Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer.

PURPOSE: To examine the prognostic significance of lumican and decorin, two abundant small leucine-rich proteoglycans in breast tissue stroma. EXPERIMENTAL DESIGN: Lumican and decorin expression was examined in a cohort of 140 invasive breast carcinomas by Western blot analysis. All cases were axillary lymph node-negative and treated by adjuvant endocrine therapy. RESULTS: Lumican and decorin expression was highly correlated (r = 0.45, P < 0.0001), but although low levels of lumican were associated with large tumor size (P = 0.0496), negative estrogen receptor (P = 0.0024) and progesterone receptor status (P = 0.0116), and increased host inflammatory response (P = 0.0077), low decorin levels were associated only with large tumor size (P = 0.0496). However, using univariate analysis, low levels of lumican and decorin were both associated with a shorter time to progression (P = 0.0013 and 0.0262) and poorer survival (P = 0.001 and 0.0076). In multivariate analysis using the Cox regression model, low decorin was also shown to be an independent predictive factor for recurrence (hazard ratio 2.25: 95% confidence interval 1-5, P = 0.047) and survival (hazard ratio 3.39: 95% confidence interval 1.2-9.6, P = 0.021). CONCLUSIONS: These results suggest that low levels of small leucine-rich proteoglycans in breast tumors may be associated with a worse prognosis in lymph node-negative invasive breast carcinomas and warrant further study with larger patient cohorts.     

Euthanasia, Physician Assisted Suicide and Other Methods of Helping Along Death

This paper introduces a series of papers dealing with the topic of euthanasia as an introduction to a variety of attitudes by health-care professionals and philosophers interested in this issue. The lead in paper--and really the lead in idea--stresses the fact that what we are discussing concerns only a minority of people lucky enough to live in conditions of acceptable sanitation and who have access to medical care. The topic of euthanasia and PAS really has three questions: (1) is killing another ever ethically acceptable; (2) is the participation of health professionals ethically different and (3) is it wiser to permit and set criteria (being fully aware of some dangers that lurk in such a move) or to forbid (knowing that it will occur clandestinely and uncontrolled). This paper takes no definite stand although it is very troubled by useless suffering (not only pain) by many who would wish their life and with it their suffering ended.     

Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity.

PURPOSE: To determine the toxicity, maximal tolerated dose, and clinical and immunologic response to autologous dendritic cells pulsed with melanoma-associated antigen gp100-derived G280-9V peptide. PATIENTS AND METHODS: Twelve HLA-A*0201(+) patients with advanced melanoma were administered dendritic cells pulsed with G280-9V peptide. Cohorts of three patients were administered 5 x 10(6), 15 x 10(6), and 50 x 10(6) cells i.v. every 3 weeks for six doses according to a dose escalation scheme. Three additional patients were treated at the highest dose. No additional cytokines or therapies were coadministered. The immunogenicity of G280-9V-pulsed dendritic cells was measured by IFN-gamma ELISPOT assay, tetramer assay, and (51)Cr release assay comparing prevaccination to postvaccination blood samples. Response to treatment was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: CD8(+) immunity to the native G280 was observed in 8 (67%) patients as measured by ELISPOT and in 12 (100%) patients as measured by tetramer assay. Of the 9 patients tested, 9 (100%) had measurable high-avidity CTL activity as defined by lysis of allogeneic melanoma lines, which coexpress HLA-A*0201 and gp100. The median follow-up of the entire cohort is 43.8 months. Two (17%) partial responses were observed and 3 (25%) patients had stable disease. The median survival of the treated population was 37.6 months. At this time, three patients are alive, including one patient who continues to respond without additional treatment. CONCLUSION: The high rate of immunization as measured by three independent assays and the occurrence of clinical regression support continued investigation of G280-9V peptide as a candidate epitope in melanoma vaccine formulations.     

Long-term active antimicrobial coatings for surgical sutures based on silver nanoparticles and hyperbranched polylysine

The goal of this study was to develop a long-term active antimicrobial coating for surgical sutures. To this end, two water-insoluble polymeric nanocontainers based on hyperbranched polylysine (HPL), hydrophobically modified by either using glycidyl hexadecyl ether, or a mixture of stearoyl/palmitoyl chloride, were synthesized. Highly stabilized silver nanoparticles (AgNPs, 2–5?nm in size) were generated by dissolving silver nitrate in the modified HPL solutions in toluene followed by reduction with L-ascorbic acid. Poly(glycolic acid)-based surgical sutures were dip-coated with the two different polymeric silver nanocomposites. The coated sutures showed high efficacies of more than 99.5% reduction of adhesion of living Staphylococcus aureus cells onto the surface compared to the uncoated specimen. Silver release experiments were performed on the HPL-AgNP modified sutures by washing them in phosphate buffered saline for a period of 30?days. These coatings showed a constant release of silver ions over more than 30?days. After this period of washing, the sutures retained their high efficacies against bacterial adhesion. Cytotoxicity tests using L929 mouse fibroblast cells showed that the materials are basically non-cytotoxic.     

Home management of INR in the public health system: feasibility of self-management of oral anticoagulation and long-term performance of individual POC devices in determining INR

The home prothrombin time/international normalized ratio (PT/INR) self-management could be convenient for patients, enhancing treatment compliance and improving the quality of the oral anticoagulation. However, patient self-management (PSM) of oral anticoagulation may not be feasible for up to half of the patients due to cognitive or educational issues. In the present study, we aimed to evaluate the feasibility of a PSM program in a public health medical center that provides care for low-income patients. We also aimed to determine the accuracy of individual point-of-care devices (CoaguChek XS^®) during long-term of home manipulation. Patients’ time-in-therapeutic range (TTR) and perception of quality of life, were evaluated at scheduled study-visits to the center. Additionally, the accuracy of individual CoaguChek XS^® was evaluated in comparison to the standard automated coagulometer at scheduled study-visits to the center. Twenty-five patients were included in the PSM program. The median TTR of patients was 75 % before inclusion, 72 % at 3 months, 75 % at 6 months and 100 % at 12 months after the beginning of self-management (P = 0.14).The median DASS scores were 64, 63, 61.5 and 71.5 before inclusion and at 3, 6 and 12 months, respectively (P = 0.09). One hundred paired INR values were obtained. Correlation between INR values delivered by individual CoaguChek XS^® and the automated coagulometer was 94 % and the mean result bias was 0.07 INR units. The coefficient of correlation and the mean bias between methods was stable during 24 months of follow-up. The present study suggests that PSM is feasible for patients treated in the public health system and that the results delivered by CoaguChek XS^® have long-term reliability.     

Aggregation‐induced changes in the chemical exchange saturation transfer (CEST) signals of proteins

Chemical exchange saturation transfer (CEST) is an MRI technique that allows mapping of biomolecules (small metabolites, proteins) with nearly the sensitivity of conventional water proton MRI. In living organisms, several tissue‐specific CEST effects have been observed and successfully applied to diagnostic imaging. In these studies, particularly the signals of proteins showed a distinct correlation with pathological changes. However, as CEST effects depend on various properties that determine and affect the chemical exchange processes, the origins of the observed signal changes remain to be understood. In this study, protein aggregation was identified as an additional process that is encoded in the CEST signals of proteins. Investigation of distinct proteins that are involved in pathological disorders, namely amyloid beta and huntingtin, revealed a significant decrease of all protein CEST signals upon controlled aggregation. This finding is of particular interest with regard to diagnostic imaging of patients with neurodegenerative diseases that involve amyloidogenesis, such as Alzheimer's or Huntington's disease. To investigate whether the observed CEST signal decrease also occurs in heterogeneous mixtures of aggregated cellular proteins, and thus prospectively in tissue, heat‐shocked yeast cell lysates were employed. Additionally, investigation of different cell compartments verified the assignment of the protein CEST signals to the soluble part of the proteome. The results of in vitro experiments demonstrate that aggregation affects the CEST signals of proteins. This observation can enable hypotheses for CEST imaging as a non‐invasive diagnostic tool for monitoring pathological alterations of the proteome in vivo.     

Brain temperature regulation in poor-grade subarachnoid hemorrhage patients – A multimodal neuromonitoring study

Elevated body temperature (T_core) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (T_brain) is usually higher than T_core. However, the implication of this difference (T_delta) remains unclear. We aimed to study factors associated with higher T_delta and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of T_core, T_brain, cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. T_brain was tightly correlated with T_core (r = 0.948, p < 0.01), and was higher in 73.7% of neuromonitoring time (T_delta +0.18°C, IQR −0.01 – 0.37°C). A higher T_delta was associated with better metabolic state, indicated by lower CMD-glutamate (p = 0.003) and CMD-lactate (p < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2, p < 0.001). During MD, T_delta was significantly lower (0°C, IQR −0.2 – 0.1; p < 0.001). A higher T_delta was associated with improved outcome (OR = 7.7, p = 0.002). Our study suggests that T_brain is associated with brain metabolic activity and exceeds T_core when mitochondrial function is preserved. Further studies are needed to understand how T_delta may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.