Age,severe comorbidity and functional impairment independently contribute to poor survival in cancer patients

Purpose With the increasing number of elderly patients suffering from cancer, comorbidity and functional impairment become common problems in patients with cancer. Both comorbidity and functional impairment are associated with a shorter survival time in cancer patients, but their independent role has rarely been addressed before. Methods Within a prospective trial we recruited 427 cancer patients, irrespective of age and type of cancer, admitted as inpatients prior to the start of chemotherapy. Comorbidity was assessed with the cumulative illness rating scale (CIRS-G), functional impairment with WHO performance status (WHO-PS), basal (ADL) and instrumental (IADL) activities of daily living. Results Median follow-up was 34.2 months. A total, 61.4%. of patients died. Median survival time was 21.0 months. Age, kind of tumour (solid vs. haematological), treatment approach (non-curative vs. curative), WHO-PS (2–4 vs. 0–1), IADL (<8 vs. 8), and severe comorbidity (CIRS-level 3–4 vs. none) were significantly associated with shorter survival time in univariate analysis. In a multivariate Cox-regression-analysis, age (HR 1.019; 95%-CI 1.007–1.032; P = 0.003), kind of tumour (HR 1.832; 95%-CI 1.314–2.554; P < 0.001), WHO-PS (HR 1.455; 95%-CI 1.059–2.000; P = 0.021), and comorbidity level 3–4 (HR 1.424; 95%-CI 1.012–2.003; P = 0.043) maintained their significant association. Conclusions Age, severe comorbidity, functional impairment, and kind of tumour are independently related to shorter survival time in cancer patients.     

Monomeric G protein-coupled receptor rhodopsin in solution activates its G protein transducin at the diffusion limit

G protein-coupled receptors mediate biological signals by stimulating nucleotide exchange in heterotrimeric G proteins (Galphabetagamma). Receptor dimers have been proposed as the functional unit responsible for catalytic interaction with Galphabetagamma. To investigate whether a G protein-coupled receptor monomer can activate Galphabetagamma, we used the retinal photoreceptor rhodopsin and its cognate G protein transducin (G(t)) to determine the stoichiometry of rhodopsin/G(t) binding and the rate of catalyzed nucleotide exchange in G(t). Purified rhodopsin was prepared in dodecyl maltoside detergent solution. Rhodopsin was monomeric as concluded from fluorescence resonance energy transfer, copurification studies with fluorescent labeled and unlabeled rhodopsin, size exclusion chromatography, and multiangle laser light scattering. A 1:1 complex between light-activated rhodopsin and G(t) was found in the elution profiles, and one molecule of GDP was released upon complex formation. Analysis of the speed of catalytic rhodopsin/G(t) interaction yielded a maximum of approximately 50 G(t) molecules per second and molecule of activated rhodopsin. The bimolecular rate constant is close to the diffusion limit in the diluted system. The results show that the interaction of G(t) with an activated rhodopsin monomer is sufficient for fully functional G(t) activation. Although the activation rate in solution is at the physically possible limit, the rate in the native membrane is still 10-fold higher. This is likely attributable to the precise orientation of the G protein to the membrane surface, which enables a fast docking process preceding the actual activation step. Whether docking in membranes involves the formation of rhodopsin dimers or oligomers remains to be elucidated.     

Neue Versorgungsstrukturen für Patienten mit chronischer Herzinsuffizienz

Frequency of chronic heart failure still increases. More and more resources have been required for the diagnosis and therapy of this disease. This burden for health-care systems will grow in the near future. In particular, clinical treatment has a major impact. New approaches are essential to ensure an efficient supply of patients with chronic heart failure in the next years.Models to improve the supply give the opportunity to optimize the medical workflow and involve the patient into the concept of care. Therefore, a variety of models have been developed and up to now tested concerning benefit and applicability in western industrial countries. The present article focuses on the fundamental models to improve the supply of patients with chronic heart failure.     

Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, and new alternative treatments are needed. AIMS: To comparatively test the angiostatic and antitumour effects of adenoviral gene transfer of angiostatin (PlgK1-4, amino acids 1-440) and full kringles 1-5 (PlgK1-5, amino acids 1-546) in a model of subcutaneously transferred HCC in mice. METHODS: PlgK1-4 and PlgK1-5 were generated from human WtPlg cDNA and used for adenovirus construction. Vector function and angiostatic effects were confirmed in vitro and in vivo. Antitumoral efficacies of intratumoral vector injections were studied in a model of subcutaneously transferred HCC model. RESULTS: Cell supernatants containing PlgK1-4 and PlgK1-5 reduced endothelial tube formation in vitro by about 30%, whereas WtPlg exerted no inhibitory effect. Endothelial cell infiltration in vivo was decreased by about 60%, but not in AdWtPlg-treated animals. Intratumoral treatment of subcutaneous HCC tumours inhibited growth by 40% for AdPlgK1-4 and 63% for AdPlgK1-5 in surviving mice 12 days after initiation of treatment, whereas treatment with AdWtPlg even led to accelerated growth. Although PlgK1-4 and PlgK1-5 have similar inhibitory effects on intratumoral microvessels, PlgK1-5 markedly improved the survival time compared with PlgK1-4. CONCLUSION: PlgK1-5 and PlgK1-4 effectively inhibited HCC growth. As PlgK1-5 could also prolong the survival time, inducing complete tumour elimination in half of the AdPlgK1-5-treated mice, PlgK1-5 might be the most potential plasminogen fragment for treatment of experimental HCC.     

Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization

Mutations in the spatacsin gene have recently been identified as the genetic cause of autosomal–recessive spastic paraplegia (SPG) with thin corpus callosum, mapping to chromosome 15p13–21. While several nonsense and frameshift mutations as well as splice mutations have been identified, large genomic deletions have not yet been found, potentially due to the absence of an efficient analysis tool. After complete sequencing of 12 autosomal recessive hereditary spastic paraplegia patients with suggestive clinical signs, we were able to define nine SPG11 cases but were left with three patients in which only one SPG11 mutation could be identified by direct sequencing. In these patients, we performed high-resolution comparative genomic hybridization using a predesigned human chromosome 15 tiling array with an average spacing of 100 bp. Data analysis suggested heterozygous genomic deletion within the spatacsin gene in all three patients. In one patient, a relatively small genomic deletion (8.2 kb) could be validated by quantitative polymerase chain reaction (PCR) and long-range PCR, allowing the diagnosis of the deletion of exons 31 through 34. For two patients, quantitative PCR validation could not confirm a genomic deletion. As high density tiling arrays are available for the entire human genome, we suggest this approach for the screening of heterozygous genomic deletions in candidate genes down to a few kilobases.     

Nocturnal pulse wave attenuation is associated with office blood pressure in a population based cohort

Objective and BackgroundPulse wave amplitude (PWA) derived from the digital vascular bed has been used in sleep studies. The nocturnal attenuation of PWA has been shown to reflect sympathetic activation during sleep. We assessed the relationship between nocturnal PWA attenuation and office blood pressure (BP).MethodsEighty-one subjects (46 men; age 60 ± 7 years; body mass index [BMI] 28.2 ± 4.3 kg/m²; apnea hypopnea index [AHI], 25.4 ± 22.6 events/h; systolic BP 137 ± 15 mmHg; diastolic BP 79 ± 7 mmHg) recruited from a population based cohort underwent simultaneous ambulatory polysomnography (PSG) and peripheral arterial tonometry (PAT) recording. Episodic attenuations of PWA derived from the pulse waveform of the PAT signal were identified and characterized. Generalized least squares regression models were used to identify the associations between median PWA attenuation (PWA.att), office BP and sleep-related disordered breathing.ResultsWe found that the association between PWA.att and office BP was independent of gender, age, BMI, antihypertensive medication, number of attenuation episodes, AHI, oxygen desaturation ?4% index (ODI4) and arousal index. Each 10% increase in PWA.att was associated with increases of 5.0 mmHg systolic BP (P = 0.02) and 3.0 mmHg diastolic BP (P = 0.005). We also found independent relationships between systolic/diastolic BP and BMI (P = 0.0006/0.001), AHI (P = 0.03/0.1) and ODI4 (P = 0.03/0.03).ConclusionsThe degree of PWA attenuation during the night is associated with office BP independent of sleep-disordered breathing. Continuous assessment of PWA during sleep may provide novel insights into cardiovascular physiology and morbidity.