Can genes influencing muscle function affect the therapeutic response to enzyme replacement therapy (ERT) in late-onset Type II Glycogenosis?

The purpose of this study is to analyze the role of genes known to influence muscle performances on the outcome after enzyme replacement treatment (ERT) in type II Glycogenosis (GSDII). We analyzed 16 patients receiving ERT for ≥two years. We assessed the changes in muscle strength by hand-held dynamometry, muscle mass by quantitative MRI, and resistance to exercise by the 6-minute walking test. Exercise gene assessment included angiotensin converting enzyme insertion/deletion polymorphism (ACE), alpha-actinin3 R577X polymorphism (ACTN3), and peroxisome proliferator activated receptor alpha G/C polymorphism (PPARα). Independent of disease severity, one third of patients had a poor response to ERT, which was found to be associated with ACE DD genotype. The ACTN3 null polymorphism appeared to exert a positive effect on treatment efficacy, while PPARα did not seem to exert any influence at all. We conclude that poor treatment outcome in ACE DD genotypes is in line with previous observation of a worse disease course in this subpopulation, and suggests the need for a more careful follow-up and individualized treatment approaches for these patients. Exercise genes may provide a new opportunity for studying the outcome after treatment and the muscle regeneration abilities in other models of genetic myopathies.     

Human dedifferentiated adipocytes show similar properties to bone marrow-derived mesenchymal stem cells

Mature adipocytes are generally considered terminally differentiated because they have lost their proliferative abilities. Here, we studied the gene expression and functional properties of mature adipocytes isolated from human omental and subcutaneous fat tissues. We also focused on dedifferentiated adipocytes in culture and their morphologies and functional changes with respect to mature adipocytes, stromal-vascular fraction (SVF)-derived mesenchymal stem cells (MSCs) and bone marrow (BM)-derived MSCs. Isolated mature adipocytes expressed stem cell and reprogramming genes. They replicated in culture after assuming a fibroblast-like shape and expanded similarly to SVF- and BM-derived MSCs. During the dedifferentiation process, mature adipocytes lost their lineage gene expression profile, assumed the typical mesenchymal morphology and immunophenotype, expressed stem cell genes and differentiated into multilineage cells. Moreover, during the dedifferentiation process, we showed changes in the epigenetic status of mature adipocytes, which led dedifferentiated adipocytes to display a similar DNA methylation condition to BM-derived MSCs. Like SVF- and BM-derived MSCs, dedifferentiated adipocytes were able to inhibit the proliferation of stimulated lymphocytes in coculture while mature adipocytes stimulated their growth. Furthermore, dedifferentiated adipocytes maintained the survival and complete differentiation characteristic of hematopoietic stem cells. This is the first study that in addition to characterizing isolated and dedifferentiated adipocytes also reports on the immunoregulatory and hematopoietic supporting functions of these cells. This structural and functional characterization might have clinical applications of both mature and dedifferentiated adipocytes in such fields, as regenerative medicine.     

Effect of 0.4% stannous fluoride gel on Streptococci mutans in relation to elastomeric rings and steel ligatures in orthodontic patients.

BACKGROUND: Patients with fixed orthodontic appliances often experience an absolute increase in the number of Streptococci mutans colony-forming units (cfu). The aim of this investigation was to study the development of biofilm and S. mutans cfu in connection with stainless steel ligatures and elastomeric rings in orthodontic patients treated with and without 0.4% stannous fluoride gel (SFG). MATERIAL: Forty-seven patients were divided into 2 groups: those treated with 0.4% SFG for 4 minutes (experimental) and those without 0.4% SFG (control). In each patient, elastomeric rings were used for ligation on 1 side of the dental arch midline, and stainless steel ligatures were used on the opposite side. Saliva samples were collected before and after appliance placement. At 15 and 30 days after appliance placement, biofilm samples from the stainless steel ligatures and the elastomeric rings were collected and subjected to microbiologic procedures and scanning electron microscopy (SEM) analysis. RESULTS: The numbers of S. mutans cfu in the saliva and biofilm were not statistically different between the teeth fitted with elastomeric rings and stainless steel ligatures, or between the experimental and control groups. SEM analysis showed biofilm formation on both ligature ties. CONCLUSIONS: Topical application of 0.4% SFG in orthodontic patients with elastomeric rings or stainless steel ligatures does not cause a significant decrease in S. mutans cfu in the saliva and biofilm.     

Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma

We present the results of a phase 2 study using thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) in the treatment of 50 patients older than 65 years with newly diagnosed multiple myeloma. Thalidomide 100 mg was administered orally at bedtime continuously, dexamethasone 40 mg was administered orally on days 1 to 4 and 9 to 12, and pegylated liposomal doxorubicin 40 mg/m2 was administered intravenously on day 1 over the 28-day cycle. Response was assessed according to the EBMT criteria. Seventeen (34%) patients achieved CR, 7 (14%) nCR, 5 (10%) VGPR, 15 (30%) PR, and 5 (10%) MR, resulting in an ORR of 98%. Only 1 patient (2%) presented progressive disease. Time to progression (TTP), event-free survival (EFS), and overall survival (OS) projected at 3 years were 60%, 57%, and 74%, respectively, and these parameters were significantly higher in those patients achieving a response of at least VGPR versus those who did not. Grade 3 and 4 nonhematologic adverse events were constipation (10%), fatigue (6%), tremors (4%), mucositis (4%), and palmar-plantar erythrodysesthesia (2%). Grade 3 and 4 neutropenia occurred in 12% of patients. Grade 3 and 4 infections and thromboembolic accidents were observed in 22% and 14% of patients, respectively. In the treatment of elderly patients with newly diagnosed multiple myeloma, ThaDD is a very effective regimen with manageable toxicity.     

Reproducibility of the items on the Stroke Specific Quality of Life questionnaire that evaluate the participation component of the International Classification of Functioning,Disability and Health

Purpose: To evaluate the reproducibility of the Stroke Specific Quality of Life (SS-QOL) items that address the participation component of the International Classification of Functioning, Disability and Health (ICF) and analyse the correlation between the subscore of these 26 items and the total SS-QOL score.

Methods: Seventy-five stroke survivors participated in this study. Reproducibility was evaluated using the intraclass correlation coefficient (ICC_2,1), standard error of measurement (SEM), minimum detectable change (MDC) and the Bland–Altman plot. The correlation between the subscore of the 26 items and the total SS-QOL score was analysed using Spearman’s correlation coefficients (rho) and simple linear regression. An alpha risk?≤?0.05 was considered for all analyses.

Results: The SS-QOL items that address the participation component of the ICF demonstrated excellent reliability (intra-rater ICC_2,1?=?0.96; inter-rater ICC_2,1?=?0.95). The SEM and MDC were adequate. The Bland–Altman plot demonstrated satisfactory agreement. A significant and strong correlation (rho?=?0.83) was found between the 26 SS-QOL items that address participation and the total SS-QOL score. Moreover, the evaluation of participation was found to explain 73% of the evaluation of health-related quality of life.

Conclusion: The 26 SS-QOL items that address the participation component of the ICF demonstrated adequate reproducibility. Thus, participation, which represents the social aspects of functionality, can be adequately evaluated with these items.

• Implications for Rehabilitation

• The 26 Stroke Specific Quality of Life items that address participation proved to be reproducible for the analysis of social participation following a stroke.

• The findings can lead to a better understanding of the social participation of individuals with chronic hemiparesis and assist in the establishment of adequate treatment for such individuals.

• The rehabilitation process can be directed towards more specific goals focused on the patient expectations, thereby contributing to greater humanization and effectiveness of treatment to improve social participation following a stroke.

     

Effect of ketotifen on the distribution and degranulation of uterine eosinophils in estrogen-treated rats

Eosinophil leukocytes migrate from the blood to the uterus under estrogen stimulation, redistribute through uterine extravascular compartment, degranulate in the organ, and release agents that are involved in several parameters of estrogen action. Agents that induce blood eosinopenia, block their migration to the uterus, interfere with their redistribution within the organ or modify their degranulation, selectively interfere with eosinophil-mediated responses to estrogen. The present study investigated whether ketotifen, an antiallergic agent that inhibits allergen-induced eosinophil degranulation, interferes with estrogen-induced eosinophil migration to the uterus and their subsequent degranulation. Ketotifen does not interfere with estrogen-induced eosinophil accumulation in the uterus, but decreases the proportion of eosinophils located in endometrium and inhibits their degranulation. These results suggest that neither histamine, calcium or slow reacting substance of anaphilaxis are involved in eosinophil migration to the uterus. The inhibition by ketotifen of eosinophil degranulation may diminish eosinophil migration through extravascular compartment via a decrease in the release from degranulating eosinophils of enzymes required for this migration. It is possible that the inhibition by ketotifen of both, eosinophil degranulation and eosinophil motility through uterine extravascular compartment, interfere with eosinophil-mediated responses to estrogen or with other functions of these cells.     

Ex vivo pharmacological purging of leukapheresis collections with nitrogen mustard: amifostine pretreatment improves both early and late peripheral blood progenitor cell recovery.

Ex vivo pharmacological purging of bone marrow has been used to eliminate clonogenic tumor cells contaminating the autograft and potentially responsible of relapse. A considerable improvement of pharmacological purging would be achieved only if normal marrow progenitor cells could be selectively protected by the cytotoxicity of these agents. Amifostine (WR-2721; Ethyol), a phosphorylated aminothiol compound, has been shown to have this property both in vivo and in vitro. We describe here, an experimental model for ex vivo purging of peripheral blood progenitor cell (PBPC) collections based on the combination of 3 mg/ml of amifostine and the alkylating agent nitrogen mustard. Amifostine pretreatment resulted in a statistically significant protection of normal late and early progenitor cells. Under the same experimental conditions, we observed a 4-6 log reduction of contaminating leukemic cells (i.e., K-562 and CEM) and in contrast to the protection of normal peripheral blood progenitor cells, preincubation of contaminating K-562 or CEM with amifostine did not significantly alter the LD95 nitrogen mustard concentration. Moreover, when we tested fresh human leukemia progenitor cells, amifostine pretreatment sensitized the leukemic cells to the cytotoxic effects of NM.