Identification of relevant ICF categories by health professionals in the acute hospital

PURPOSE: To identify the most relevant problems of patients in the acute hospital in the view of health professionals using focus groups followed by a Delphi process. METHODS: Focus group and Delphi methodology were applied. The focus groups were conducted at three university hospitals. Three groups focusing on the problems in patients with neurological/neurosurgical, cardiopulmonary and musculoskeletal conditions were conducted at each hospital. The participants had to decide about which categories of the International Classification of Functioning, Disability and Health are relevant to patients in the acute hospital. The results from the focus groups were then followed by a Delphi process. RESULTS: Forty health professionals participated in the nine focus groups, 14 in the three neurological/neurosurgical groups, 13 in the three musculoskeletal groups, 13 in the three cardiopulmonary groups. One hundred and sixty-four of the second-level ICF categories (61.7% of all second-level categories) were considered as relevant by the health professionals of the neurological group, 100 categories (37.6%) by the musculoskeletal group and 91 (34.2%) by the cardiopulmonary group. CONCLUSIONS: The involvement of experts from different health professions is a valuable tool to identify typical patient characteristics, expressed as distinct ICF categories, which can be used across different acute conditions.     

Trimodal cancer treatment: beneficial effects of combined antiangiogenesis, radiation, and chemotherapy

It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.     

Effect of retrobulbar versus subconjunctival anaesthesia on retrobulbar haemodynamics

AIM: To investigate the effect of retrobulbar and subconjunctival anaesthesia on retrobulbar haemodynamics by colour Doppler imaging. METHOD: 39 patients (mean age 71 (SD 9) years; 19 females, 20 males) undergoing planned cataract surgery were included in the prospective study. Colour Doppler imaging (Siemens Sonoline Sienna, Germany) was performed before, directly after either subconjunctival (16 patients) or retrobulbar (23 patients) anaesthesia, and after cataract surgery to measure the peak systolic (PSV) and end diastolic velocities (EDV) in the ophthalmic artery (OA), central retinal artery (CRA), and central retinal vein (CRV). RESULTS: After retrobulbar anaesthesia there was a significant reduction of the PSV and of the EDV in all investigated vessels. After surgery the flow velocities increased again. Subconjunctival anaesthesia had no significant effects on retrobulbar haemodynamics. CONCLUSION: Retrobulbar anaesthesia induces a high reduction of velocity in the retrobulbar vessels in contrast with subconjunctival anaesthesia. Therefore subconjunctival anaesthesia should be preferred particularly in patients with problems of the ocular perfusion (for example, glaucoma).     

Antioxidant effect of squeezed juice from black radish (Raphanus sativus L. var niger) in alimentary hyperlipidaemia in rats

Black radish (Raphanus sativus L. var. niger) root has been used in folk medicine since antiquity as a natural drug for the stimulation of bile function. According to in vitro studies the squeezed juice from black radish root exhibited significant antioxidant properties. In the present study, the beneficial effect of the black radish juice on some free radical reactions in rats fed with a diet rich in lipids (20% sunflower oil, 2% cholesterol, 0.5% cholic acid in normal chow) was examined. Thiobarbituric acid reactive substances and conjugated diene concentrations were significantly higher, while the antioxidant enzyme activities and the free radical scavenging capacity were lower in hyperlipidaemic rats compared with normal controls. Supplementation of the lipid-rich diet with black radish juice resulted in a significant improvement of the parameters mentioned above. Although the exact mechanism of the biologically active compounds in black radish on the lipid metabolism and lipid peroxidation is not clear yet, a beneficial effect of the drug was evident in alimentary hyperlipidaemia.     

Neoadjuvant radiochemotherapy for locally advanced gastric cancer: long-term results of a phase I trial

PURPOSE: To assess the long-term results of radiation therapy (RT) when added preoperatively to systemic chemotherapy in patients with locally advanced gastric cancer. METHODS AND MATERIALS: Patients presenting with T3-4 or N+ gastric cancer received two cycles of cisplatin 100 mg/m2 d1, 5FU 800 mg/m2 d1-4, and Leucovorin 60 mg twice daily d1-4; one cycle before and one concomitantly with hyperfractionated RT (median dose, 38.4; range, 31.2-45.6 Gy). All patients underwent a total or subtotal gastrectomy with D2 lymph node resection. RESULTS: Nineteen patients were accrued and 18 completed the neoadjuvant therapeutic program. All patients were subsequently operated and no fatality occurred. At a mean follow-up of 8 years for the surviving patients, no severe late toxicity was observed. The 5-year locoregional control, disease-free, and overall survival were of 85%, 41%, and 35%, respectively. The peritoneum was the most frequent site of relapse. Among long terms survivors, no severe (Radiation Therapy Oncology Group Grade 3-4) late complication was reported. CONCLUSIONS: The present neoadjuvant treatment does not seem to increase the operative risk, nor the late side effects. The encouraging locoregional control rate suggests that the neoadjuvant approach should be considered for future trials in locally advanced gastric cancer. Also, the frequency of peritoneal recurrence stresses the need for a more efficient systemic or intraperitoneal treatment.     

Generation of mouse polyclonal and human monoclonal antibodies against Bacillus anthracis toxin

High titer antisera against the protective antigen (PA) from Bacillus anthracis were generated immunizing Balb/c mice two times intraperitoneally with PA in combination with lipopeptide adjuvant P3CSK4. The sera were able to protect the mouse macrophage cell line J774A.1 from an anthrax toxin challenge. We also tested the blood of anthrax vaccine-immunized persons for PA- and lethal factor (LF)-specific antibodies. An increased titer was found after three immunizations, and the sera were also able to protect the mouse macrophage cell line from a toxin challenge. For the preparation of human monoclonal antibodies, we used peripheral blood lymphocytes. After in vitro stimulation using PA or synthetic peptides derived from PA, B lymphocytes were immortalized by PEG fusion with the human mouse heteromyeloma cell line CB-F7. We obtained several clones producing high amounts of PA-specific immunoglobulin (Ig).     

Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.     

Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants

Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.     

Improved posthypoxic recovery in vitro on treatment with drugs used for secondary stroke prevention

Besides aspirin several new drugs for inhibition of platelet aggregation and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition are used in secondary stroke prevention. Pharmacology and clinical effects, however, are not fully explained by current understanding of underlying mechanisms. Population spike amplitude (PSAP), an established marker of slice integrity, was measured during hypoxia and recovery thereof in hippocampal slices from control CD1 mice (25-35 g) and animals pretreated in vivo with a single i.p. injection of clopidogrel, ticlopidine, or atorvastatine at different time intervals and dosages. Posthypoxic recovery of PSAP was 20 +/- 35% in control CD1 mice. Upon pretreatment with clopidogrel (1-24 h, 0.5-2 mg/kg body weight) an increase up to 81 +/- 20% (p < 0.01 to control) was observed at 1h interval and 1mg/kg. Application of ticlopidine (1-24 h, 1-4 mg/kg body weight) resulted in an improvement of posthypoxic recovery to 61 +/- 41% (p < 0.05 to control) while administration of atorvastatine (1-24 h, 1-4 mg/kg body weight) caused an increase up to 87 +/- 31% (p < 0.01 to control) at 1h interval and 2 mg/kg. On application of these substances in vitro the NADH autofluorescence spectrum in hippocampal slices is blue-shifted suggesting an alteration of oxidative metabolism. The present data demonstrate a shared neuroprotective effect of agents known to inhibit platelets (acetylsalicylic acid, clopidogrel, and ticlopidine) and HMG-CoA reductase (atorvastatine). The time course of this neuroprotective action in the current experimental study (onset within an hour, duration of several hours in contrast to several days) resembles clinical practice in dosing these substances. We hypothesize that an increase of hypoxic tolerance resulting from mild mitochondrial inhibition by these substances is a principal constituent of the effectiveness of these drugs.