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Biomedical subjects

R Arnold

Publications and source records attributed to R Arnold.

At least 19 recordsLinked to original sources
PubMed2006

Anti-endotoxin hyperimmune globulin attenuates portal cytokinaemia, phagocytic cell priming, and acute lung injury after lower limb ischaemia-reperfusion injury.

OBJECTIVES: Acute limb ischaemia is a common and often lethal clinical event. Reperfusion of an ischaemic limb has been shown to induce a remote gut injury associated with transmigration of endotoxin into the portal and systemic circulation, which in turn has been implicated in the conversion of the sterile inflammatory response to a sepsis syndrome, after lower torso ischaemia-reperfusion injury. This study tests the hypothesis that an anti-endotoxin hyperimmune globulin attenuates ischaemia-reperfusion (I/R) associated sepsis syndrome. DESIGN: Prospective, randomised placebo controlled trial, animal experiment. MATERIALS AND METHODS: Experimental porcine model, bilateral hind limb I/R injury, randomised to receive anti-endotoxin hyperimmune globulin or placebo. RESULTS: Bilateral hind limb I/R injury significantly increased intestinal mucosal acidosis, portal endotoxaemia, plasma cytokine (TNF-alpha, IL-6, IL-8) concentrations, circulating phagocytic cell priming and pulmonary leukosequestration, oedema, and capillary-alveolar protein leak. Conversely, pigs treated with anti-endotoxin hyperimmune globulin (IgG) 20mg/kg at onset of reperfusion had significantly reduced portal endotoxaemia, early circulating phagocytic cell priming, plasma cytokinaemia and attenuation of acute lung injury. CONCLUSIONS: Endotoxin translocation across a hyperpermeable gut barrier, phagocytic cell priming and cytokinaemia are key events of limb I/R injury induced systemic inflammation and acute lung injury. This study shows that an anti-endotoxin hyperimmune globulin attenuates portal endotoxaemia, which may reduce early phagocytic cell activation, cytokinaemia and ultimately acute lung injury.

Animals↗
PubMed2006

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation.

We studied monocytic differentiation of primary mouse progenitor cells to understand molecular mechanisms of differentiation. We found a tightly controlled non-apoptotic activation of caspase-3 that correlated with differentiation. Although caspase activity was already detected during monocytic differentiation, a caspase-3 target has not been identified yet. We show that hematopoietic progenitor kinase 1 (HPK1) is processed towards its N- and C-terminal fragments during monocytic differentiation. While HPK1 is an immunoreceptor-proximal kinase in T and B cells, its role in myeloid cells is elusive. Here, we show that the N-terminal cleavage product, HPK1-N, comprising the kinase domain, confers progenitor cell survival independent of the growth factor IL-3. Furthermore, HPK1-N causes differentiation of progenitor cells towards the monocytic lineage. In contrast to full-length kinase, HPK1-N is constitutively active causing sustained JNK activation, Bad phosphorylation and survival. Blocking of caspase activity during differentiation of primary mouse progenitor cells leads to reduced HPK1-N levels, suppressed JNK activity and attenuated monocytic differentiation. Our work explains growth factor-independent survival during monocytic differentiation by caspase-mediated processing of HPK1 towards HPK1-N.

Animals↗
PubMed2006

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Adolescent↗
PubMed2006

Prognostic value of N-terminal pro-B-type natriuretic peptide for conservatively and surgically treated patients with aortic valve stenosis.

OBJECTIVE: To evaluate the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with aortic stenosis being treated conservatively or undergoing aortic valve replacement (AVR). METHODS: 159 patients were followed up for a median of 902 days. 102 patients underwent AVR and 57 were treated conservatively. NT-proBNP at baseline was raised in association with the degree of severity and of functional status. RESULTS: During follow up 21 patients (13%) died of cardiac causes or required rehospitalisation for decompensated heart failure. NT-proBNP at baseline was higher in patients with an adverse outcome than in event-free survivors (median 623 (interquartile range 204-1854) pg/ml v 1054 (687-2960) pg/ml, p = 0.028). This difference was even more obvious in conservatively treated patients (331 (129-881) pg/ml v 1102 (796-2960) pg/ml, p = 0.002). Baseline NT-proBNP independently predicted an adverse outcome in the entire study group and in particular in conservatively treated patients (area under the curve (AUC) = 0.65, p = 0.028 and AUC = 0.82, p = 0.002, respectively) but not in patients undergoing AVR (AUC = 0.544). At a cut-off value of 640 pg/ml, baseline NT-proBNP was discriminative for an adverse outcome. CONCLUSION: NT-proBNP concentration is related to severity of aortic stenosis and provides independent prognostic information for an adverse outcome. However, this predictive value is limited to conservatively treated patients. Thus, the data suggest that assessing NT-proBNP may have incremental value for selecting the optimal timing of valve replacement.

Aged↗
PubMed2006

[Clinical significance of gastrooesophageal reflux in asthma].

In clinical practice, gastrooesophageal reflux (GER) and bronchial asthma often coincide. In the case of sufficient asthma control, the asthma does not need to be taken into account when treatment of GER is being evaluated. In patients with symptomatic asthma despite adequate antiasthmatic treatment, a possible causal relationship between GER and the poor responsiveness to asthma therapy has to be considered. An algorithm to guide the diagnostic and therapeutic steps in such cases is presented.

Asthma↗
PubMed2005

First results of the search for neutrinoless double-beta decay with the NEMO 3 detector.

The NEMO 3 detector, which has been operating in the Fréjus underground laboratory since February 2003, is devoted to the search for neutrinoless double-beta decay (beta beta 0v). The half-lives of the two neutrino double-beta decay (beta beta 2v) have been measured for 100Mo and 82Se. After 389 effective days of data collection from February 2003 until September 2004 (phase I), no evidence for neutrinoless double-beta decay was found from approximately 7 kg of 100Mo and approximately 1 kg of 82Se. The corresponding limits are T1/2(beta beta0v) > 4.6 x 10(23) yr for 100Mo and T1/2(beta beta 0v) > 1.0 x 10(23) yr for 82Se (90% C.L.). Depending on the nuclear matrix element calculation, the limits for the effective Majorana neutrino mass are < 0.7-2.8 e/v for 100Mo and < 1.7-4.9 eV for 82Se.

Journal Article↗
PubMed2005

Cardiac angiosarcoma: case report and review of the literature.

Angiosarcoma of the heart, the most common primary malignant cardiac tumor in adults is known to carry a dismal prognosis. The diagnosis is often delayed because of the nonspecific clinical presentation. Symptoms are determined by the size and location of the tumor. Echocardiography has become the primary diagnostic technique because of its high degree of accuracy, noninvasiveness, and cost effectiveness. Complete surgical resection is required for improved survival. Conventional postoperative chemotherapy does not appear to modify the clinical course. We report a case of cardiac angiosarcoma with a large mural mass infiltrating the right atrial and ventricular walls and critically review the pertinent literature.

Female↗
PubMed2005

Endocrine tumours of the gastrointestinal tract. Introduction: definition, historical aspects, classification, staging, prognosis and therapeutic options.

Synonyms for gastroenteropancreatic endocrine tumours are 'endocrine tumours' and 'neuroendocrine tumours', and for pancreatic tumours 'islet cell tumours'. The term 'carcinoid' should only be used for endocrine tumours of the gastrointestinal tract and not for those of the pancreas. Endocrine tumours should be classified according to a recent World Health Organization proposal that provides clinically and prognostically important information. The prognosis of well-differentiated endocrine tumours is variable and, in general, favourable. However, we have few histological data from which to predict tumour growth and long-term prognosis in well-differentiated tumours. Poorly differentiated, small-cell tumours have an unfavourable prognosis. Patients with endocrine tumours have an increased risk of developing synchronous and metachronous non-endocrine malignancies. Most current treatment options are not supported by prospective, randomised and controlled trials.

Carcinoma, Neuroendocrine↗
PubMed2005

Endocrine tumours of the gastrointestinal tract: Chemotherapy.

Malignant neuroendocrine tumours are less sensitive to chemotherapy than other epithelial malignancies. If chemotherapy is considered, tumours of pancreatic origin have a higher sensitivity than tumours from the gastrointestinal tract ('carcinoids'). Chemotherapy with streptozocin combinations and with dacarbazine should be considered in patients with progressive malignant neuroendocrine tumours of the pancreas. A favourable response to chemotherapy can be expected in up to 60% of patients receiving a combination of streptozocin plus doxorubicin, and in up to 40% of patients receiving dacarbazine. A survival benefit has been shown for streptozocin combinations. Treatment regimens are effective in functioning and non-functioning tumours. The response to treatment cannot be predicted. Poorly differentiated neuroendocrine tumours, independent of their origin, respond to a combination of etoposide plus cisplatin. Chemotherapy is, however, almost ineffective in patients with well-differentiated neuroendocrine tumours originating in the gastrointestinal tract ('carcinoids').

Antibiotics, Antineoplastic↗
PubMed2005

Autologous hematopoietic stem cell transplantation for autoimmune diseases.

Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86+/-4% at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7+/-3% at 3 years) or disease progression (N=22; 9+/-4% at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71% of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57-6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11-0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96-3.42)); low intensity, RR2.34 (1.074-5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.

Autoimmune Diseases↗
PubMed2005

Survival after reduced-intensity conditioning is not inferior to standard high-dose conditioning before allogeneic haematopoietic cell transplantation in acute leukaemias.

To assess the role of allogeneic stem cell transplantation (SCT) after reduced-intensity conditioning (RIC) in acute leukaemias, we retrospectively compared 25 patients with acute lymphoblastic leukaemia or acute myelogenous leukaemia after RIC to a historical group of 50 matched controls after high-dose conditioning. Engraftment, acute GvHD and severe infections were comparable in both groups. During the observation period, 1/25 patients (4%) after RIC and 14/50 (28%) after standard SCT died due to transplant-related causes; cumulative nonrelapse mortality (NRM) was 4% after RIC and 24% after standard SCT (P=0.029). In total, 15/25 patients (60%) relapsed after RIC and 20/50 (40%) after standard SCT; probability of disease-free survival (DFS) at 3 years was 43% after RIC and 49% after standard SCT (NS). Overall survival (OS) was 40% after RIC and 37% after standard SCT (NS). Stage of disease, cytogenetic risk profile, acute and chronic GvHD, chimerism status at day 90 and severe infections after transplantation were risk factors with significant impact on DFS and/or OS. In retrospective analysis, patients with acute leukaemias who receive RIC because of contraindications against standard SCT have a comparable outcome to standard SCT, but the higher relapse rate warrants further studies.

Acute Disease↗
PubMed2005

[Multidetector CT for the diagnosis of congenital vascular anomalies and associated complications in newborns and infants].

PURPOSE: To assess the value of multidetector CT (MDCT) for evaluation of vascular anomalies (VA) and associated complications in newborns and infants. MATERIALS AND METHODS: Seventy-five children (mean age: 9 +/- 6 months, range: 2 weeks to 24 months) with VA were examined using MDCT (4-, 8- or 16-row; collimation 0.5-1.25 mm; scan time 7-30 s), which was performed under controlled ventilation or free breathing. Image quality was rated using a 5-point scale. Image findings were correlated to echocardiography, conventional catheter angiography (CCA), bronchoscopy, and intraoperative findings. RESULTS: High quality MDCT data were almost free of cardiac and respiratory motion. In all cases, VA morphology and topography in relation to adjacent structures, e. g. tracheal and esophageal compression caused by an aortic ring, could be assessed exactly and allowed the final diagnosis. Even aberrant vessels, such as aorto-pulmonary collaterals (MAPCA) with a diameter of less than 1 mm, could be identified and excellently visualized. Eighty percent (60/75) of all patients had benefited from the MDCT: in 31 patients CCA was neither necessary to perform surgical planning nor to exclude a VA; in an additional 29 patients radiation doses and sedation time due to interventional procedures could be reduced markedly. CONCLUSIONS: MDCT can now be regarded as the modality of choice as a minimally invasive, robust, and accurate technique for the diagnosis of complex VA, their potentially life-threatening complications and preoperative planning even in newborns and infants. Its accuracy for detecting VA appears equivalent to CCA while it is more accurate in delineating potential life-threatening complications.

Arteriovenous Malformations↗
PubMed2005

Ghrelin-induced stimulation of colonic propulsion is dependent on hypothalamic neuropeptide Y1- and corticotrophin-releasing factor 1 receptor activation.

Peptides participating in the hypothalamic control of feeding behaviour are also involved in the central autonomic control of gastrointestinal functions, such as secretion and motility. An anatomical interaction and functional relationship in the central nervous system between the feeding-related peptides neuropeptide Y and ghrelin is well documented. Furthermore, it has been shown that feeding-related peptides can influence digestive function via central corticotrophin-releasing factor (CRF) pathways. In the present study, we investigated the role of ghrelin in the central autonomic control of colonic motility. Furthermore, we addressed the hypothesis that ghrelin is involved in the hypothalamic control of colonic motor function, utilizing central neuropeptide Y receptors and hypothalamic CRF pathways. Ghrelin (0.03, 0.06 and 0.12 nmol) bilaterally microinjected into the paraventricular nucleus (PVN) induced a significant stimulation of colonic propulsion. In particular, the colonic transit time decreased from 312+/-7 min to 198+/-12 min. Microinjection of the neuropeptide Y1 receptor antagonist, BIBP-3226 (200 pmol), or the nonselective CRF receptor antagonist, astressin (30 pmol), into the PVN abolished the stimulatory effect of ghrelin injected into the PVN on colonic transit time, whereas pretreatment with the selective CRF2 receptor, antisauvagine-30 (28 pmol), failed to affect the effect of PVN-ghrelin injection on colonic propulsion. These results suggest that ghrelin can act as central modulator of gastrointestinal motor functions at the level of the PVN via neuropeptide Y1- and CRF1 receptor-dependent mechanisms.

Animals↗