The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921).

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.     

Chy-3 mice are Vegfc haploinsufficient and exhibit defective dermal superficial to deep lymphatic transition and dermal lymphatic hypoplasia.

Recent advances in molecular lymphology and lymphatic phenotyping techniques in small animals offer new opportunities to delineate mutant mouse models. Chy-3 mutant mice were originally named for their chylous ascites, but the underlying lymphatic disorder was not defined. We now re-examined these mice and applied advanced genotyping and lymphatic phenotyping techniques to pinpoint the specific lymphatic defect in this mouse model. We demonstrated that Chy-3 mice carry a large chromosomal deletion that includes Vegfc and narrowed this region by monitoring the heterozygosity of genetic markers. We found that Chy-3 mice not only exhibited chylous ascites but also lymphedema of the hind paws and, in approximately half of the males, lymphedema of the penis. Visual lymphangiography and immunofluorescence staining showed a hypoplastic dermal lymphatic network, whereas the blood vasculature appeared unaffected. This hypoplastic lymphatic network was functional, and all adult Chy-3 mice exhibited a lateral lymphatic pathway directly connecting the inguinal to the axillary lymph node. The dermal superficial to deep lymphatic connections in upper limbs and in all cervical regions were intact and functionally drained the upper body. Lymphatic tracer was not transported from the dermal to the deep truncal lymphatic system in the lower limbs, even though the deep lymphatic vessels and nodes were present and patent. These findings further delineate the lymphatic phenotype of Chy-3 mice, identify a collateral lymph drainage pathway previously undescribed in other genetic models of lymphedema, and demonstrate a predilection for lymphatic abnormalities of the lower limbs.     

Projektauswahl und Protokollerstellung im Studienzentrum der Deutschen Gesellschaft für Chirurgie

BACKGROUND: The Study Centre of the German Surgical Society (SDGC) designs, conducts, and analyses multicentre randomised controlled surgical trials. The aim of this paper is to present the decision-making process and responsibilities of the SDGC from submission of a study idea to full protocol development in order to achieve transparency in trial selection. METHODS: The process is divided into four steps. Study ideas can be submitted electronically by members of the German Surgical Society using a form via the homepage of the institution. Firstly, ideas are screened by staff members within 4 weeks for methodological and clinical relevance. Feasible and novel ideas are then converted to trial outlines in cooperation with the submitting surgeon. As a third step, the Steering Committee of the SDGC decides whether to accept the project using a list of defined criteria. Finally, the SDGC draws up a full protocol together with the submitting surgeon. All ideas and decisions are accessible via the SDGC homepage. CONCLUSIONS: The process described should help in the selection of relevant projects, acquisition of grants, and maintenance of transparency in trial selection and the protocol development process.     

The Cathlocator: A novel non-radiological method for the localization of enteral tubes

Safe placement of nasogastric tubes requires reliable positioning of the tip of the tube within the stomach. Radiology and aspiration are currently used to confirm tube position, but suffer from significant problems of cost and efficacy, respectively. We have developed a novel method to locate the position of a catheter tip within the body, using the detection of a low energy electromagnetic field generated in a coil located in the catheter with an external hand-held unit (Cathlocator). In vitro, the unit detected the distance of the coil from the detector with an accuracy of 0.1 cm over a range of 4–12 cm. In vivo studies were performed in 11 healthy volunteers using a purpose-built manometric assembly that incorporated the signal generating coil in its tip. In all subjects the Cathlocator showed the position of the signal generating coil to be cranial to the xiphisternum when manometric and transmucosal potential difference criteria showed it to be located above the lower oesophageal sphincter. When the coil was within the stomach, the Cathlocator identified its position within the epigastric, umbilical and left hypochondrial regions of the abdomen. The distance of the coil from the surface was significantly greater when in the duodenum mean (±s.e.m. 7.6±0.3 cm; P<0.001) and oesophagus (8.6±0.2 cm; P<0.002) than the stomach (5.0±0.4 cm). In one subject studied twice there was a close correlation between the location and depth measured by the device on each occasion. The Cathlocator is a novel non-radiological device that has the potential to be useful in the placement of gastrointestinal catheters.     

Recombinant human interferon-alpha induced cytoreduction in chronic myelogenous leukemia

Summary Fourteen patients with Ph'-chromosome positive chronic myelogenous leukemia (CML) in first chronic phase were treated with recombinant interferon-_2c. Interferon-_2c 5 to 10×10⁶ units s.c. was given for 12 weeks as an induction therapy. Maintenance treatment consisted of interferon-_2c 5 × 10⁶ units twice weekly s.c.. Two patients (14%) attained a complete clinical remission and 6 (43%) a partial remission, 3 of whom developed progressive disease during maintenance therapy. A complete disappearance of Ph'-chromosome was achieved in 1 patient. All patients had a more than 45% initial decline of the leukocyte count. Four out of ten patients with an initially enlarged spleen demonstrated reduction in spleen size. Influenza-like symptoms, anorexia, nausea, weight loss and fatigue were common side effects. Interferon-alpha is active in CML but additional clinical investigations are warranted to assess more precisely the therapeutic value of the interferons in this disease.     

New spectral detection and elimination test algorithms of ECG and EOG artefacts in neonatal EEG recordings

New methods for the detection of ECG and EOG artefacts in the EEG are introduced, which can also be used for the evaluation of the quality of the elimination procedure. These algorithms are based on the estimation of the power or coherence spectrum by means of FFT. The advantage of this method is that the EEG spectrum is monitored by the test algorithm. The spectrum will be plotted if no influence of the ECG and EOG can be found. On the other hand, if artefacts are detected the correction of the EEG time series will be carried out and the spectrum of the corrected EEG time series will be plotted after repeated monitoring by the test algorithm.     

Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary–adrenal axis

Synthetic glucocorticoids are administered to pregnant women in premature labour to accelerate fetal lung maturation at a time when fetal cerebrovascular and endocrine systems are maturing. Exposure to glucocorticoids at 0.8–0.9 of gestation increases peripheral and cerebrovascular resistance (CVR) in fetal sheep. We examined whether the increase of CVR and its adverse effect on cerebral blood flow (CBF) depend on the current level of maturation of the pituitary–adrenal axis and the cerebrovascular system. Using fluorescent microspheres, regional CBF was measured in 11 brain regions before and 24 h and 48 h after the start of 3.3 μg kg⁻¹ h⁻¹ betamethasone ( n = 8) or vehicle ( n = 7) infusions to fetal sheep at 0.73 of gestation. Hypercapnic challenges were performed before and 24 h after the onset of betamethasone exposure to examine betamethasone effects on cerebrovascular reactivity. Betamethasone exposure decreased CBF by approximately 40% in all brain regions after 24 h of infusion ( P < 0.05). The decline in CBF was mediated by a CVR increase of 111 ± 16% in the cerebral cortex and 129 ± 29% in subcortical regions ( P < 0.05). Hypercapnic cerebral vasodilatation and associated increase in CBF were blunted ( P < 0.05). Fetal CBF recovered after 48 h of betamethasone administration. There were no differences in glucocorticoid induced CBF and CVR changes compared with our previous findings at 0.87 of gestation. We conclude that the cerebrovascular effects of antenatal glucocorticoids are independent of cerebrovascular maturation and preparturient increase in activity of the fetal pituitary–adrenal axis.     

Decrease of potassium permeability by intracellular application of sodium ions in snail neurons

In the identified neurons B1, B2 and B3 of Helix pomatia an intracellular injection of Na+ induced an outward current in 10% and an inward current in 90% of the experiments. The outward current was associated with an increase and the inward current with a decrease of the membrane conductance. Both currents reversed at membrane potentials of between -60 and -70 mV. Inward currents were also elicited by intracellular Li+ or tris-[hydroxymethyl]-aminomethane (Tris+) injection. All inward currents were reduced by extracellular administration of tetraethylammonium or quinine. It is suggested that the outward current represents a calcium-activated potassium current and that the inward current is due to a blockade of potassium channels from the intracellular side.     

DNA microarray analysis reveals novel gene expression profiles in collagen-induced arthritis

Global gene expression was analyzed in early and late collagen-induced arthritis (CIA). Of 8734 cDNAs analyzed, 330 were induced and 55 downregulated greater than twofold in early or late disease. Hierarchical clustering of these 385 cDNAs demonstrated five distinct expression patterns differentiating early from late disease and correlating with histopathologic changes in the paw. Of the 385 cDNAs, 185 are known, characterized genes, the majority of which are not described as playing a role in arthritis. However, several of these genes are involved in pathological processes relating to arthritis, including apoptosis, inflammation, and cellular proliferation. One interesting gene, follistatin-like gene, is highly expressed along the margin of contact between inflammatory synovial pannus and eroding bone, suggesting a role in joint destruction. These results demonstrate that global gene expression profiles distinguish early and late CIA and reveal several genes novel to arthritis the further characterization of which will advance our understanding of arthritis.     

Conservation of receptor antagonist anti-tumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed

Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.