dominant reaction type in the initial stage, and this means that little or no soluble organic product are released. However, endolytic cuts gradually and locally promote chain mobility and hence the density of attack sites on the surface. This leads to an upward concave progress curve; a behavior sometimes termed lag‐phase kinetics. [ABSTRACT FROM AUTHOR]

Aim: Heart Failure with preserved Ejection Fraction (HFpEF) is characterized by diastolic dysfunction and reduced cardiac output, but its pathophysiology remains poorly understood. Animal models of HFpEF are challenging due to difficulties in assessing the degree of heart failure in small animals. This study aimed at inducing HFpEF in a mouse model to probe preload‐dependency. Methods: Increased body mass and arterial hypertension were induced in mice using a Western diet and NO synthase inhibition. Preload dependence was tested ex vivo. Results: Mice with obesity and hypertension exhibited reduced cardiac output, indicating a failing heart. Increased left ventricular filling pressure during diastole suggested reduced compliance. Notably, the ejection fraction was preserved, suggesting the development of HFpEF. Spontaneous physical activity at night was reduced in HFpEF mice, indicating exercise intolerance; however, the cardiac connective tissue content was comparable between HFpEF and control mice. The HFpEF mice showed increased vulnerability to reduced preload ex vivo, indicating that elevated left ventricular filling pressure compensated for the rigid left ventricle, preventing a critical decrease in cardiac output. Conclusion: This animal model successfully developed mild HFpEF with a reduced pump function that was dependent on a high preload. A model of mild HFpEF may serve as a valuable tool for studying disease progression and interventions aimed at delaying or reversing symptom advancement, considering the slow development of HFpEF in patients. [ABSTRACT FROM AUTHOR]

Carboxypeptidase II (CBPII) in brain metabolizes the neuroactive substance N‐acetyl‐L‐aspartyl‐L‐glutamate (NAGG) to yield the elements of glutamate and N‐acetyl‐aspartate (NAA). In peripheral organs, CBPII is known as prostrate specific membrane antigen (PSMA), which presents an important target for nuclear medicine imaging in prostate cancer. Available PSMA ligands for PET imaging do not cross the blood–brain barrier, and there is scant knowledge of the neurobiology of CBPII, despite its implication in the regulation of glutamatergic neurotransmission. In this study we used the clinical PET tracer [18F]‐PSMA‐1007 ([18F]PSMA) for an autoradiographic characterization of CGPII in rat brain. Ligand binding and displacement curves indicated a single site in brain, with KD of about 0.5 nM, and Bmax ranging from 9 nM in cortex to 19 nM in white matter (corpus callosum and fimbria) and 24 nM in hypothalamus. The binding properties of [18F]PSMA in vitro should enable its use for autoradiographic investigations of CBPII expression in animal models of human neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

The Wandel Sea Basin in North Greenland was part of the epicontinental Boreal Sea in Triassic time. The basin formed the western margin of the northernmost Atlantic elongated sea connecting southwards with basins along the conjugate Greenland—Norwegian margins. A multidisciplinary dataset including sedimentology, biostratigraphy, organic geochemistry and sedimentary provenance, allow to document its basin evolution. The Wandel Sea Basin was transgressed in the Dienerian with marine deposition prevailing until the Norian. Sediments were mainly sourced from the Greenlandic Caledonian basement and deposited on a 100 km wide shallow marine shelf during the Early Triassic. In Middle Triassic, oil‐prone mudstones formed in oxygen‐depleted deep shelf settings, including eastern Wandel Sea Basin. Detrital zircon U–Pb ages show that by Carnian times, the >1000 km wide, Uralian‐sourced, deltaic shelf had prograded westward across the Barents Sea reaching the eastern north Greenland and de facto nearly closed the northernmost Atlantic Sea. [ABSTRACT FROM AUTHOR]

The rate response of poly(ethylene terephthalate) (PET)‐hydrolases to increased substrate crystallinity (XC) of PET manifests as a rate‐lowering effect that varies significantly for different enzymes. Herein, we report the influence of XC on the product release rate of six thermostable PET‐hydrolases. All enzyme reactions displayed a distinctive lag phase until measurable product formation occurred. The duration of the lag phase increased with XC. The recently discovered PET‐hydrolase PHL7 worked efficiently on "amorphous" PET disks (XC≈10 %), but this enzyme was extremely sensitive to increased XC, whereas the enzymes LCCICCG, LCC, and DuraPETase had higher tolerance to increases in XC and had activity on PET disks having XC of 24.4 %. Microscopy revealed that the XC‐tolerant hydrolases generated smooth and more uniform substrate surface erosion than PHL7 during reaction. Structural and molecular dynamics analysis of the PET‐hydrolyzing enzymes disclosed that surface electrostatics and enzyme flexibility may account for the observed differences. [ABSTRACT FROM AUTHOR]

Physiological properties and function of the lymphatic system is still somewhat of a mystery. We report the current knowledge about human lymphatic vessel contractility and capability of adaptation. A literature search in PubMed identified studies published January 2000–September 2022. Inclusion criteria were studies investigating parameters related to contraction frequency, fluid velocity, and lymphatic pressure in vivo and ex vivo in human lymphatic vessels. The search returned 2885 papers of which 28 met the inclusion criteria. In vivo vessels revealed baseline contraction frequencies between 0.2 ± 0.2 and 1.8 ± 0.1 min1, velocities between 0.008 ± 0.002 and 2.3 ± 0.3 cm/s, and pressures between 4.5 (range 0.5–9.2) and 60.3 ± 2.8 mm Hg. Gravitational forces, hyperthermia, and treatment with nifedipine caused increases in contraction frequency. Ex vivo lymphatic vessels displayed contraction frequencies between 1.2 ± 0.1 and 5.5 ± 1.2 min−1. Exposure to agents affecting cation and anion channels, adrenoceptors, HCN channels, and changes in diameter‐tension properties all resulted in changes in functional parameters as known from the blood vascular system. We find that the lymphatic system is dynamic and adaptable. Different investigative methods yields alternating results. Systematic approaches, consensus on investigative methods, and larger studies are needed to fully understand lymphatic transport and apply this in a clinical context. [ABSTRACT FROM AUTHOR]

Background: The Purkinje fibers convey the electrical impulses at much higher speed than the working myocardial cells. Thus, the distribution of the Purkinje network is of paramount importance for the timing and coordination of ventricular activation. The Purkinje fibers are found in the subendocardium of all species of mammals, but some mammals also possess an intramural Purkinje fiber network that provides for relatively instantaneous, burst‐like activation of the entire ventricular wall, and gives rise to an rS configuration in lead II of the ECG. Aim: To relate the topography of the horse heart and the distribution and histology of the conduction system to the pattern of ventricular activation as a mechanism for the unique electrical axis of the equine heart. Methods: The morphology and distribution of the cardiac conduction system was determined by histochemistry. The electrical activity was measured using ECG in the Einthoven and orthogonal configuration. Results: The long axis of the equine heart is close to vertical. Outside the nodal regions the conduction system consisted of Purkinje fibers connected by connexin 43 and long, slender parallel running transitional cells. The Purkinje fiber network extended deep into the ventricular walls. ECGs recorded in an orthogonal configuration revealed a mean electrical axis pointing in a cranial‐to‐left direction indicating ventricular activation in an apex‐to‐base direction. Conclusion: The direction of the mean electrical axis in the equine heart is determined by the architecture of the intramural Purkinje network, rather than being a reflection of ventricular mass. [ABSTRACT FROM AUTHOR]

Whether Archean tectonics were horizontally or vertically dominated is controversially discussed because arguments bear on the kinematics and thermal state of the Archean mantle and constrain the mode of formation of the earliest continental crust. Highly deformed strata of Archean greenstone belts figure prominently in this debate because they record long periods of time and multiple deformation phases. Among the best‐preserved greenstone belts counts the Barberton Greenstone Belt (BGB) of southern Africa. Geological mapping of part of the southern BGB in Eswatini (Swaziland), combined with U‐Pb zircon dating, shows that the region preserves a tightly re‐folded imbricate thrust stack in which metavolcanic and ‐volcaniclastic strata of the Onverwacht Group, deposited at 3.34–3.29 Ga, have been thrust on top of ca. 3.22 Ga siliciclastic strata of the Moodies Group. The structurally highest element, the Malolotsha Syncline, forms a tectonic klippe of substantial size and is >1,450 m thick. Forward modeling of a balanced cross section indicates that this thrust stack was part of a northwestward‐verging orogen along the southern margin of the BGB and records a minimum horizontal displacement of 33 km perpendicular to its present‐day faulted, ductily strained and multiply metamorphosed margin. Because conglomerate clasts indicate a significantly higher degree of prolate strain which extends further into the BGB than at its northern margin, late‐stage tectonic architecture of the BGB may be highly asymmetrical. Our study documents that the BGB, and perhaps other Archean greenstone belts, preserves a complex array of both vertically‐ and horizontally‐dominated deformation styles that have interfered with each other at small regional and short temporal scales. Plain Language Summary: Worldwide, only a few regions exist where ancient rock strata document how earth cooled, surface strata deformed, and continents grew. It is debated whether vertical movements dominated (akin to a lava lamp) and when major horizontal motions (as they dominate Earth today) began; certainly, there was also overlap between these regimes. Radiometric age dating of zircons extracted from strata along the southern margin of one of the best‐preserved ancient regions in southern Africa, the Barberton Greenstone Belt in Eswatini, show that older strata were thrust there over younger strata for at least 33 km distance subhorizontally. Then they were shingled, and then folded. The results show that even at a time when Earth's oldest continents were just forming, significant horizontal displacements existed already. Key Points: U‐Pb zircon dating and geological mapping confirm a folded thrust‐stack along part of the southern margin of the Archean Barberton Greenstone Belt (BGB)Forward modeling of a balanced cross‐section indicates >33 km of horizontal shortening toward the northwestVertically‐ and horizontally‐dominated tectonics interfered with each other in the BGB and may have done so in other Archean greenstone belts as well [ABSTRACT FROM AUTHOR]

We present new zircon U/Pb provenance data using laser ablation induced coupled plasma mass spectroscopy (LA‐ICP‐MS) for eight samples of mature quartz arenites and subarkosic sandstones of the Lower Ordovician Khabour Formation, northern Iraq, to establish their depositional age and provenance. The samples were collected from thin‐ to medium‐bedded sandstones along profiles of the Chalky Nasara and Ora sections. Most analysed detrital zircon analyses are concordant within 100 ± 10% and include a prevalence of Proterozoic over Archean ages. Collectively, the data can be divided into four main age groups: (a) Neoproterozoic ages, 570–1,000 Ma (58%); (b) Mesoproterozoic ages, 1,000–1,500 Ma (10%); (c) Palaeoproterozoic ages, 1,620–2,480 Ma (21%); and (d) Archean ages, 2,500–3,300 Ma (11%). The predominance of Cryogenian–Ediacaran ages (850–550 Ma) reflects major magmatic events associated with the assembly of northern Gondwana. The major age group at ~600 Ma likely represents the unroofing of late‐stage granitic rocks from the Arabian‐Nubian Shield. The lack of zircons younger than 490 Ma suggests that Lower Ordovician sandstones in northern Iraq were probably deposited on the distal shelf of the northern Gondwana passive margin and were not influenced by rifting and magmatism in northern Gondwana caused by the opening of Palaeo‐Tethys. Diagenetic xenotime overgrowths are common on detrital zircon grains, but radiometric dating of these was not possible. [ABSTRACT FROM AUTHOR]

Aim: Cardiac arrhythmias and sudden deaths have diurnal rhythms in humans. The underlying mechanisms are unknown. Mice with cardiomyocyte‐specific disruption of the molecular clock genes have lower heart rate than control. Because changes in the QT interval on the electrocardiogram is a clinically used marker of risk of arrhythmias, we sought to test if the biological rhythms of QT intervals are dependent on heart rate and if this dependency is changed when the molecular clock is disrupted. Methods: We implanted radio transmitters in male mice with cardiomyocyte‐specific Bmal1 knockout (CBK) and in control mice and recorded 24‐h ECGs under diurnal and circadian conditions. We obtained left ventricular monophasic action potentials during pacing in hearts ex vivo. Results: Both RR and QT intervals were longer in conscious CBK than control mice (RR: 117 ± 7 vs 110 ± 9 ms, P <.05; and QT: 53 ± 4 vs 48 ± 2 ms, P <.05). The prolonged QT interval was independent of the slow heart rate in CBK mice. The QT interval exhibited diurnal and circadian rhythms in both CBK and control mice. The action potential duration was longer in CBK than in control mice, indicating slower repolarization. Action potential alternans occurred at lower pacing rate in hearts from CBK than control mice (12 ± 3 vs 16 ± 2 Hz, respectively, P <.05). Conclusion: The bradycardic CBK mice have prolonged ventricular repolarization independent of the heart rate. Diurnal and circadian rhythms in repolarization are preserved in CBK mice and are not a consequence of the 24‐h rhythm in heart rate. Arrhythmia vulnerability appears to be increased when the cardiac clock is disrupted. [ABSTRACT FROM AUTHOR]

Aim: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type‐2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. Methods: Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca2+ transients in isolated SAN preparations. Results: While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose‐dependent manner. These arrhythmias were completely abolished by atropine pre‐treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. Conclusion: Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a β‐adrenergic agonist. Ex vivo, higher Ca2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias. [ABSTRACT FROM AUTHOR]

Objectives: To investigate dogs with acute onset of intracranial signs suspected of stroke by primary veterinary clinicians, and establish possible differential diagnoses and long‐term outcome. In addition, serum C‐reactive protein and plasma cytokines were investigated as potential biomarkers of disease. Materials and Methods: All cases were evaluated by neurologic examination, routine haematology and biochemistry and measurement of serum C‐reactive protein, plasma cytokine concentrations (interleukin‐2, ‐6, ‐8, ‐10, tumour necrosis factor) and low‐field MRI. Results: Primary veterinarians contacted the investigators with 85 suspected stroke cases. Only 20 met the inclusion criteria. Of these, two were diagnosed with ischaemic stroke. Other causes were idiopathic vestibular syndrome (n=6), brain tumour (n=5) and inflammatory brain disease (n=2); in five cases a precise diagnosis could not be determined. Median survival times were: brain tumour, 3 days, idiopathic vestibular syndrome, 315 days, ischaemic stroke, 365 days and inflammatory central nervous system (CNS) disease, 468 days. The median plasma concentrations of interleukin‐2, ‐6, ‐8, ‐10 or tumour necrosis factor were not significantly increased in any of the diagnosis groups compared to healthy controls. Serum C‐reactive protein was higher in dogs with brain tumours and inflammatory brain disease but not above the upper bound of the reference interval. Clinical Significance: Dogs that present with acute onset intracranial disease may have ischaemic stroke but are more likely to have other causes. Many dogs with such acute onset of neurological dysfunction (brain tumours excluded) may recover within a couple of weeks despite their initial severe clinical appearance. [ABSTRACT FROM AUTHOR]

Mutation of Dedicator of cytokinesis 8 (DOCK8) has previously been reported to provide resistance to the Th17 cell dependent EAE in mice. Contrary to expectation, we observed an elevation of Th17 cells in two different DOCK8 mutant mouse strains in the steady state. This was specific for Th17 cells with no change in Th1 or Th2 cell populations. In vitro Th cell differentiation assays revealed that the elevated Th17 cell population was not due to a T cell intrinsic differentiation bias. Challenging these mutant mice in the EAE model, we confirmed a resistance to this autoimmune disease with Th17 cells remaining elevated systemically while cellular infiltration in the CNS was reduced. Infiltrating T cells lost the bias toward Th17 cells indicating a relative reduction of Th17 cells in the CNS and a Th17 cell specific migration disadvantage. Adoptive transfers of Th1 and Th17 cells in EAE‐affected mice further supported the Th17 cell‐specific migration defect, however, DOCK8‐deficient Th17 cells expressed normal Th17 cell‐specific CCR6 levels and migrated toward chemokine gradients in transwell assays. This study shows that resistance to EAE in DOCK8 mutant mice is achieved despite a systemic Th17 bias. [ABSTRACT FROM AUTHOR]

The cardiovascular safety of liraglutide, a glucagon‐like peptide‐1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double‐blind, placebo‐controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time‐to‐event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person‐years) compared to 10 participants in the comparators group (3.65 events/1000 person‐years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17‐1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis. [ABSTRACT FROM AUTHOR]

Aim In this study, we investigate the impact of altered action potential durations ( APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K+-channel-interacting protein 2 ( KCh IP2−/− and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia. Methods Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time ( AT), APD and repolarization time (= AT + APD) were measured in isolated hearts using floating microelectrodes. Results Proarrhythmia in WT and KCh IP2−/− was not sensitive to changes in refractory periods. Action potentials were longer in KCh IP2−/− hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion of repolarization time, whereas hearts from KCh IP2−/− mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KCh IP2−/− mice in vivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice. Conclusion Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and the amplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability. [ABSTRACT FROM AUTHOR]

Zircon U-Pb geochronometry, heavy mineral analyses and conventional seismic reflection data were used to interpret the provenance of the Lower Triassic Bunter Sandstone Formation. The succession was sampled in five Danish wells in the northern part of the North German Basin. The results show that sediment supply was mainly derived from the Ringkøbing-Fyn High situated north of the basin and from the Variscan belt located south of the basin. Seismic reflection data document that the Ringkøbing-Fyn High was a local barrier for sediment transport during the Early Triassic. Hence, the Fennoscandian Shield did not supply much sediment to the basin as opposed to what was previously believed. Sediment from the Variscan belt was transported by wind activity across the North German Basin when it was dried out during deposition of the aeolian part of the Volpriehausen Member (lower Bunter Sandstone). Fluvial sand was supplied from the Ringkøbing-Fyn High to the basin during precipitation events which occurred most frequently when the Solling Member was deposited (upper Bunter Sandstone). Late Neoproterozoic to Carboniferous zircon ages predominate in the Volpriehausen Member where the dominant age population with a peak age of 337 Ma corresponds to the culmination of Variscan high-grade metamorphism, whereas a secondary age population with a peak at 300 Ma matches the timing of volcanism and magmatism at the Carboniferous/Permian boundary in the northern Variscan belt. Parts of the basement in the Ringkøbing-Fyn High were outcropping during the Early Triassic and zircon ages similar to this Mesoproterozoic basement are present in the Bunter Sandstone. The heavy mineral assemblage of the Solling Member is uniform and has a high garnet content compared to the contemporaneous sediments in the Norwegian-Danish Basin and in the southern part of the North German Basin. This finding confirms that a local source in the Ringkøbing-Fyn High supplied most of the fluvial sediment in the northern part of the North German Basin. The northernmost part of the Bunter Sandstone is situated on a platform area that is separated from the basin area by a broad WNW- ESE-oriented fault zone. The most promising reservoir in the basin area is the aeolian Volpriehausen Member since the sandstone has a wide lateral distribution and a constant thickness. The alluvial to ephemeral fluvial Solling Member may be a good reservoir in the platform area and marginal basin area, but the complex sand-body architecture makes it difficult to predict the reservoir quality. [ABSTRACT FROM AUTHOR]

Aims To confirm superiority on glycaemic control by switching from sitagliptin to liraglutide 1.8 mg/d versus continued sitagliptin. Materials and methods A randomized, multicentre, double-blind, double-dummy, active-controlled trial across 86 office- or hospital-based sites in North America, Europe and Asia. Subjects with type 2 diabetes who had inadequate glycaemic control (glycated haemoglobin [ HbA1c] 7.5−9.5% on sitagliptin (100 mg/d) and metformin (≥1500 mg daily) for ≥90 days were randomized to either switch to liraglutide (n = 203) or continue sitagliptin (n = 204), both with metformin. The primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a confirmatory secondary endpoint. Results Greater reduction in mean HbA1c was achieved with liraglutide than with continued sitagliptin [−1.14% vs. −0.54%; estimated mean treatment difference ( ETD): −0.61% (95% CI −0.82 to −0.40; p < 0.0001)], confirming superiority of switching to liraglutide. Body weight was reduced more with liraglutide [−3.31 kg vs. −1.64 kg; ETD: −1.67 kg (95% CI −2.34 to −0.99; p < 0.0001)]. Nausea was more common with liraglutide [44 subjects (21.8%)] than with continued sitagliptin [16 (7.8%)]. Three subjects (1.5%) taking sitagliptin reported a confirmed hypoglycaemic episode. Conclusions Subjects insufficiently controlled with sitagliptin who switch to liraglutide can obtain clinically relevant reductions in glycaemia and body weight, without compromising safety. A switch from sitagliptin to liraglutide provides an option for improved management of type 2 diabetes while still allowing patients to remain on dual therapy. [ABSTRACT FROM AUTHOR]

To examine the effect on serum lipase activity and protein concentration of intravenous infusions of glucagon-like peptide-1 ( GLP-1) and peptide YY ( PYY3-36) and of an ad libitum meal in healthy overweight men. Twenty-five healthy, male subjects participated in this randomized, double-blinded, placebo-controlled 4-arm crossover study (Body Mass Index ( BMI): 29 ± 3 kg/m2, age: 33 ± 9 years). On separate days, the subjects received a 150-min intravenous infusion of either (1) 0.8 pmol/kg/min PYY3-36, (2) 1.0 pmol/kg/min GLP-1, (3) 1 + 2, or (4) placebo. Samples were collected throughout the infusion and after intake of an ad libitum meal for measurement of serum lipase. Serum lipase levels measured by enzyme-linked immunosorbent assay ( ELISA) following mono-infusions of GLP-1 and PYY3-36 were comparable to serum lipase levels following placebo ( P = 0.054 and P = 0.873, respectively). Following the co-infusion of GLP-1 and PYY3-36, serum lipase levels measured by ELISA decreased over time compared to placebo ( P = 0.012). However, the between-group difference was not consistent when each time point was analyzed separately. On the placebo day, serum lipase levels measured by ELISA after an ad libitum meal rose slightly compared to the preprandial values ( P = 0.003). There was strong correlation between serum lipase levels measured by ELISA and LIPC Lipase colorimetric assay ( COBAS) (0.94 < r; <0.0001). Infusions of GLP-1 and PYY3-36, separately or in combination, did not increase serum lipase. However, a small increase in serum lipase may occur in response to a meal. [ABSTRACT FROM AUTHOR]

Objectives To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4). Patients and methods A matched-pair analysis was conducted. In all, 215 patients with Gleason score 6 or 7 (3 + 4) prostate cancer on biopsy who underwent RP before 31 December 2005 (pre-ISUP group), were matched 1:1 by biopsy Gleason score, clinical tumour category, PSA level, and margin status to patients undergoing RP between 1 January 2008 and 31 December 2011 (post-ISUP group). Patients were followed until BCR defined as a PSA level of ≥0.2 ng/mL. Risk of BCR was analysed in a competing-risk model. Results The median follow-up was 9.5 years in the pre-ISUP group and 4.8 years in the post-ISUP group. The 5-year cumulative incidences of BCR were 34.0% and 13.9% in the pre-ISUP and post-ISUP groups, respectively (P < 0.001). The difference in cumulative incidence applied to both patients with Gleason score 6 (P < 0.001) and 7 (3 + 4) (P = 0.004). There was no difference in the 5-year cumulative incidence of BCR between patients with pre-ISUP Gleason score 6 and post-ISUP Gleason score 7 (3 + 4) (P = 0.34). In a multiple Cox-proportional hazard regression model, ISUP 2005 grading was a strong prognostic factor for BCR within 5 years of RP (hazard ratio 0.34; 95% confidence interval 0.22–0.54; P < 0.001). Conclusion The revision of the Gleason grading system has reduced the risk of BCR after RP in patients with biopsy Gleason score 6 and 7 (3 + 4). This may have consequences when comparing outcomes across studies and historical periods and may affect future treatment recommendations. [ABSTRACT FROM AUTHOR]

An increased risk of malignant melanoma has been observed in men with prostate cancer. To assess potential shared risk factors and confounding factors, we analysed risk of melanoma in men with prostate cancer including information on tumor characteristics and demographics including socioeconomic status. In The Prostate Cancer data Base Sweden, risk of melanoma was assessed in a cohort of men with prostate cancer and in a comparison cohort of prostate-cancer free men. Data on prostate cancer risk category, melanoma stage, basal cell carcinoma, location of residency, and socioeconomic status were obtained from nationwide registers. Melanoma was diagnosed in 830/108,145 (0.78%) men with prostate cancer and in 3,699/556,792 (0.66%) prostate cancer-free men. In multivariable Cox regression models, men with prostate cancer had a significantly increased risk of melanoma (HR 1.18, 95% CI 1.09-1.27), and so had married men, men with high education and income, and men residing in southern Sweden. The strongest associations were observed for stage 0 melanoma in men with low-risk prostate cancer (HR 1.45, 1.14-1.86), high education (HR 1.87, 1.60-2.18) and top income (HR 1.61, 1.34-1.93), respectively, whereas there was no association between these factors and late-stage melanoma. Men with prostate cancer also had an increased risk of basal cell carcinoma (HR 1.18, 1.15-1.22). In conclusion, men with low-risk prostate cancer, high education, high income and residency in southern Sweden had an increased risk of early-stage melanoma. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical implications of interobserver variation in the assessment of re-biopsies obtained during active surveillance ( AS) of prostate cancer. Patients and Methods In all, 107 patients with low-risk prostate cancer with 93 diagnostic biopsy sets and 109 re-biopsy sets were included. The International Society of Urological Pathology 2005 Gleason scoring system was used for the histopathological assessment of all biopsies. Three different definitions of histopathological progression were applied. Unweighted and linear weighted Kappa (κ) statistics were used to compare the interobserver agreement. Results The overall Gleason score agreement was 68.8% with a weighted κ of 0.670. The interobserver agreement was 79.6% for meeting the AS selection criteria. According to the three progression definitions applied, overall agreement was between 80.7% and 89.0% with weighted κ values of 0.746-0.791. Treatment recommendations would have changed in up to 10.1% (95% confidence interval 5.4-17.7%) of the 109 re-biopsy sets. Conclusion Kappa statistics showed strong agreement between the histological evaluations. However, up to 10% of patients on AS would receive a different treatment recommendation depending upon which histopathological evaluation of re-biopsies was used for treatment planning. [ABSTRACT FROM AUTHOR]

The Role of KChIP2 in Heart Failure Introduction KV4 together with KV Channel-Interacting Protein 2 (KChIP2) mediate the fast recovering transient outward potassium current ( Ito,f) in the heart. KChIP2 is downregulated in human heart failure (HF), potentially underlying the loss of Ito,f. We investigated remodeling associated with HF hypothesizing that KChIP2 plays a central role in the modulation of outward K+ currents in HF. Methods and Results HF was induced by aortic banding in wild-type (WT) and KChIP2 deficient (KChIP2-/-) mice, evaluated by echocardiography. Action potentials were measured by floating microelectrodes in intact hearts. Ventricular cardiomyocytes were isolated and whole-cell currents were recorded by patch clamp. Left ventricular action potentials in KChIP2-/- mice were prolonged in a rate dependent manner, consistent with patch-clamp data showing loss of a fast recovering outward K+ current and upregulation of the slow recovering Ito,s and IKur. HF decreased all outward K+ currents in WT mice and did not change the relative contribution of Ito,f in WT mice. Compared to WT HF, KChIP2-/- HF had a larger reduction of K+-current density. However, the relative APD prolongation caused by HF was shorter for KChIP2-/- compared with WT, and the APs of the 2 HF mouse types were indistinguishable. Conclusion Ito,f is just one of many K+ currents being downregulated in murine HF. The downregulation of repolarizing currents in HF is accentuated in KChIP2-/- mice. However, the prolongation of APs associated with HF is less in KChIP2-/- compared to WT, suggesting other compensatory mechanism(s) in the KChIP2-/- mouse. [ABSTRACT FROM AUTHOR]

BACKGROUND Germ-cell cancer (GCC) patients aged ≥40 years have a two-fold higher GCC-specific mortality. It has been hypothesized that reduced treatment intensity combined with increased treatment related toxicity could be the explanation. The objective was to analyze chemotherapy intensity, treatment related toxicity and survival in patients aged ≥40 years treated with standard chemotherapy for GCC compared with a younger control group that received similar treatment during the same period. METHODS From 1984 to 2011, 135 patients aged ≥40 years with disseminated GCC treated with bleomycin, etoposide and cisplatin (BEP). A control-group of 135 patients aged 18-35 years was randomly selected matched on year of BEP treatment. Cumulated doses of BEP as well as bone marrow toxicity, renal- and lung functions were recorded before, during and after termination of treatment. All patients were followed until death or October 1, 2011. RESULTS The cumulated doses of BEP were comparable between the two groups, however, more patients aged ≥40 years were reduced in bleomycin doses based on a decrease in carbon monoxide diffusion capacity corrected for haemoglobin (P = 0.03). No differences between the two groups were found regarding bone marrow toxicity or mean percentage changes in lung- or renal function. Patients aged ≥40 year had increased cancer specific mortality, HR = 4.8 (P = 0.005). In particular patients with disease progression after first line chemotherapy had increased mortality (P = 0.015). Moreover, the 5-year overall survival for patients aged ≥40 years was 82.5% compared to the expected 5-year survival of the background population of 96.3% (P <0.001). CONCLUSIONS Treatment related toxicity could not explain the increased cancer specific mortality in patients aged ≥40 years compared to a younger control-group, and while there were no differences in the administrated doses of cisplatin/etoposide, a decreased number of bleomycin doses were administered in the older patients. Apart from this, the inferior prognosis could be related to tumour biology, increased co-morbidity, or more severe toxicity in relation to second line treatment. Cancer 2014;120:43-51. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Aim The murine electrocardiogram ( ECG) is a valuable tool in cardiac research, although the definition of the T wave has been a matter of debate for several years potentially leading to incomparable data. By this study, we seek to make a clear definition of the murine T wave. Moreover, we investigate the consequences of performing QT interval correction in anaesthetized mice. Methods Electrocardiograms from conscious mice were recorded by implanted telemetry devices. Surface ECGs were recorded from anaesthetized mice before and during pharmacological interventions, ventricular ischaemia and heart failure. Right atrial pacing was performed to evaluate the relationship between heart rate and QT intervals. Results Electrocardiogram traces of conscious and anaesthetized mice (lead II) showed separable positive J waves and negative T waves. The end of the T wave was determined as the point where the T wave returned to the isoelectric line. Atrial pacing revealed that the duration of the QT interval is independent of heart rate in anaesthetized mice. The calcium channel blocker, verapamil, prolonged the PR interval; however, the polarities of the J and T waves were not changed. Local cardiac ischaemia and β-adrenergic stimulation caused indistinguishable positive J and T waves. In contrast, chronic heart failure caused entirely negative J and T waves. In every case, the end of the T wave was clearly distinguishable on the ECG. Conclusion The end of the T wave is readily available from conscious and anaesthetized mice. Heart rate correction of QT interval duration in the anaesthetized mouse is not recommended. [ABSTRACT FROM AUTHOR]

Key points Previous studies have suggested that the K+ channel auxiliary subunit K+ channel-interacting protein 2 (KChIP2) serves as a regulator of cardiac remodelling leading to heart failure and increased risk of arrhythmias., The results presented here show that the progression of cardiac remodelling and heart failure induced by transverse aortic constriction follows a similar time course in wild-type and KChIP2−/− mice., Protein expression analysis shows that ventricular KChIP2 is significantly downregulated in heart failure in wild-type mice., The electrophysiological analysis reveals enlarged J and T wave amplitudes and lower vulnerability to pacing-induced ventricular arrhythmias in KChIP2−/− control mice compared to wild-type control mice. Heart failure in wild-type and KChIP2−/− mice prompted comparable prolongation of QT intervals and ventricular effective refractory periods., Collectively, these results demonstrate that KChIP2 does not influence the structural and functional development of heart failure. Moreover, in contrast to previously reported data, downregulation of KChIP2 expression in heart failure may reduce the risk of cardiac arrhythmia., Abstract Abnormal ventricular repolarization in ion channelopathies and heart disease is a major cause of ventricular arrhythmias and sudden cardiac death. K+ channel-interacting protein 2 (KChIP2) expression is significantly reduced in human heart failure (HF), contributing to a loss of the transient outward K+ current ( Ito). We aim to investigate the possible significance of a changed KChIP2 expression on the development of HF and proarrhythmia. Transverse aortic constrictions (TAC) and sham operations were performed in wild-type (WT) and KChIP2−/− mice. Echocardiography was performed before and every 2 weeks after the operation. Ten weeks post-surgery, surface ECG was recorded and we paced the heart in vivo to induce arrhythmias. Afterwards, tissue from the left ventricle was used for immunoblotting. Time courses of HF development were comparable in TAC-operated WT and KChIP2−/− mice. Ventricular protein expression of KChIP2 was reduced by 70% after 10 weeks TAC in WT mice. The amplitudes of the J and T waves were enlarged in KChIP2−/− control mice. Ventricular effective refractory period, RR, QRS and QT intervals were longer in mice with HF compared to sham-operated mice of either genotype. Pacing-induced ventricular tachycardia (VT) was observed in 5/10 sham-operated WT mice compared with 2/10 HF WT mice with HF. Interestingly, and contrary to previously published data, sham-operated KChIP2−/− mice were resistant to pacing-induced VT resulting in only 1/10 inducible mice. KChIP2−/− with HF mice had similar low vulnerability to inducible VT (1/9). Our results suggest that although KChIP2 is downregulated in HF, it is not orchestrating the development of HF. Moreover, KChIP2 affects ventricular repolarization and lowers arrhythmia susceptibility. Hence, downregulation of KChIP2 expression in HF may be antiarrhythmic in mice via reduction of the fast transient outward K+ current. [ABSTRACT FROM AUTHOR]

Aims To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2 years in patients with type 2 diabetes. Methods In the 26-week the Liraglutide Effect and Action in Diabetes ( LEAD)-2 core trial, patients (n = 1091) were randomized (2 : 2 : 2 : 1: 2) to liraglutide (0.6, 1.2 or 1.8 mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80 years old with HbA1c 7.0-11.0% (previous monotherapy ≥3 months), or 7.0-10.0% (previous combination therapy ≥3 months), and body mass index ≤40 kg/m2. Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. Results HbA1c decreased significantly with liraglutide (0.4% with 0.6 mg, 0.6% with 1.2 and 1.8 mg) versus 0.3% increase with metformin monotherapy (p < 0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9 kg with 0.6, 1.2 and 1.8 mg, respectively) compared to weight gain (0.7 kg) with glimepiride (p < 0.0001). Weight loss with liraglutide 1.2 and 1.8 mg was significantly greater than with metformin monotherapy (1.8 kg; p = 0.0185 and p = 0.0378 for 1.2 and 1.8 mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p < 0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. Conclusions Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes. In an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day ( n = 225), liraglutide 1.8 mg/day ( n = 221) or sitagliptin 100 mg/day ( n = 219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension. Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA from baseline (8.4-8.5%) to 52 weeks: −1.29% and −1.51% vs. −0.88% respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: −0.40% (95% confidence interval −0.59 to −0.22) for 1.2 mg and −0.63% (−0.81 to −0.44) for 1.8 mg (both p < 0.0001). Weight loss was greater with liraglutide 1.2 mg (−2.78 kg) and 1.8 mg (−3.68 kg) than sitagliptin (−1.16 kg) (both p < 0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p = 0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks. Liraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports. [ABSTRACT FROM AUTHOR]

Aims Patient-reported outcomes from clinical trials offer insight into the impact of disease on health-related quality of life, including treatment satisfaction. This patient-reported outcomes evaluation was a substudy of a 26-week randomized, open label trial comparing the once-daily injectable human GLP-1 analogue liraglutide with once-daily oral sitagliptin, both added to metformin. The patient reported outcomes substudy aimed to evaluate treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at baseline and 26 weeks. Methods In themain 26-week randomized, open-label study (n = 658), liraglutide, 1.2 or 1.8 mg, injected with a pen, led to greater HbA1c reduction than oral sitagliptin, 100 mg once daily, both added to metformin = 1500 mg daily: mean HbA1c reduction was 1.5, 1.2 and 0.9% (7, 10 and 14 mmol/ mol) for liraglutide 1.8 mg, 1.2 mg and sitagliptin, respectively (P < 0.0001 for both liraglutide doses vs. sitagliptin) and liraglutide patients lost more weight (3 vs.1 kg; P < 0.0001). In this patient-reported outcomes substudy (liraglutide 1.8 mg, n = 171; 1.2 mg, n = 164; sitagliptin, n = 170) DTSQ scores were analyzed by ANCOVA with treatment and country as fixed effects and baseline value as covariate. Results Overall treatment satisfaction, calculated by adding satisfaction scores for 'current treatment', 'convenience', 'flexibility', 'understanding', 'recommend', and 'continue', improved in all groups at 26 weeks; greater improvement with liraglutide (4.35 and 3.51 vs. 2.96; P = 0.03 for liraglutide 1.8 mg vs. sitagliptin) may reflect greater HbA1c reduction and weight loss. Patients perceived themselves to be hyperglycaemic significantly less frequently with liraglutide 1.8 mg (difference = )0.88; P < 0.0001) and 1.2 mg(difference = )0.49; P = 0.01). Perceived frequency of hypoglycaemiawas similar across all groups. Conclusions Injectable liraglutide may lead to greater treatment satisfaction than oral sitagliptin, potentially by facilitating greater improvement in glycaemic control, weight loss and/ or perception of greater treatment efficacy. [ABSTRACT FROM AUTHOR]

Introduction: High-rate pacing may have an inhibitory effect on the initiation of Torsade de Pointes arrhythmias (TdP). However, permanent pacing is only indicated in high-risk patients. We performed a proof of concept study into automatic overdrive pacing for prevention of drug-induced TdP, using short-term variability of repolarization (STV) as a feedback parameter of arrhythmic risk. Methods and Results: The minimal signal sampling frequency required for measuring STV was determined through computer simulation. Arrhythmogenic response to dofetilide (25 μg/kg/5minutes) was tested at two different paced heart rates (60-65 bpm vs 100-110 bpm) in 7 dogs with chronic atrioventricular block, while recording right and left ventricular (LV) monophasic action potential (MAP) and LV electrogram (EGM). Simulations showed a sampling frequency of 500 Hz is sufficient to capture relevant STV values. High-rate pacing prevented dofetilide-induced TdP seen at the low rate (low: 6/7 vs high: 1/7). At the low rate, STV from LV MAP duration increased before occurrence of spontaneous, ectopic activity and TdP (1.7 ± 0.6-3.0 ± 1.8 ms, P < 0.05), but at the high-rate STV did not change significantly (0.9 ± 0.2-1.5 ± 1.4 ms, NS). Regression analysis showed a close relation between STV calculated from LV MAP and from LV EGM (R= 0.71). Conclusions: High-rate pacing increases repolarization reserve in dogs with chronic atrioventricular block, preventing dofetilide-induced TdP. Changes in repolarization reserve are reflected in values of STV. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1384-1391, December 2010) [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 10.1111/j.1471-4159.2009.06544.x The brain forms a vascular barrier system comprised of the blood–brain barrier (BBB) and the blood–CSF barriers. Together they prevent the passage of a number of drugs from the bloodstream into the brain parenchyma, because their molecules are either hydrophilic, too large or both. In many disorders affecting the CNS, these barriers are physically intact, which limits the entry of large molecules with potentially important therapeutic implications. The BBB is the most relevant barrier against drug delivery to the brain as the area of the BBB is about 1000 times larger than that of the blood–CSF barrier. Moreover, the transport through the choroid plexus is directed to the ventricular system, only allowing the transported molecules to access cells near the ventricular and subarachnoid surfaces. This review outlines possible routes for targeted entry of macromolecules like polypeptides, siRNA and cDNA. In the vascular compartment, targeting molecules should interact specifically with proteins expressed exclusively by these barrier cells, and therefore prevent uptake elsewhere in the body. Preferably, the targeting molecule should be conjugated to a drug carrier that allows uptake of a defined cargo. However, evidence for transport of such targetable drug-carrier complexes through the barriers, in particular the BBB, is contentious, and is discussed with emphasis on the different attempts that have evinced transport through the BBB not only from blood-to-endothelium, but also from endothelium-to-brain. [ABSTRACT FROM AUTHOR]

Background: Most studies on trauma and trauma systems have been conducted in the United States. We aimed to describe the factors predicting mortality in European trauma patients, with focus on triage. Methods: We prospectively registered all trauma patients in Eastern Denmark over 12 consecutive months. We analysed the flow of trauma patients through the system, the time spent at different locations, and we assessed the risk factors of mortality. Results: We included 2875 trauma patients, of whom 158 (5.5%) died before arrival at the hospital. Most patients (75.3%) were brought to local hospitals and patients primarily ( n=82) or secondarily triaged ( n=203) to the level I trauma centre were the most severely injured. Secondarily transferred patients spent a median of 150 min in the local hospital before transfer to the level I trauma centre and 48 min on transportation. Severe injury with an injury severity score >15 was seen in 345 patients, of whom 118 stayed at the local hospital. They had a significantly higher mortality than 116 of those secondarily transferred [45/118, 38.1% vs. 11/116, 9.7% ( P<0.0001)]. Mortality within 30 days was 4.3% in admitted patients, and significant risk factors of death were violence [odds ratio (OR)=5.72], unconsciousness (OR=4.87), hypotension (OR=4.96), injury severity score >15 (OR=27.42), and age. Conclusions: Around 50% of all trauma deaths occurred at the scene. Increased survival of severely injured patients may be achieved by early transfer to highly specialised care. [ABSTRACT FROM AUTHOR]

The nociceptive trigeminal inhibitory (NTI) splint has been claimed to decrease the electromyographic (EMG) activity of jaw-closing muscles and relieve symptoms of various types of temporomandibular disorders (TMD) and bruxism. The present study was designed to address the question about EMG-changes during sleep. Ten patients (age: 23–39 years) with a self-report of tooth-grinding during sleep were recruited. Patients were examined at baseline and after each treatment period with the use of the Research Diagnostic Criteria for TMD. A portable EMG-device was used to record EMG-activity from the masseter muscle during sleep. The patients received two 2-week splint treatments in a randomized cross-over fashion; an NTI splint and a standard flat occlusal splint (OS). EMG data were analysed according to published criteria. Using a 10% of maximum clenching EMG-activity cut-off threshold to determine the number of EMG-events h−1 of sleep, the NTI splint was associated with a significant reduction (9·2 ± 3·2 events h−1) compared with baseline EMG (19·3 ± 4·0;anova: P = 0·004, Tukey post hoc: P = 0·006), whereas there were no differences between the OS (16·2 ± 4·7) and baseline EMG (19·2 ± 4·1; P = 0·716). There were no effects of either NTI or OS on clinical outcome measures (anovas: P > 0·194). This short-term study indicated a strong inhibitory effect on EMG-activity in jaw closing muscles during sleep of the NTI, but not the OS. However, the EMG-activity was not directly related to clinical outcome. Further studies will be needed to determine long-term effects and possible side effects of the NTI splint. [ABSTRACT FROM AUTHOR]

Background & purpose:The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects.Experimental approach & Key results:In transfected HEK cells, the IC50s for I hERG were 45±6 and 856±259 μg ml-1 for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg-1 moxifloxacin (total peak-plasma concentrations 4.6±1.5 and 22.9±6.8 μg ml-1) prolonged the QTc in 6 anaesthetized dogs with chronic AV block by 7±3 and 21±19%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.4±1.3 and 20.8±4.9 μg ml-1) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 μg kg-1 i.v.) caused QTc prolongation (29±15%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.8±0.7 to 3.8±1.5 ms; P<0.05).Conclusion & implications:As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.British Journal of Pharmacology (2006) 149, 1039–1048. doi:10.1038/sj.bjp.0706900; published online 6 November 2006 [ABSTRACT FROM AUTHOR]

Abstract: Background: In Denmark, opioids have been used liberally for many years in the treatment of non-malignant pain, but long-term consequences as tolerance and influence on health related quality of life remain unknown. Aim: Adherence to medical treatment, opioid dose escalation, health related quality of life, anxiety, depression, coping strategies and health care utilization were evaluated in chronic pain patients 10 years after treatment in a multidisciplinary pain centre. Methods: Information was gathered from medical records, postal questionnaires and a central hospital register. Results: Opioid dose escalation occurred in only a few patients. Increase and decrease in opioid dose were almost equally frequent. Sixty percent of those discharged on long acting opioids were still on that treatment at follow-up. Twenty-eight percent of the patients initiated opioid treatment after discharge from the pain centre. Occupational status was identified as a determining factor for future opioid use. Opioid users had a lower health related quality of life, higher occurrence of depression and more frequent use of coping strategies like ‘Catastrophizing’ and ‘Hoping and Praying’. Adjuvant analgesics were highly discontinued. Multidisciplinary pain treatment reduced the number of hospital admissions and in-hospital days. Conclusion: We recommend that future research on opioid treatment does not only focus on biological issues. The effect of opioids needs to be viewed in a much more complex context where consequences like health related quality of life, depression and the role of various coping strategies are included. [Copyright &y& Elsevier]

The rate of infusion has been suggested to be important for drug-induced torsades de pointes (TdP) arrhythmias. We investigated the repolarisation-prolonging effects and proarrhythmic properties of NS-7, a neuroprotective drug in development, using two different infusion rates.A fast (5?min intravenously (i.v.)) escalating dosing regimen (0.3 and 3.0?mg?kg-1, n=4) of NS-7 was investigated in anaesthetised control dogs in sinus rhythm (SR). This was compared to a slow infusion (60?min i.v.) of one dose (3.0?mg?kg-1, n=4) NS-7. The similar dosing regimens were investigated in anaesthetised dogs with chronic, complete AV block (CAVB), an animal model of TdP (n=6).No electrophysiological effects were seen after 0.3?mg?kg-1 NS-7. Fast infusion of 3.0?mg?kg-1 caused prolongation of repolarisation, for example, heart rate corrected QT interval (QTc): in SR: 6±1%; in CAVB: 10±7%, which was accompanied by TdP in three of six CAVB dogs. No TdP were seen in SR dogs.Slow infusion did not cause TdP in the same CAVB dogs, although NS-7 caused repolarisation to prolong with a similar magnitude (QTc: 12±7%) as in the fast-infusion experiment.Short-term variability (STV) is a novel parameter for the prediction of drug-induced TdP analysing the beat-to-beat variability of repolarisation. STV was only increased after the fast infusion in CAVB dogs (2.6±0.3 versus 6.0±1.4?ms, P<0.05), while there was no increase (2.1±0.2 versus 2.5±1.0?ms) after the slow infusion of NS-7.Peak plasma concentrations attained were lower in slow (0.5±0.1?µg?ml-1 after 50?min) than in fast-infusion regimen (2.1±0.4?µg?ml-1 after 5?min; P<0.05).The results support the conclusion that limiting peak plasma concentration by decreasing the rate of infusion of NS-7 reduces the proarrhythmic risk despite comparable prolongation in repolarisation parameters. The relevance of STV in predicting drug-induced TdP was confirmed.British Journal of Pharmacology (2005) 145, 397-404. doi:10.1038/sj.bjp.0706203 Published online 21 March 2005 [ABSTRACT FROM AUTHOR]

Minimally invasive parathyroid surgery in patients with primary hyperparathyroidism (PHPT) demands high imaging accuracy. By increasing blood flow to the parathyroid adenoma before injection of a perfusion marker, we intended to improve the parathyroid scintigraphy. We have named the technique stimulated parathyroid scintigraphy (SPS). Twenty minutes after injection of 100 MBq99mTc-pertechnetate a thyroid scintigram was performed in 25 patients with PHPT. During the thyroid scintigraphy sodium citrate was infused which lowered plasma calcium by a mean of 14 ± 1·3%. Then 700 MBq99mTc-sestamibi was injected and another scintigram of the neck was obtained. Perchlorate was given at the end of the sestamibi scintigram to increase the wash-out of99mTc-pertechnetate from the thyroid gland, and after 2 h a delayed scintigram was obtained. A subtraction of the thyroid scintigram from the initial sestamibi scintigram was performed. The results of SPS and a conventional99mTc-sestamibi dual-phase parathyroid scintigraphy were compared with the operative findings. In nine patients the parathyroid adenoma was also localized with ultrasound and the flow pattern before and after citrate infusion was visualized with Doppler technique. Eighty-eight per cent of the adenomas were localized correctly with the SPS technique compared with 62% at the conventional parathyroid scintigraphy. Tissue perfusion of the nine adenomas increased after citrate infusion. SPS has a high accuracy and it is easy to perform. If only subtraction SPS is performed the whole examination can be completed within an hour, which is acceptable for same day surgery. [ABSTRACT FROM AUTHOR]

The authors reflect on the contribution of human atrial fibroblasts in supraventricular arrhythmia. Topics discussed include the important functions of cardiac fibroblasts for keeping the three-dimensional structure of the heart, its effect on cardiac electrophysiology, and a study by C. Poulet and collegues on electrophysiological properties of human atrial fibroblasts.

Background: The clinical advantage of opioid rotation is probably due to incomplete cross-tolerance favouring analgesia more than adverse effects. The objectives of opioid rotation in chronic non-malignant patients are 1): rotation between different long-acting opioids (LAO) to improve analgesia and reduce side-effects, and 2): rotation from short-acting opioids (SAO) to LAO to establish stable analgesia in order to minimise withdrawal symptoms, risk of tolerance and addiction.Methods: A retrospective analysis of 37 rotations between different LAO and 59 rotations from SAO to LAO.Results: The main reason for opioid rotation was insufficient pain relief. Opioid rotations resulted in significantly better pain control in 59% (CI95=49-76%) of the patients rotated between different LAO and 73% (CI95=60-84%) of the patients rotated from SAO to LAO. During rotations symptoms of withdrawal and overdosing were relatively frequent in both groups. No significant dose changes were seen when rotating between different LAO. However, the consequence of rotation from SAO to LAO was a 74% increase in the opioid dose (CI95=30-117%).Conclusion: Opioid rotations between different LAO resulted in better pain control and fewer side-effects at dose levels predicted to be equianalgesic. The majority of the patients rotated from SAO to LAO obtained improved analgesia, but the cost was a 74% increase in the opioid dose. [ABSTRACT FROM AUTHOR]

In order to determine more precisely the location of the barley leaf stripe gene, called the 'Vada-resistance gene', on barley chromosome 2, 63 chromosome-doubled barley lines were tested. Using data on known chromosome 2 genetic markers, the 'Vada-resistance gene' was estimated to be located between the markers MSU21 and Xris45b. and at a distance of about 20% recombination from the powdery mildew resistance gene MILa. We suggest that the 'Vada-resistance gene' is designated Rdg 1a and that ali former leaf stripe resistance gene designations should be rejected. To identify possible new sources of resistance, 11 barley cultivars/lines known to possess leaf stripe resistance and originating from different parts of the world, were tested with one Danish and two Syrian isolates of the leaf stripe fungus. Three apparently genetically different sources of race-specific resistance were found. The 'Vada-resistance' in the cultivar 'Golf' was effective against seven out of eight isolates/ populations of the leaf stripe fungus differing in geographical origin. [ABSTRACT FROM AUTHOR]