„Oxygen to see“ bei der computertomographiegesteuerten Sympathikolyse

Background

The indications for chemical sympathectomy (CS) for sympathicolytic treatment of peripheral artery occlusive disease (PAOD) are still controversially discussed. This measure is not mentioned in the current guidelines of the transatlantic inter-society consensus document on management of peripheral arterial disease (TASC II). The reason is that CS could cause an increase in arteriovenous shunts and an improvement in oxygen saturation by CS has not yet been confirmed. Additionally, it was difficult to determine ex ante which patients could benefit from CS. “Oxygen to see” (O2C) allows a non-invasive measurement of microvascular perfusion under static conditions and an estimate of endothelial integrity by functional tests. This study tested the utilization of O2C in CS.

Material and methods

Patients with PAOD Fontaine stages III and IV underwent CS using a standard clinical protocol (temporary and definitive CS). Microcirculatory parameters (e.g. tissue oxygen saturation and blood flow) were recorded in a standardized protocol including baseline and functional measurements with O2C before and after CS. A total of eight patients with chronic ischemia of the extremities and no possibility of surgical and interventional revascularization were included in the study.

Aims

This pilot study investigated the effects on microvascular perfusion before and after CS using the O2C procedure to characterize potential pathophysiological mechanisms also in patients with diabetes.

Results

A clinical response to CS was shown by seven out of the eight patients. The O2C procedure was capable of discriminating between the clinically more prominent extremity and the contralateral side (baseline and functional oxygen saturation and flow). Functional measurements with a defined high positioning of the extremity (65 cm equivalent to 50 mmHg) were more qualified than static measurements to show CS-induced changes in tissue microcirculation.

Discussion

As measurable effects of CS on the microcirculation were evident which correlated with the clinical response, this method could be used to characterize microcirculatory changes when performing prospective controlled clinical trials in patients with chronic limb ischemia. This is particularly true for patients who are difficult to assess with clinical parameters (e.g. diabetic neuropathy).     

The Development of Drug-Free Therapy for Prevention of Dental Caries

Purpose

The purpose of this study was to develop a novel, drug-free therapy that can reduce the over-accumulation of cariogenic bacteria on dental surfaces.

Methods

We designed and synthesized a polyethylene glycol (PEG)-based hydrophilic copolymer functionalized with a pyrophosphate (PPi) tooth-binding anchor using “click” chemistry. The polymer was then evaluated for hydroxyapatite (HA) binding kinetics and capability of reducing bacteria adhesion to artificial tooth surface.

Results

The PPi-PEG copolymer can effectively inhibit salivary protein adsorption after rapid binding to an artificial tooth surface. As a result, the in vitro S. mutans adhesion study showed that the PPi-PEG copolymer can inhibit saliva protein-promoted S. mutans adhesion through the creation of a neutral, hydrophilic layer on the artificial tooth surface.

Conclusions

The results suggested the potential application of a PPi-PEG copolymer as a drug-free alternative to current antimicrobial therapy for caries prevention.     

In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets

Although the prognosis of pediatric leukemias has improved considerably, many patients still have relapses. Tipifarnib, a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25). AML samples were significantly more sensitive to tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples. Within AML, French-American-British (FAB) M5 samples were most sensitive to tipifarnib. T-cell ALL samples were significantly more sensitive than BCP ALL and N BM samples. In AML there was a marked correlation between tipifarnib resistance and daunorubicin or etoposide resistance, but not to cytarabine or 6-thioguanine. RAS mutations were present in 32% of AML and 18% of ALL samples, but there was no correlation between RAS mutational status and sensitivity to tipifarnib. Future studies are needed to identify biomarkers predictive of tipifarnib sensitivity. In addition, clinical studies, especially in T-cell ALL, seem warranted.     

Activating mutations in human acute megakaryoblastic leukemia

Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non-Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.     

The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6–10%, 11–20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.