Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.     

Impact of depression and/or anxiety on the presentation of cardiovascular events in a cohort with metabolic syndrome. StreX project: Five years of follow-up

Objectives

To determine the role of anxiety and depression on the incidence of cardiovascular events (CVE) in a Catalonian population with metabolic syndrome (MetS) over a five-year follow-up according to the number/type of MetS criteria.

Microtubule reassembly in surface-activated platelets

It is generally accepted that a circumferential microtubule supports the discoid shape of resting platelets. The fate of the many-coiled polymer following platelet activation, however, has been a subject of considerable debate. Morphological investigations have suggested that the circumferential coils are constricted into tight rings around centrally concentrated organelles during platelet shape change. Biochemical studies employing colchicine-binding assays, on the other hand, have indicated that the bundle of microtubules dissolves almost completely within seconds after activation and reassembles in a new location one to four minutes later. The present study has accepted the latter hypothesis in order to examine the second part of the disassembly-reassembly theory proposed in biochemical studies. Platelets exposed to low temperatures sufficient to remove all microtubules were placed on glass slides and microscope grids to cause surface activation during rewarming. The combined stimuli of rewarming and surface activation might have been expected to cause more rapid assembly than warming alone or activation alone. This was not the case. Reassembly of microtubules during rewarming and simultaneous surface activation was not accelerated. In contrast to the constriction of microtubule rings observed during activation in control platelets, the diameters of coils that developed in chilled platelets one to two hours after rewarming and surface activation were twice those of control cells.     

Rehabilitación respiratoria

Pulmonary rehabilitation (PR) has been shown to improve dyspnea, exercise capacity and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). PR has also shown benefits in diseases other than COPD but the level of evidence is lower. The fundamental components of PR programs are muscle training, education and chest physiotherapy. Occupational therapy, psychosocial support and nutritional intervention should also be considered. Home programs have been shown to be as effective as hospital therapy. The duration of rehabilitation programs should not be less than 8 weeks or 20 sessions. Early initiation of PR, even during exacerbations, has proven safe and effective. The use of oxygen or noninvasive ventilation during training is controversial and dependent on the patient's situation. At present, the best strategy for maintaining the benefits of PR in the long term is unknown. Longer PR programs or telemedicine could play a key role in extending the results obtained.     

Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a growing class of natural products that are found in all domains of life. These compounds possess vast structural diversity and have a wide range of biological activities, promising a fertile ground for exploring novel natural products. One challenging aspect of RiPP research is the difficulty of structure determination due to their architectural complexity. We here describe a method for automated structural characterization of RiPPs by tandem mass spectrometry. This method is based on the combined analysis of multiple mass spectra and evaluation of a collection of hypothetical structures predicted based on the biosynthetic gene cluster and molecular weight. We show that this method is effective in structural characterization of complex RiPPs, including lanthipeptides, glycopeptides, and azole-containing peptides. Using this method, we have determined the structure of a previously structurally uncharacterized lanthipeptide, prochlorosin 1.2, and investigated the order of the posttranslational modifications in three biosynthetic systems.Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a major class of natural products as revealed by the genome-sequencing efforts of the past decade (1). RiPPs are biosynthesized from genetically encoded and ribosomally produced precursor peptides, which typically consist of a core peptide that is transformed to the final product and an N-terminal extension called the leader peptide that is usually important for recognition by the posttranslational modification (PTM) enzymes (1). Because of the highly diverse PTMs, these compounds possess vast structural diversity and have a wide range of biological activities, thus representing a fertile ground for exploration. Furthermore, the ribosomal origin of RiPPs makes them particularly well suited for genome mining efforts. By using genome mining to explicitly avoid species harboring biosynthetic gene clusters identical to those that produce known compounds, a combination of strain prioritization and mass spectrometry (MS)-based analysis offers a new route to discovering natural products that can overcome the burden of rediscovery that has increasingly hampered discovery efforts (2, 3). One challenging aspect of high-throughput genome mining for new natural products is the difficulty to determine their molecular structures in high throughput. We present here a method that allows automated RiPP structure elucidation.In contrast to nonribosomal peptides that have an average molecular weight of less than 1,000 Da, as documented in the NORINE database (4), RiPPs in many cases have molecular weights larger than 2,500 Da. Molecules of this size are difficult to rapidly analyze by NMR spectroscopy, rendering MS the most convenient tool for RiPP structural characterization. Even when the precursor peptide sequences are known and the types of PTMs can be predicted based on the sequences of the biosynthetic enzymes (5–8), multiple possible PTM sites on the precursor peptide typically result in a myriad of structures that are often difficult to differentiate. This challenge is further exacerbated by the frequent occurrence of one or more cross-links in RiPPs, which complicates traditional tandem MS-based structure elucidation. One of the main difficulties is that the spectra only contain a small fraction of informative signals among a large number of less diagnostic signals that cloud spectrum interpretation. As the spectra often also vary significantly with different instrument settings (9), selection of the most suitable spectra for drawing conclusions is time consuming and sometimes introduces bias. Indeed, a number of incorrect structural assignments of RiPPs have been reported based on insufficient information content of tandem MS data (10–15). Here, we report use of hypothetical structure enumeration and evaluation (HSEE) for automated and unbiased interpretation of tandem MS data. The method is based on the prediction of a collection of hypothetical structures for a RiPP of certain mass and known biosynthetic information. By listing all of the theoretical daughter ions from this enumeration and automated evaluation of their matches with one or several experimental spectra, the most probable RiPP structure can be determined. We demonstrate here for multiple classes of known RiPPs with complex structures that HSEE is highly effective in analyzing tandem MS data and predicting the correct structure. In addition, we used HSEE to characterize a lanthipeptide whose structure was elusive despite our previous efforts, and to determine the directionality of thiazole-forming enzymes and lanthipeptide synthetases.     

Expanding the indications for the bone anchored hearing system (BAHS) in patients with single sided deafness

PurposeProvide data to support expansion of FDA indications for the Bone anchored hearing system (BAHS).Materials and methodsThis retrospective study in a tertiary otologic referral center included106 consecutive subjects who were implanted with a Bone Anchored Hearing System (BAHS) between January 2009 and January 2015 for single sided deafness. Subjects were divided into three groups by bone conduction pure tone average (PTA) of the better hearing ear: 0–20 dB (group 1), 21–40 dB (group 2) and 41–55 dB (group 3). All patients underwent BAHS implantation. Speech perception data (Hearing In Noise Test and Consonant-Nucleus-Consonant testing) was collected before and after surgical intervention. Patient-reported quality of life measures were obtained at least 6 months after activation. These included the Abbreviated Profile of Hearing Aid Benefit and Glasgow Benefit Inventory.ResultsAll three groups of subjects demonstrated statistically significant improvement in outcome measures following BAHS. Subject reported quality of life outcome measures demonstrated significant improvement in disability from hearing loss and in quality of life.ConclusionsPatients with single sided deafness who have bone conduction thresholds worse than 20 dB in their contralateral ear are still able to benefit significantly from BAHS.