Alternating gemcitabine plus nab-paclitaxel and gemcitabine alone versus continuous gemcitabine plus nab-paclitaxel after induction treatment of metastatic pancreatic cancer (ALPACA): a multicentre, randomised, open-label, phase 2 trial.

Background: A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination.

Methods: ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany.

Subgroup analyses from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial.

Background: In the pivotal phase III RECOURSE trial, trifluridine/tipiracil (FTD/TPI) improved progression-free and overall survival (PFS, OS) of patients with pre-treated metastatic colorectal cancer (mCRC). Subsequently, the TALLISUR trial provided post-authorisation efficacy and safety data and patient-reported outcomes on quality of life (QoL) in a German patient cohort. The present analysis reports the final data on efficacy, safety and QoL and investigates the impact of baseline characteristics and associated prognostic subgroups on outcome.

Autonomic nervous system responses in the intermediate band to cranial cutaneous stimulation.

Cardiovascular rhythms representing functional states of the autonomic nervous system (ANS) are insufficiently reflected by the current physiological model based on low and high frequency bands (LF, HF, resp.). An intermediate (IM) frequency band generated by a brainstem pacemaker was included in systemic physiological ANS analyses of forehead skin perfusion (SP), ECG, and respiration.

On the cardiorespiratory coordination assessed by the photoplethysmography imaging technique.

Cardiorespiratory coordination (CRC) probes the interaction between cardiac and respiratory oscillators in which cardiac and respiratory activity are synchronized, with individual heartbeats occurring at approximately the same temporal positions during several breathing cycles. An increase of CRC has previously been related to pathological stressful states. We studied CRC employing coordigrams computed from non-contact photoplethysmography imaging (PPGI) and respiratory data using the optical flow method.

Validation of subjective manual palpation using objective physiological recordings of the cranial rhythmic impulse during osteopathic manipulative intervention.

Intermediate (IM) band physiology in skin blood flow exhibits parallels with the primary respiratory mechanism (PRM) or cranial rhythmic impulse (CRI), controversial concepts of osteopathy in the cranial field (OCF). Owing to inconsistent manual palpation results, validity of evidence of PRM/CRI activity has been questionable. We therefore tried to validate manual palpation combining instrumented tracking and algorithmic objectivation of frequencies, amplitudes, and phases.

Efficacy, safety and quality-of-life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial.

Introduction: Trifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted.

Neural correlates of fluctuations in the intermediate band for heart rate and respiration are related to interoceptive perception.

Supratentorial brain structures such as the insula and the cingulate cortex modulate the autonomic nervous system (ANS). The neural underpinnings of separate frequency bands for variability in cardiac and respiratory data have been suggested in explaining parasympathetic and sympathetic ANS modulation. As an extension, an intermediate (IM) band in peripheral physiology has been considered to reflect psychophysiological states during rest.

Vkorc1 sequencing suggests anticoagulant resistance in rats in New Zealand.

Background: Anticoagulant toxins are used globally to control rats. Resistance of Rattus species to these toxins now occurs in at least 18 countries in Europe, America and Asia. Resistance is often associated with single nucleotide polymorphisms (SNPs) in the Vkorc1 gene.

[Rodenticide resistance and consequences].

Resistance to anticoagulant rodenticides, such as warfarin was first described in 1958. Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene and respective substitutions of amino acids in the VKOR enzyme are the major cause for rodenticide resistance. Resistant Norway rats in Germany are characterized by the Tyr139Cys genotype, which is spread throughout the northwest of the country.

The repelling effect of plant secondary metabolites on water voles, Arvicola amphibius.

Background: Water voles (Arvicola amphibius Linnaeus 1758) are abundant in most parts of Germany and other European countries. They are known to cause serious damage in fruit and horticulture as well as in agriculture. Currently available repellents, scaring devices and household remedies are mostly inefficient.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration.

Distribution of rodenticide resistance and zoonotic pathogens in Norway rats in Lower Saxony and Hamburg, Germany.

Background: Genetically based resistance to anticoagulants has led to increasing difficulties in the control of rodents over recent decades. The possible impact of rodenticide-resistant rats on the infection risk of humans and livestock by zoonotic pathogens is generally unknown. Hence, in a monitoring programme in the German federal states of Lower Saxony and Hamburg, more than 500 Norway rats were analysed for both Tyr139Cys polymorphisms within the VKORC1 gene and zoonotic agents.

Vitamin K requirement and reproduction in bromadiolone-resistant Norway rats.

Background: Nucleotide polymorphisms in the VKORC1 gene can be linked to anticoagulant rodenticide resistance in Norway rats (Rattus norvegicus Berkenhout). This provides a fitness advantage to rats exposed to anticoagulant actives, but may also cause fitness costs. The vitamin K requirement and reproductive parameters of bromadiolone-resistant rats (Westphalian resistant strain; VKOR variant Tyr139Cys) and bromadiolone-susceptible Norway rats were compared.

Distribution and frequency of VKORC1 sequence variants conferring resistance to anticoagulants in Mus musculus.

Background: Emerging resistance to anticoagulant rodenticides may significantly impair house mouse (Mus musculus L.) control. As in humans and rats, sequence variants in the gene vitamin K epoxide reductase complex subunit 1 (VKORC1) of house mice are strongly implicated in the responses of mice to anticoagulants.

A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats.

BACKGROUND: The inhibition of the vitamin K cycle by warfarin promotes arterial calcification in the rat. Conceivably, genetically determined vitamin K-deficiency owing to a mutant epoxide reductase subcomponent 1 (Vkorc1) gene, a key component of the vitamin K cycle, might also promote arterial calcification. In the absence of an available Vkorc1 gene knockout model we used a wild-derived Vkorc1 mutant rat strain (Rattus norvegicus) to explore the validity of this hypothesis.

Novel mutations in the VKORC1 gene of wild rats and mice--a response to 50 years of selection pressure by warfarin?

Background: Coumarin derivatives have been in world-wide use for rodent pest control for more than 50 years. Due to their retarded action as inhibitors of blood coagulation by repression of the vitamin K reductase (VKOR) activity, they are the rodenticides of choice against several species. Resistance to these compounds has been reported for rodent populations from many countries around the world and poses a considerable problem for efficacy of pest control.

Network "Rodent-borne pathogens" in Germany: longitudinal studies on the geographical distribution and prevalence of hantavirus infections.

Hantavirus infections are known in Germany since the 1980s. While the overall antibody prevalence against hantaviruses in the general human population was estimated to be about 1-2%, an average of 100-200 clinical cases are recorded annually. In the years 2005 and 2007 in particular, a large increase of the number of human hantavirus infections in Germany was observed.

The genetic basis of resistance to anticoagulants in rodents.

Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin (e.

Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.

Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors.

Locus-specific genetic differentiation at Rw among warfarin-resistant rat (Rattus norvegicus) populations.

Populations may diverge at fitness-related genes as a result of adaptation to local conditions. The ability to detect this divergence by marker-based genomic scans depends on the relative magnitudes of selection, recombination, and migration. We survey rat (Rattus norvegicus) populations to assess the effect that local selection with anticoagulant rodenticides has had on microsatellite marker variation and differentiation at the warfarin resistance gene (Rw) relative to the effect on the genomic background.

A scheme for the placement of rodenticide baits for rat eradication on confinement livestock farms.

We investigated whether the allocation of rodenticide baiting points to specific structural elements would result in complete rat eradication on livestock farms, as opposed to assigning the baiting points only to places where there were obvious signs of rat activity. The goal was to establish an effective rodent-control program that is easy for untrained persons to conduct.Rat-control strategies were examined on 25 farms in Velen (Muensterland), Germany, where an average of 20% of trapped rats were resistant for bromadiolone according to a blood-clotting response (BCR) test.

A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans.

The locus underlying hereditary resistance to the anticoagulant warfarin (symbol in the rat, Rw) was placed in relation to 8 positionally mapped gene-anchored microsatellite loci whose positions were known in the genome maps of the rat, mouse, and human. Rw segregated with the markers Myl2 (zero recombinants) and Itgam, Il4r, and Fgf2r (one recombinant each) during linkage analysis in a congenic warfarin- and bromadiolone-resistant laboratory strain of rats. Comparative ortholog mapping between rat, mouse, and human placed Rw onto mouse chromosome 7 at about 60 to 63 cM and onto one of the human chromosomes 10q25.

Natural selection mapping of the warfarin-resistance gene.

In theory, genes under natural selection can be revealed by unique patterns of linkage disequilibrium (LD) and polymorphism at physically linked loci. However, given the effects of recombination and mutation, the physical extent and persistence of LD patterns in natural populations is uncertain. To assess the LD signature of selection, we survey variation in 26 microsatellite loci spanning an approximately 32-cM region that includes the warfarin-resistance gene (Rw) in five wild rat populations having resistance levels between 0 and 95%.

Genomic assignment of the warfarin resistance locus, Rw, in the rat.

The locus responsible for resistance to the anticoagulants warfarin and bromadiolone (locus symbol Rw) was integrated into the rat (Rattus norvegicus) microsatellite genome map. Seventh-generation offspring of a segregating strain of rats heterozygous resistant to both compounds were tested with a blood-clotting-response (BCR) test. No recombination between resistance to warfarin and bromadiolone was observed, indicating a common genetic basis.