Metabolism of desflurane and isoflurane to fluoride ion in surgical patients

The metabolism of isoflurane and the investigational volatile anaesthetic desflurane to fluoride ion was examined in 25 surgical patients. The patients were randomly assigned to four groups, to receive isoflurane or desflurane at either 0.65 MAC or 1.25 MAC. Anaesthesia was induced in all patients with thiopentone and midazolam and included nitrous oxide 60% in addition to the volatile agent. Blood was drawn before induction and at the end of the operation for determination of serum fluoride ion concentration. Plasma fluoride ion concentrations increased (+ 1.36 +/- 0.93 microM, P less than 0.01) in patients receiving isoflurane but were unchanged (-0.13 +/- 0.50 microM) in patients receiving desflurane. Metabolic release of fluoride ion is less with desflurane than with isoflurane during administration of the anaesthetics to surgical patients, and is unlikely to be of clinical significance.     

Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.

PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (> or = 3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune response.     

Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults.

Folate and methionine metabolism is involved in DNA synthesis and methylation processes. Polymorphisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In a case-control study, we evaluated whether four common polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A2756G), and methionine synthase reductase (MTRR A66G) genes may have a role in altering susceptibility to adult acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). We analyzed DNA of 120 adult ALL, 200 NHL, and 257 healthy control subjects. Individual carrying the MTHFR 677TT genotype showed a 3.6-fold decreased ALL risk [odds ratio (OR) 0.28, 95% confidence interval (95% CI) 0.12-0.72] than wild-types. Similarly, MS 2756GG individuals showed a 5.0-fold decreased ALL risk (OR 0.20, 95% CI 0.02-1.45) than wild-types. In combined results, subjects with the MTHFR 677CT/TT and MS 2756AG/GG genotypes revealed a 3.6-fold ALL risk reduction (OR 0.28, 95% CI 0.14-0.58) and those with the MTHFR 677TT and MTRR 66AG genotypes revealed a 4.2-fold ALL risk reduction (OR 0.24, 95% CI 0.06-0.81). Finally, those with the MS 2756AG/GG and MTRR 66AG/GG genotypes revealed a 2.2-fold ALL risk reduction (OR 0.45, 95% CI 0.10-0.85). Single analysis for NHL did not show any significant difference for all the polymorphisms investigated, but in the low-grade NHL subgroup, we found a 2.0-fold risk reduction for the MTRR 66GG homozygous genotype (OR 0.50, 95% CI 0.25-0.99), which was higher (OR 0.37, 95% CI 0.14-0.85) when analyzed in combination with MS 2756AA genotype. These data are in accordance with the hypothesis that polymorphisms in the genes for folate and methionine metabolism might play a greater role in the occurrence of ALL than NHL by influencing DNA synthesis and/or DNA methylation.     

Morphologically Typical and Atypical B-Cell Chronic Lymphocytic Leukemias Display a Different Pattern of Surface Antigenic Density

Recent evidences suggest that B-cell chronic lymphocytic leukemia (B-CLL) may have heterogeneous biological and clinical features. Immunological phenotype may be useful for distinguishing these different forms of disease.

We used a quantitative flow cytometric approach to analyze the expression of several membrane molecules (CD19, CD20, CD22, CD23, CD11c, CD5, CD79b) commonly used to diagnose and characterize B-CLL in a choort of 84 consecutive B-CLL patients diagnosed according to morphological and immunological findings. We found that morphologically so-called “atypical” B-CLL displayed a significantly higher number of CD20 and CD22 molecules than typical forms. On the other hand, CD19 was found to be more expressed in typical B-CLL, although without reaching statistical significance. Finally, no difference was detected with respect to CD23, CD79b, CD11c and CD5 number of molecules/per cell between typical and atypical B-CLL. Other clinico-biological features, such as surface membrane immunoglobulin density, percentage of CD79b and FMC7 expression, peripheral blood lymphocytosis, trisomy 12 and advanced clinical stages were also found to be more frequent in atypical B-CLL. In conclusion, our data confirm the hypothesis that atypical B-CLL is a disease sustained by more mature B-cells, closely related but, at the same time, clearly distincted from neoplastic cells of typical B-CLL.     

Engineering a DNA origami mediated multicolour quantum dot platform for sub-diffraction spectral separation imaging

The validation of super-resolution optical imaging techniques requires well-defined reference samples that can be used repeatedly and reliably as model standards. Here, we engineer a DNA origami scaffold-mediated multicolour quantum dot hybrid nanostructure and test it using a recently proposed Quantum Dot-based spectral separation technique. We show that multivalent DNA structures offer a robust and precise nanoscale quantum dot placement scaffold, while the spectral resolution method provides relatively simple and fast image acquisition capabilities using any standard confocal or fluorescence microscope capable of spectral signal separation and a single excitation laser wavelength.

The validation of super-resolution optical imaging techniques requires well-defined reference samples that can be used repeatedly and reliably as model standards.     

Hybrid Ti6Al4V/Silk Fibroin Composite for Load-Bearing Implants: A Hierarchical Multifunctional Cellular Scaffold

Despite the tremendous technological advances that metal additive manufacturing (AM) has made in the last decades, there are still some major concerns guaranteeing its massive industrial application in the biomedical field. Indeed, some main limitations arise in dealing with their biological properties, specifically in terms of osseointegration. Morphological accuracy of sub-unital elements along with the printing resolution are major constraints in the design workspace of a lattice, hindering the possibility of manufacturing structures optimized for proper osteointegration. To overcome these issues, the authors developed a new hybrid multifunctional composite scaffold consisting of an AM Ti6Al4V lattice structure and a silk fibroin/gelatin foam. The composite was realized by combining laser powder bed fusion (L-PBF) of simple cubic lattice structures with foaming techniques. A combined process of foaming and electrodeposition has been also evaluated. The multifunctional scaffolds were characterized to evaluate their pore size, morphology, and distribution as well as their adhesion and behavior at the metal–polymer interface. Pull-out tests in dry and hydrated conditions were employed for the mechanical characterization. Additionally, a cytotoxicity assessment was performed to preliminarily evaluate their potential application in the biomedical field as load-bearing next-generation medical devices.     

Correlation between diminished vagal tone and somatic dysfunction severity in very and extremely low birth weight preterm infants assessed with frequency spectrum heart rate variability and salivary cortisol

Osteopathic manipulative treatment (OMT) is evolving in the neonatal intensive care unit (NICU) setting. Studies showed its efficacy in length of stay and hospitalization costs reduction. Moreover, it was suggested that OMT has a modulatory effect on the preterm infants’ autonomic nervous system (ANS), influencing saturation and heart rate. Even if OMT is based on the palpatory examination of the somatic dysfunctions (SD), there are controversies about its identification and clinical relevance. The objective of this study was to evaluate the inter-rater reliability, clinical characteristics, and functional correlation of the SD Grade score with the heart rate variability (HRV) and the salivary cortisol (sCor) using a multivariate linear model approach. To evaluate those features, we implemented an ad hoc SD examination for preterm infants that was performed by 2 trained osteopaths. It was based on the new variability model of SD that includes an SD Grade assessment procedure. The ANS features were assessed by frequency parameters of HRV studying high frequency (HF), low frequency (LF), and HF/LF, whereas sCor was tested with a radioimmunoassay. The ANS assessment was standardized and performed before SD testing. Sixty-nine premature infants were eligible. SD Grade showed excellent concordance between the blinded raters. Using SD Grade as a grouping variable, the infants presented differences in GA, Apgar, pathological findings, length of stay, and ventilatory assistance. In our multivariate model, HF, LF, and LF/HF resulted linearly correlated with SD Grade. Instead, sCor presented a linear correlation with 5’ Apgar and respiratory distress syndrome but not with SD Grade. SD Grade was in line with the natural history of the underdevelopment due to prematurity. Our models indicate that the cardiac vagal tone is linearly related with SD Grade. This finding may improve the multidisciplinary decision making inside NICU and the management of modifiable factors, like SD, for cardiac vagal tone regulation.     

Good response to the late treatment with ataluren in a boy with Duchenne muscular dystrophy: could the previous mild course of the disease have affected the outcome?

Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked recessive disorder, caused by the absence of the dystrophin protein. A resolutive therapy for DMD is not yet available. The first approved drug for DMD patients with nonsense mutations is ataluren, approved for the treatment of children aged ≥ 2 yrs, that seems effective in slowing the disease progression. An earlier introduction of ataluren seems to give better results.We report the case of a 14-year-old DMD patient with a nonsense mutation in exon 70, still ambulant, who started taking ataluren at 12 years and remained stable for the following two years. The patient was on steroid since the age of 6, with beneficial effects. At two-years follow-up, an optimal disease evolution was observed, associated with a constant decrease of creatine kinase blood levels. Despite the late start of the treatment, ataluren seems to have significantly contributed to the stabilization of the functional status in this patient though it cannot be excluded that the result may have been influenced by the previous favorable course of the disease. However, further studies should be planned in patients with similar age treated with ataluren to better evaluate the treatment’s results compared to the natural course of the disease.Key words: Duchenne muscular dystrophy, target therapy, nonsense mutation, ataluren, time function tests